HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) All Versions of this Article: 294/2/L161    most recent 00169.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lagan, A. L. Articles by Quinlan, G. J. Search for Related Content PubMed PubMed Citation Articles by Lagan, A. L. Articles by Quinlan, G. J.

INVITED REVIEW

INVITED REVIEW

Pathogenesis of the systemic inflammatory syndrome and acute lung injury: role of iron mobilization and decompartmentalization

Department of Critical Care Medicine, Imperial College School of Medicine, Royal Brompton Hospital, London, United Kingdom

	ABSTRACT

TOP ABSTRACT GRANTS REFERENCES

 
Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover, and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.

systemic inflammatory response; hemolysis; oxidative stress

SIRS is seen in association with a wide variety of noninfective insults, including major trauma and surgical procedures, especially those necessitating cardiopulmonary bypass (CPB) (16). The incidence of SIRS is high, afflicting up to 33% of patients requiring hospital admission and as many as 70% after CPB. The majority of patients with SIRS and its sequelae who fail to survive succumb to multiple organ dysfunction syndrome (MODS), the commonest manifestation of which is acute lung injury (ALI) (123). Fewer patients with SIRS develop the extreme manifestation of ALI, termed the acute respiratory distress syndrome (ARDS). However, ARDS is relatively common in patients with sepsis and severe sepsis, in whom incidences of 40% and 80%, respectively, have been reported (14, 123). The management of patients with the sepsis syndromes remains largely supportive and is aimed at correcting cardiopulmonary abnormalities. Despite a rise in the provision of intensive care unit (ICU) facilities in the developed world, the sepsis syndromes together represent the leading cause of death in adult general ICUs, with an associated mortality of 30–45%, rising even higher in those who develop ALI/ARDS (49, 94).

Pathophysiology of Acute Lung Injury

ALI and ARDS complicate a wide variety of serious medical and surgical conditions, not all of which involve the lung directly. Both are defined by refractory hypoxemia associated with lung inflammation and increased pulmonary vascular permeability. The first widely accepted radiological and physiological criteria were developed by an American-European Consensus Conference (13), which recognized ALI and ARDS as separate, yet related, states on a continuum of pulmonary damage. To diagnose ALI and ARDS in a patient with one or more recognized risk factors three criteria should be fulfilled. First, new, bilateral, diffuse, patchy, or homogeneous pulmonary infiltrates consistent with pulmonary edema must be demonstrated on chest radiography. Second, there should be no clinical evidence that heart failure, fluid overload, or chronic lung disease is responsible for the infiltrates. Alternatively, if the pulmonary artery occlusion pressure is measured, then this should be <18 mmHg. Finally, an arterial PO₂-to-inspired O₂ fraction ratio <300 mmHg defines ALI, and a ratio <200 mmHg defines ARDS. Susceptibility to ALI/ARDS is determined in part by the nature of the precipitating condition. Thus some 40–60% of patients with sepsis, severe sepsis, and septic shock develop lung injury, regardless of the anatomic site of infection (49, 74, 124, 176). By contrast, only around 15% of trauma victims are so afflicted (49, 166). Estimates of the overall incidence of ARDS have varied from 1.5 to 75 cases per 100,000 population (103), although recent European epidemiologic data found the defining criteria to be fulfilled in 15.8% of patients requiring ICU admission because of acute respiratory failure of all causes (17). Some 16.1% required mechanical ventilation. Of those who developed ALI/ARDS, 65.4% of cases fulfilled the relevant criteria early in ICU admission and the remainder did so within a median of 3 days. Of those who developed ALI within the first 24 h, 54.4% evolved to ARDS. By contrast, only 18.4% of patients with established ARDS had preceding ALI (17). In North America, a high crude incidence of ALI (78.9 per 100,000 population) has been identified, the incidence increasing with age (16 per 100,000 for patients aged 15–19 yr, 306 per 100,000 for those aged 75–84 yr) (147). Overall, this study suggested that there are around 190,000 cases of ALI per year in the US, with 74,500 deaths and accounting for 3.6 million hospital days (147).

Oxidative Stress

Oxidative stress is an inevitable consequence of aerobic respiration and metabolism. The production of oxygen intermediates, or reactive oxygen species (ROS), with the potential to modulate an array of cell signaling processes and at higher concentrations to cause oxidative damage, characterizes oxidative stress. In normal, healthy individuals, such prooxidant effects are more than adequately balanced by an array of protective stratagems including endogenous and dietary antioxidants, together with removal and repair mechanisms. However, in the long term the effects of oxidative stress become more apparent, demonstrated in the aging process and also in disease states such as chronic hyperglycemia and cancer (65). Moreover, in circumstances where excessive oxidative stress occurs acutely, these protective stratagems can become rapidly overwhelmed, resulting in pronounced levels of oxidative damage to biomolecules. Oxidative stress also modifies physiological redox-based signaling responses with consequences for pro- and anti-inflammatory processes. However, such modifications are not limited to the actions of ROS alone; indeed, production of, and interactions with, allied reactive nitrogen (RNS) and halogen (RHS) species appear to be equally important in this regard (64).

Oxidative stress is thought to be central to the pathogenesis of ALI. Alveolar macrophages and recruited, activated neutrophils release ROS, which cause injury through interactions with proteins, lipids, and DNA. It is thought that excessive production of ROS in patients with ALI overwhelms endogenous antioxidant systems that normally regulate redox state within the lung (91). There is an established literature indicating that ARDS is associated with pronounced oxidative/nitrosative/halogenic modification of biomolecules of systemic and lung-specific origin (Table 1). Furthermore, numerous studies have demonstrated that antioxidant protective stratagems are deficient in this population (61, 112). In addition, genomic studies (see Genetic Predisposition) suggest that variation in aspects of potential host-mediated responses to reactive species and catalysts may represent predisposing factors for disease onset in patients with ARDS (89). Nevertheless, the extent to which the release of ROS/RNS/RHS contributes to the onset and progression of ALI remains a matter of debate, not least because such modifications per se are seen as a general consequence of tissue injury (65). However, a number of studies utilizing in vivo models have suggested a causative link (see Table 2).

Absorption, transport, and compartmentalization. A fundamental and yet frequently overlooked aspect of ROS/RNS/RHS biochemistry is the role of variable-valence transition metal ion catalysts in the generation and potentiation of oxidative stress. Iron is the most abundant such metal ion in the body and is frequently utilized within protein/enzyme complexes involved in the physiological metabolism, storage, and transport of oxygen. The ability of such transition metal ions to freely donate and accept electrons singly overcomes subatomic kinetic stabilization arising in molecular oxygen because of parallel electron spin. Iron thereby allows the energetically favorable activation of what is in fact a relatively unreactive free radical gas. When incorporated within protein systems iron-catalyzed reactions are regulated and purposeful, but if freed from such constraints low-molecular-mass iron catalyzes an array of inorganic and organic electron transfer reactions involving oxygen and/or nitrogen and halogen species that ultimately lead to the formation of aggressive and damaging reactive species capable of modifying biomolecules. Furthermore, iron is an absolute requirement for microbial growth, and invading microbes utilize diverse mechanisms to acquire iron from hosts. Finally, iron is a valuable resource for the body, being required for essential functions including biosynthesis and cellular proliferation. Despite this, iron is relatively poorly absorbed from the gut, and elaborate reprocessing is necessary to maintain and supplement specific iron pools. Balancing the body's requirement for iron against potential adverse consequences therefore represents a physiological challenge, particularly in states of tissue injury or inflammation. Thus during episodes of sepsis the limitation of iron availability prevents deleterious ROS generation and counteracts microbial invasion and virulence.

A coordinated system facilitates this rapid sequestration and compartmentalization of liberated free iron both extra- and intracellularly (Fig. 1). Iron absorbed in the gut is immediately bound to transferrin, while that liberated by cellular lysis is tightly bound as ferric iron by circulating transferrin and lactoferrin. In addition, ceruloplasmin binds and converts ferrous iron to ferric iron for subsequent binding by transferrin. Furthermore, plasma haptoglobin and hemopexin bind iron-based hemoglobin and heme, respectively (59). Albumin, the most abundant plasma protein, has a nonspecific iron binding potential and one high- plus several low-affinity binding sites for heme, which it sequesters especially under conditions of haptoglobin depletion (7, 18). These specific binding molecules physically enclose the iron moieties and thus hinder prooxidant reactions (59, 62, 114). Moreover, macrophages, which are the primary cell type responsible for the removal of decompartmentalized iron, largely within the liver and reticuloendothelial system, possess cell surface receptors specific for both haptoglobin and hemopexin and facilitate their removal (76, 129).

View larger version (27K): [in this window] [in a new window]   Fig. 1. This scheme depicts extra- and intracellular iron/heme transport, uptake, and storage mechanisms together with the potential for altered cellular signaling responses. Hb, hemoglobin; HO, heme oxygenase; NRAMP, natural resistance-associated macrophage protein; IRP, iron regulatory protein.

Although the most abundant, iron is not the sole metal cation participating in cellular redox chemistry. Other transition metals such as copper and cobalt are also involved in superoxide generation and Fenton chemistry and are therefore also under tight regulation (119, 170). Furthermore, zinc, which is a fixed-valence transition metal, acts indirectly as an antioxidant. Its uptake is partly in competition with iron such that in iron-deficient states zinc absorption and its incorporation as zinc protoporphyrin are promoted in place of heme (iron protoporphyrin) (88). Although it is recognized that zinc protoporphyrin is an inhibitor of the heme catabolic enzyme HO, the physiological and pathophysiological significance of this interaction is not well described.

Iron and lung injury. Our own studies in patients with ALI (61, 111, 125, 136, 139) have shown that altered plasma and lung iron chemistry/mobilization are features of, and contribute to, the development and propagation of this acute inflammatory process. In studies by others, elevated serum levels of the iron storage protein ferritin in patients at risk of developing lung injury were found to be predictive for the subsequent development of ALI (27, 150). Serum ferritin is an indicator of body iron status. Studies utilizing bronchoalveolar lavage fluid have demonstrated increased levels of nonheme iron in patients with ALI compared with normal individuals (60) and elevated levels of iron and heme-binding proteins including ferritin, lactoferrin, transferrin, and haptoglobin (44). Furthermore, elevated expression of the heme-catabolizing enzymes HO-1 and -2 is detected in lungs of such patients (116), supporting a key role for iron turnover in pulmonary tissues. Moreover, a series of experiments in lung epithelium have identified iron uptake, detoxification, and excretion systems that may protect against iron-catalyzed oxidant production and the associated deleterious consequences (46).

However, despite such protection iron-mediated lung injury can occur, particularly in circumstances in which increased oxidant production is also present. Thus lung injury induced by ozone exposure has been shown to be an iron-dependent process (45), as have the effects of hyperoxia when HO-1 expression and activity are elevated (30, 157). There is also evidence that instillation of iron or iron products into the lungs results in marked oxidative injury and pulmonary dysfunction (43). Disruption of iron homeostasis in transplanted lung appears to be closely linked to the development of bronchiolitis obliterans and eventual graft failure (12, 15, 102, 131, 142). Evidence of prooxidant iron (60)- and hydroxyl radical-mediated protein modifications in the lungs suggests a role for a iron-catalyzed process in the pathogenesis of ALI (90).

Heme/hemoglobin. The presence of free hemoglobin within the circulation represents a considerable prooxidant risk. Oxidative reactions from the interaction of heme proteins (hemoglobin and myoglobin) with peroxides are known to occur, resulting in the formation of end products, including isoprostanes, that contribute to disease pathology (141). Furthermore, release of prooxidant iron from the heme moiety of hemoglobin occurs in the presence of peroxides (60). Hemolysis and hemoglobin release also lead to systemic nitric oxide (NO) deficiency (146), with adverse effects on vascular tone and coagulation. Thus hemoglobin rapidly reacts with free NO in an irreversible fashion, producing nitrate and methemoglobin. In addition, methemoglobin (but not heme or hemoglobin) activates endothelial cells to produce the proinflammatory chemokines interleukin (IL)-6 and -8, with membrane expression of E-selectin. These responses appear to be regulated via the expression of the cell signaling moiety NF-B but are independent of direct effects of heme catabolism (101). Additionally, in vivo models have shown hemolysis to be associated with pronounced neutrophil activation and recruitment (55), the release of proinflammatory chemokines on exposure to the malarial pigment hemozoin in a model of malaria (75), and pronounced epithelial and endothelial cell destruction related to iron turnover and nitrosative/oxidative stress in a hemorrhagic model of lung trauma (54). Exposure of human neutrophils to the heme analog hemin significantly delays spontaneous neutrophil apoptosis (5, 110), thereby extending their proinflammatory potential. Finally, free heme and hemoglobin are microbial virulence factors (7, 37, 145).

The release of hemoglobin and heme as a result of hemolytic disease or injury therefore has the potential to mediate prooxidant, proinflammatory, and promicrobial responses. Infections including malaria, meningitis. and Escherichia coli, blood transfusion reactions. and surgery necessitating CPB are all associated with hemolytic events and are recognized risk factors for the development of ALI, possibly via these mechanisms (25, 31, 104, 121, 152, 154, 158). Moreover, chronic alcohol abuse is now recognized to be an independent risk factor for the development of ARDS (82, 115). Dysregulation of iron homeostasis is characteristic of chronic and acute liver disease/failure associated with alcoholism (162), as is elevated serum ferritin (also seen in established ARDS) (97). Aberrant iron processing and turnover by the liver in this population may contribute to the heightened risk for the development of ALI/ARDS.

Iron-mediated cell signaling responses. Changes in iron levels within cells can also modify signaling events during the inflammatory response. A direct role for iron as a cellular signaling agent is established; indeed, the activity of the IRPs is dictated by cellular iron levels. The IRPs regulate cellular iron uptake and storage at the posttranscriptional level via binding to iron-responsive elements encoded on several genes, including those for the transferrin receptor and ferritin. However, it is now apparent that other stimuli relevant to the onset of ALI, such as lipopolysaccharide and oxidative stress, can regulate IRP activity and hence cellular iron status (21, 169). Iron can signal independently of the IRPs, most likely via redox-based signaling processes. Indeed, the activity of the proinflammatory transcription factors NF-B (80, 179), AP-1, and SP-1 (86, 167) have been shown to be influenced by either the supply of iron or its withdrawal. Moreover, the proinflammatory transcription factor hypoxia-inducible factor (HIF) is known to be regulated by iron as well as oxygen levels (113). Finally, iron signaling processes in endothelial cells have been described that dictate cellular fate. Iron uptake regulated via the transferrin receptor, coupled to increased levels of cellular oxidant production, mediates activation of caspase 3 and endothelial cell apoptosis (160). Such responses appear to be further regulated by NO (108).

It therefore appears that cellular iron can act as a proinflammatory signaling agent, with the potential to influence responses as diverse as chemokine production and cellular fate. Therefore, iron/heme/hemoglobin cellular uptake and subsequent metabolism may well contribute to the promotion of inflammation in certain patient groups at risk for ALI.

Heme oxygenase. The HO enzymes are key to the sequestration of iron in the sepsis syndromes and after hemolysis. HO-1, the inducible isoform of the enzyme, is upregulated by binding of hemoglobin/haptoglobin complexes to the specific CD163 macrophage receptor after CPB (129). In the nucleus heme binds to, and removes, a specific transcriptional repressor, BACH-1, from the HO-1 promoter region, thus inducing the enzyme (156). Moreover, prior induction of the enzyme has been shown to ameliorate the deleterious effects of heme in a number of models (79, 95, 117, 171). Numerous studies have shown that the induction of HO-1 is protective in ALI and MODS through antioxidant, anti-inflammatory, antiproliferative, and antiapoptotic mechanisms (148). Although these actions are largely ascribed to the generation of its products, carbon monoxide and bilirubin, there is also evidence that the metabolism of heme itself is a key anti-inflammatory function of the enzyme. Furthermore, it has recently been suggested that HO-1 is localized to the mitochondrion and may lead to the metabolism of the iron-containing cytochromes in the electron transport chain (28, 155). Thus the enzyme directly downregulates mitochondrial ROS production and enhances cellular tolerance to oxidative stress during inflammation. Finally, ferritin is coinduced with HO-1, suggesting that the sequestration of liberated iron is also essential to the enzyme's protective function (149). In conditions of heme excess it has been suggested that the HO/ferritin system becomes overwhelmed and that the liberation of free iron may have deleterious consequences through the generation of prooxidant species (157).

Acute-phase response and iron sequestration. The physiological changes witnessed during the systemic inflammatory response arise in part as a result of cytokine induction following both infectious and noninfectious insults. Such physiological changes are also accompanied by the modulation of a wide range of plasma proteins, largely produced by the liver and collectively termed acute-phase response proteins (40). Included within this group are components of the complement, coagulation, and fibrinolytic systems, serum antiproteases and transport proteins, and others including granulocyte colony-stimulating factor, serum amyloid A, and, most widely used in the clinical setting, the C-reactive protein. Although these indexes of the acute-phase response may be useful for predicting outcome in patients with sepsis and ALI, their integrated role in the onset and resolution of such inflammation is not well understood.

The key modulators of iron homeostasis hepcidin, haptoglobin, hemopexin, lactoferrin, and ferritin, which promote iron sequestration, are all recognized as acute-phase proteins induced during inflammation (118, 151). Conversely, proteins that promote iron accumulation, transferrin and ferroportin, are suppressed. Together these changes have the effect of promoting a hypoferremic state (9). Thus during the acute-phase response the increase in iron-binding plasma proteins represents an active mechanism for the sequestration of excess iron rather than a purely passive defense. IL-1, IL-6, tumor necrosis factor-, interferon-, and interferon- are cytokines recognized to promote hypoferremia, thus denying microorganisms and neoplastic cells an essential growth factor and simultaneously minimizing the availability of iron for participation in deleterious prooxidant chemistry (11, 35, 47, 175). The coordinated induction of hypoferremia in response to a wide range of stimuli including bacterial and viral infection, malignancy, and extreme exercise suggests its fundamental importance as a protective mechanism during inflammation (72, 85, 163). Furthermore, the strength of the mechanism is highlighted during conditions of chronic inflammation, when it is now recognized that the prolonged elevation of hepcidin and its subsequent hypoferremic action are sufficient to induce the anemia of chronic disease (174).

Although the induction of hypoferremia represents an early response to infectious and noninfectious proinflammatory stimuli, there is evidence that this system may become overwhelmed and that a failure of iron sequestration and inappropriately elevated levels of tissue iron may contribute to disease pathogenesis.

Such decompartmentalized iron arises primarily from cell necrosis and lysis. The deleterious effects of iron release consequent upon hemolysis are recognized in both acute and chronic disease. Thus, after surgery, especially that involving CPB, and in severe fulminant infections such as malaria and E. coli, hemolysis may potentiate the inflammatory response (63, 87, 154). Additionally, in chronic hemolytic conditions such as sickle-cell disease and the thalassemias, iron release and sequestration contribute to disease pathogenesis (10, 173). By contrast, the release of myoglobin during rhabdomyolysis and subsequent acute renal tubular necrosis is perhaps the most widely described example of nonhematologic iron decompartmentalization contributing to tissue injury (3, 36). Free iron is also implicated in the pathogenesis of a wide variety of other tissue injuries following necrosis (83, 130, 143, 185). Finally, there is some evidence that under certain circumstances iron is transported from cells by specific mechanisms during inflammation, although the mechanisms for this are not fully understood (46, 73).

Cardiopulmonary bypass, hemolysis, SIRS, and development of ALI. SIRS is a common complication of surgery necessitating CPB, but the reasons for its development are not well understood. Iron mobilization appears to be associated with SIRS. ALI is associated with CPB (26), during which hemolysis occurs with release of heme, the primary source of such iron. Moreover, acute hemolysis is a recognized feature of several infectious diseases associated with severe sepsis and ARDS. Despite this, the contribution of hemolysis to morbidity has yet to be explored, and it is considered a marker of illness severity rather than a target for therapeutic intervention. However, removal of iron would theoretically both deny infecting organisms an essential probiotic and reduce prooxidant stress. Strategies that have sought to reduce hemolysis during CPB include changes in pump design and surgical practice, which have been associated with reduced indexes of inflammation and morbidity (93, 154, 177).

Although hemolysis is a common feature of CPB and likely to contribute to the manifestation of SIRS, only a small minority of patients go on to develop ALI and/or severe sepsis. It therefore seems likely that a predisposition exists in a minority of at-risk individuals for the development of these life-threatening syndromes.

Genetic Predisposition

Prospective studies have indicated that only a proportion of individuals at risk of ARDS go on to develop the syndrome, ranging from 14% to 40% in patients suffering trauma (166) and sepsis (124), respectively, thereby raising the possibility of genetic susceptibility. This is a complex hypothesis to explore, not only because of the incomplete penetrance of genetic traits and heterogeneity of the loci involved but also because of the influences of variable, nongenetic risk factors and of treatment strategies. Any genetic association must therefore be stratified by potential gene-gene and gene-environment interactions. Recent advances in molecular genetics and bioinformatics have enhanced the study of complex genetic disease. Most sequence variation in DNA is present at the single base level [e.g., substitution, deletion or insertion polymorphisms (DIPs)]; and is also present as DIPs and repeat regions of variable magnitude. A further level of complexity has recently been introduced with the release of the first-generation copy number polymorphism (CNP) map (140).

Methods of investigating complex genetic diseases utilizing familial linkage studies are not feasible in patients with ALI because of the sporadic nature of the syndrome. Candidate gene association studies are therefore often employed. Single nucleotide polymorphism (SNP) analysis is the method of choice for candidate gene studies because of the high density mapping required and their relative stability compared with microsatellites. SNPs are defined as variations in DNA fixed at an allele frequency of 1% of the population, in which a single base is changed for an alternative. Several characteristic aspects of ALI such as inflammation and antioxidant imbalance are already reported to be under genetic control, and the functionality of the genes that are involved is influenced by polymorphism. Host-mediated responses to insults associated with the development of lung injury at a genetic level may predispose certain individuals to ALI.

Peer-reviewed publications investigating genetic polymorphism in ALI/ARDS have so far indicated a role for 16 genes in predisposition to and/or mortality from the syndromes (Table 3). The most convincing associations to date are with polymorphisms in genes encoding angiotensin-converting enzyme (ACE) (1, 81, 105) and surfactant protein B (SP-B) (51, 100, 132), where positive associations have been reported by more than one institution. Thus, considering the wealth of biochemical evidence supporting the involvement of oxidative stress-related parameters in ALI, genetic research in this field is sparse. However, genes encoding proteins involved in oxidative stress play a role in lung disease per se. HO-1 (GT)n long repeats are linked to the decline in lung function and risk of emphysema in smokers (57, 70). Polymorphisms in the gene coding for haptoglobin, the hemoglobin scavenger, are linked to increased risk of bronchial asthma (78) and to mortality from tuberculosis (84). NADPH oxidase and catalase polymorphisms have a role to play in patients with sepsis, a risk factor for ALI (126).

In preliminary studies, we found evidence of SNPs in a panel of nine genes encoding iron-metabolizing proteins in a case control study of 123 patients with ARDS. A role for polymorphisms of the Ferritin Light chain gene in susceptibility to ARDS of extrapulmonary origin and for HO-2 gene in a protective role against ARDS of pulmonary origin emerged (89). While the functional significance of these data is at present not clear, they strongly indicate that variation in the iron-regulatory response at the genotypic level may be a significant predisposing factor in the development of ARDS, the most severe manifestation of the sepsis syndromes.

Large-scale prospective cohort studies are already planned on ICU "at-risk" surgical groups (51, 107). Careful characterization of phenotypes in these cohorts will avoid dilution of the underlying genotype effect. An approach to candidate gene studies is also evolving that uses hypothesis-generating tools such as expression arrays and time series analysis of involved tissues and cells, which should help to direct candidate gene research together with utilization of tools such as HapMap (77a) and CNPmap (140).

Iron Decompartmentalization and Clinical Presentation

Acute-phase changes in iron homeostasis that characterize proinflammatory responses act to ameliorate the effects of inflammation. A reduction in the potential for microbial growth and for uncontrolled iron-catalyzed oxidant production would seem to be the ultimate goal of the observed hypoferremic state. However, as illustrated in the previous sections of this review, the presentation of acute inflammatory conditions including SIRS and life-threatening ALI is accompanied by perturbations in body iron and heme status that contribute to both microbial growth and excessive oxidative stress. The compromise of systemic mechanisms that usually act to specifically limit iron availability enhances the potential for damaging ROS production, and this has implications for endothelium/vascular damage and dysfunction and accompanying organ failures. Decompartmentalization of iron/heme will further impact on compromised defenses, with potential adverse implications. Oxidative damage directly alters the function of modified biomolecules, and, moreover, some end products formed (e.g., aldehydes from lipid oxidation) may be cytotoxic at high concentrations and bioactive at lower concentrations (33). Thus lung-orientated lipid peroxidation is likely to generate chemotactic end products, promote lung neutrophilia, and enhance proinflammatory signaling between other inflammatory cells. Even cellular iron uptake in the lung is fraught with risk. In particular, transferrin receptor-mediated uptake of transferrin-bound iron by epithelial cells increases the labile reactive iron pool within the cytosol and not the safe storage of iron in ferritin, thereby rendering these cells extremely vulnerable to oxidative damage and or altered redox-based signaling responses that may be either pro- or anti-inflammatory (46). There are also implications for cellular fate and remodeling, because iron is known to modulate apoptosis and promote fibroproliferation in both liver and lung (39, 128, 182). Therefore, aspects of pulmonary hypertension and the organizational phase of ARDS may be influenced by such mechanisms (146, 164). The roles of heme metabolism and HO-1 induction in neutrophils and antiapoptotic responses are also important in this regard.

It seems apparent that release, uptake, metabolism, and storage of iron/heme during inflammation may well have profound implications for disease onset and progression in those who are in some way predisposed to develop these syndromes. Figure 2 outlines the means by which iron/heme decompartmentalization is modulated and impacts on inflammation in at-risk populations for the onset and progression of SIRS, ALI, and indeed other organ injury.

View larger version (14K): [in this window] [in a new window]   Fig. 2. This scheme summarizes the mechanisms by which iron decompartmentalization contributes to the propagation of the inflammatory response and organ dysfunction. The hypoferremic response (see Fig. 1) attenuates these effects and may be influenced by genetic variability in at-risk populations. CPB, cardiopulmonary bypass.

Many investigations have been performed to evaluate the potential of pharmacotherapeutic interventions for the treatment of ALI (23). Most were designed to reduce cellular and mediator-driven inflammation. In the light of some of the data presented above, attempts have been made to introduce antioxidants to improve mortality, in particular employing the scavenging antioxidant and glutathione precursor N-acetylcysteine (NAC), but have failed to demonstrate a survival benefit or even a reproducible effect on pulmonary physiology. Human serum albumin (HSA), a pharmaceutical in common use in the critical care setting, also has antioxidant functions and has been shown to improve plasma antioxidant status in patients with ALI (138). Interventions specifically targeting the prooxidant and promicrobial properties of low-molecular-mass iron and free heme/hemoglobin have not yet been investigated in patients with ALI. However, in vivo studies have been performed (144) in which the combined use of NAC and the iron chelator desferrioxamine were shown to ameliorate in an additive fashion proinflammatory indexes in rodent models of sepsis and ARDS. While these results seem logical and encouraging, translation to human-based studies may well not be appropriate. Thus NAC in high doses can aggravate prooxidant responses via redox cycling of transition metal ions. Furthermore, desferrioxamine is a particularly potent iron chelator, and its use in individuals who are not iron overloaded may deplete essential iron stores in excess of those iron pools that are contributing to unwanted prooxidant responses. However, the advent of new, more specific iron chelators may now improve the feasibility of such a therapeutic approach. Perhaps a better way to limit the effects of extracellular iron mobilization would be to utilize or augment interventions based on in vivo binding and removal mechanisms. Potential therapies could include the iron-binding proteins transferrin and lactoferrin for the removal of free redox active iron. As for limiting iron-mediated effects related to hemolysis, heme removal could be achieved with hemopexin, a heme-binding protein with antioxidant function (62), and an associated in vivo removal system or with HSA, which is also an efficient heme-binding protein (127) that has established therapeutic usage in the critically ill, albeit for different reasons than those suggested here. Finally, free hemoglobin is avidly bound by haptoglobin and removed from the circulation mainly via the CD163 receptor of macrophages. Haptoglobin also has reported antioxidant functions (58), and transgenic mice that overexpress haptoglobin have demonstrated a markedly protective response against hemoglobin-induced lung injury (180). Indeed, replacement of haptoglobin has been studied as a protective stratagem during CPB, with limited results (69, 161). Trials in patients at greater risk of developing ALI may prove more fruitful and provide a paradigm for the treatment of those diseases associated with severe sepsis and organ dysfunction in which hemolysis is present.

While the reasoning proposed for the use of antioxidant therapy to treat patients with ARDS seems to be justifiable, caution is required. The potential pitfalls associated with chelation therapy have been mentioned, but limiting the effects of oxidative stress directly may also alter both pro- and anti-inflammatory redox signaling responses (29). The use of antioxidants may therefore limit not only unwanted ROS-mediated responses but also the induction of protective endogenous stratagems. A targeted approach with defined aims therefore seems appropriate. In this sense, the predisposing insult will determine the nature of the therapeutic approach adopted, and the timing and duration of any intervention would be of crucial importance. Prophylactic use in "at-risk" groups may prove a more fruitful approach than administration to those with established disease. Perhaps the lack of success reported, in terms of survival benefit, with previous antioxidant trials is related to such shortfalls.

Summary

Iron mobilization and decompartmentalization may be significant in the pathogenesis of SIRS and associated organ system failure, specifically ALI. Experimental and clinical investigations suggest that iron-catalyzed oxidative stress and the proinflammatory effects of hemolysis, coupled to decreased antioxidant, anti-inflammatory moieties, lead to increased cytotoxicity in patients with SIRS and ALI. Moreover, such redox imbalance has implications for the modulation of signaling pathways relevant to the inflammatory response, especially in genetically predisposed populations. Specific therapeutic interventions based on endogenous stratagems may emerge from these hypotheses.

	GRANTS

TOP ABSTRACT GRANTS REFERENCES

 
A. L. Lagan, G. J. Quinlan, and T. W. Evans thank the British Heart Foundation for their support. G. J. Quinlan and T. W. Evans also thank the Dunhill Medical Trust and the David Boston Trust. D. D. Melley thanks the Garfield Weston Trust for support.

	FOOTNOTES

 

Address for reprint requests and other correspondence: G. J. Quinlan, Dept. of Critical Care Medicine, Royal Brompton Hospital, Sydney St., London SW3 6NP, UK (e-mail: g.quinlan{at}imperial.ac.uk)

	REFERENCES

TOP ABSTRACT GRANTS REFERENCES

 

1. Adamzik M, Frey U, Sixt S, Knemeyer L, Beiderlinden M, Peters J, Siffert W. ACE I/D but not AGT (–6)A/G polymorphism is a risk factor for mortality in ARDS. Eur Respir J 29: 482–488, 2007.[Abstract/Free Full Text]
2. Adamzik M, Frey UH, Rieman K, Sixt S, Beiderlinden M, Siffert W, Peters J. Insertion/deletion polymorphism in the promoter of NFKB1 influences severity but not mortality of acute respiratory distress syndrome. Intensive Care Med 33: 1199–1203, 2007.[CrossRef][Medline]
3. Adornato BT, Kagen LJ, Garver FA, Engel WK. Depletion of serum hemopexin in fulminant rhabdomyolysis. Evidence for an interaction of hemopexin with myoglobin-derived heme. Arch Neurol 35: 547–548, 1978.[Abstract/Free Full Text]
4. Anonymous. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med 20: 864–874, 1992.[Web of Science][Medline]
5. Arruda MA, Rossi AG, de Freitas MS, Barja-Fidalgo C, and Graca-Souza AV. Heme inhibits human neutrophil apoptosis: involvement of phosphoinositide 3-kinase, MAPK, and NF-B. J Immunol 173: 2023–2030, 2004.[Abstract/Free Full Text]
7. Ascenzi P, Bocedi A, Visca P, Altruda F, Tolosano E, Beringhelli T, Fasano M. Hemoglobin and heme scavenging. IUBMB Life 57: 749–759, 2005.[Medline]
8. Bajwa EK, Yu CL, Gong MN, Thompson BT, Christiani DC. Pre-B-cell colony-enhancing factor gene polymorphisms and risk of acute respiratory distress syndrome. Crit Care Med 35: 1290–1295, 2007.[CrossRef][Medline]
9. Ballantyne GH. Rapid drop in serum iron concentration as a host defense mechanism. A review of experimental and clinical evidence. Am Surg 50: 405–411, 1984.[Medline]
10. Ballas SK. Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease. Semin Hematol 38: 30–36, 2001.[CrossRef][Medline]
11. Baynes RD, Bezwoda WR, Dajee D, Lamparelli RD, Bothwell TH. Effects of alpha-interferon on iron-related measurements in human subjects. S Afr Med J 78: 627–628, 1990.[Medline]
12. Baz MA, Ghio AJ, Roggli VL, Tapson VF, Piantadosi CA. Iron accumulation in lung allografts after transplantation. Chest 112: 435–439, 1997.[CrossRef][Web of Science][Medline]
13. Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, Lamy M, LeGall JR, Morris A, Spragg R. The American-European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med 149: 818–824, 1994.[Abstract]
14. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB. The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 336: 912–918, 1997.[Abstract/Free Full Text]
15. Bonnell MR, Visner GA, Zander DS, Mandalapu S, Kazemfar K, Spears L, Beaver TM. Heme-oxygenase-1 expression correlates with severity of acute cellular rejection in lung transplantation. J Am Coll Surg 198: 945–952, 2004.[CrossRef][Web of Science][Medline]
16. Brun-Buisson C, Doyon F, Carlet J. Bacteremia and severe sepsis in adults: a multicenter prospective survey in ICUs and wards of 24 hospitals. French Bacteremia-Sepsis Study Group. Am J Respir Crit Care Med 154: 617–624, 1996.[Abstract]
17. Brun-Buisson C, Minelli C, Bertolini G, Brazzi L, Pimentel J, Lewandowski K, Bion J, Romand JA, Villar J, Thorsteinsson A, Damas P, Armaganidis A, Lemaire F. Epidemiology and outcome of acute lung injury in European intensive care units. Results from the ALIVE study. Intensive Care Med 30: 51–61, 2004.[CrossRef][Web of Science][Medline]
18. Bunn HF, Jandl JH. Exchange of heme among hemoglobins and between hemoglobin and albumin. J Biol Chem 243: 465–475, 1968.[Abstract/Free Full Text]
19. Bunnell E, Pacht ER. Oxidized glutathione is increased in the alveolar fluid of patients with the adult respiratory distress syndrome. Am Rev Respir Dis 148: 1174–1178, 1993.[Web of Science][Medline]
20. Cairo G, Pietrangelo A. Iron regulatory proteins in pathobiology. Biochem J 352: 241–250, 2000.[CrossRef][Web of Science][Medline]
21. Cairo G, Recalcati S, Pietrangelo A, Minotti G. The iron regulatory proteins: targets and modulators of free radical reactions and oxidative damage. Free Radic Biol Med 32: 1237–1243, 2002.[CrossRef][Web of Science][Medline]
22. Carpenter CT, Price PV, Christman BW. Exhaled breath condensate isoprostanes are elevated in patients with acute lung injury or ARDS. Chest 114: 1653–1659, 1998.[CrossRef][Web of Science][Medline]
23. Cepkova M, Matthay MA. Pharmacotherapy of acute lung injury and the acute respiratory distress syndrome. J Intensive Care Med 21: 119–143, 2006.[Abstract/Free Full Text]
24. Christofidou-Solomidou M, Kennel S, Scherpereel A, Wiewrodt R, Solomides CC, Pietra GG, Murciano JC, Shah SA, Ischiropoulos H, Albelda SM, Muzykantov VR. Vascular immunotargeting of glucose oxidase to the endothelial antigens induces distinct forms of oxidant acute lung injury: targeting to thrombomodulin, but not to PECAM-1, causes pulmonary thrombosis and neutrophil transmigration. Am J Pathol 160: 1155–1169, 2002.[Abstract/Free Full Text]
25. Clark IA, Awburn MM, Harper CG, Liomba NG, Molyneux ME. Induction of HO-1 in tissue macrophages and monocytes in fatal falciparum malaria and sepsis. Malar J 2: 41, 2003.[CrossRef][Medline]
26. Clark SC. Lung injury after cardiopulmonary bypass. Perfusion 21: 225–228, 2006.[Abstract/Free Full Text]
27. Connelly KG, Moss M, Parsons PE, Moore EE, Moore FA, Giclas PC, Seligman PA, Repine JE. Serum ferritin as a predictor of the acute respiratory distress syndrome. Am J Respir Crit Care Med 155: 21–25, 1997.[Abstract]
28. Converso DP, Taille C, Carreras MC, Jaitovich A, Poderoso JJ, Boczkowski J. HO-1 is located in liver mitochondria and modulates mitochondrial heme content and metabolism. FASEB J 20: 1236–1238, 2006.[Abstract/Free Full Text]
29. Cross CE, van Asbeck BS, Halliwell B. More antioxidants in sepsis: still paved with uncertainties. Crit Care Med 34: 569–571, 2006.[CrossRef][Medline]
30. Dennery PA, Spitz DR, Yang G, Tatarov A, Lee CS, Shegog ML, Poss KD. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest 101: 1001–1011, 1998.[Web of Science][Medline]
31. DeVoe IW. The meningococcus and mechanisms of pathogenicity. Microbiol Rev 46: 162–190, 1982.[Free Full Text]
32. Douabin-Gicquel V, Soriano N, Ferran H, Wojcik F, Palierne E, Tamim S, Jovelin T, McKie AT, Le Gall JY, David V, Mosser J. Identification of 96 single nucleotide polymorphisms in eight genes involved in iron metabolism: efficiency of bioinformatic extraction compared with a systematic sequencing approach. Hum Genet 109: 393–401, 2001.[CrossRef][Web of Science][Medline]
33. Esterbauer H. Cytotoxicity and genotoxicity of lipid-oxidation products. Am J Clin Nutr 57: 779S–785S, 1993.[Web of Science]
34. Exner M, Minar E, Wagner O, Schillinger M. The role of heme oxygenase-1 promoter polymorphisms in human disease. Free Radic Biol Med 37: 1097–1104, 2004.[CrossRef][Web of Science][Medline]
35. Feelders RA, Vreugdenhil G, Eggermont AM, Kuiper-Kramer PA, van Eijk HG, Swaak AJ. Regulation of iron metabolism in the acute-phase response: interferon gamma and tumour necrosis factor alpha induce hypoferraemia, ferritin production and a decrease in circulating transferrin receptors in cancer patients. Eur J Clin Invest 28: 520–527, 1998.[CrossRef][Web of Science][Medline]
36. Feinfeld DA, Cheng JT, Beysolow TD, Briscoe AM. A prospective study of urine and serum myoglobin levels in patients with acute rhabdomyolysis. Clin Nephrol 38: 193–195, 1992.[Web of Science][Medline]
37. Francis RT Jr, Booth JW, Becker RR. Uptake of iron from hemoglobin and the haptoglobin-hemoglobin complex by hemolytic bacteria. Int J Biochem 17: 767–773, 1985.[CrossRef][Medline]
38. Frerking I, Sengler C, Gunther A, Walmrath HD, Stevens P, Witt H, Landt O, Pison U, Nickel R. Evaluation of the –26GA CC16 polymorphism in acute respiratory distress syndrome. Crit Care Med 33: 2404–2406, 2005.[CrossRef][Medline]
39. Fubini B, Hubbard A. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radic Biol Med 34: 1507–1516, 2003.[CrossRef][Web of Science][Medline]
40. Gabay C, Kushner I. Acute-phase proteins and other systemic responses to inflammation. N Engl J Med 340: 448–454, 1999.[Free Full Text]
41. Gao L, Flores C, Fan-Ma S, Miller EJ, Moitra J, Moreno L, Wadgaonkar R, Simon B, Brower R, Sevransky J, Tuder RM, Maloney JP, Moss M, Shanholtz C, Yates CR, Meduri GU, Ye SQ, Barnes KC, Garcia JG. Macrophage migration inhibitory factor in acute lung injury: expression, biomarker, and associations. Transl Res 150: 18–29, 2007.[CrossRef][Medline]
42. Gao L, Grant A, Halder I, Brower R, Sevransky J, Maloney JP, Moss M, Shanholtz C, Yates CR, Meduri GU, Shriver MD, Ingersoll R, Scott AF, Beaty TH, Moitra J, Ma SF, Ye SQ, Barnes KC, Garcia JG. Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Biol 34: 487–495, 2006.[Abstract/Free Full Text]
43. Ghio AJ, Carter JD, Richards JH, Brighton LE, Lay JC, Devlin RB. Disruption of normal iron homeostasis after bronchial instillation of an iron-containing particle. Am J Physiol Lung Cell Mol Physiol 274: L396–L403, 1998.[Abstract/Free Full Text]
44. Ghio AJ, Carter JD, Richards JH, Richer LD, Grissom CK, Elstad MR. Iron and iron-related proteins in the lower respiratory tract of patients with acute respiratory distress syndrome. Crit Care Med 31: 395–400, 2003.[CrossRef][Medline]
45. Ghio AJ, Turi JL, Madden MC, Dailey LA, Richards JD, Stonehuerner JG, Morgan DL, Singleton S, Garrick LM, Garrick MD. Lung injury after ozone exposure is iron dependent. Am J Physiol Lung Cell Mol Physiol 292: L134–L143, 2007.[Abstract/Free Full Text]
46. Ghio AJ, Turi JL, Yang F, Garrick LM, Garrick MD. Iron homeostasis in the lung. Biol Res 39: 67–77, 2006.[Medline]
47. Goldblum SE, Cohen DA, Jay M, McClain CJ. Interleukin 1-induced depression of iron and zinc: role of granulocytes and lactoferrin. Am J Physiol Endocrinol Metab 252: E27–E32, 1987.[Abstract/Free Full Text]
48. Gole MD, Souza JM, Choi I, Hertkorn C, Malcolm S, Foust RF III, Finkel B, Lanken PN, Ischiropoulos H. Plasma proteins modified by tyrosine nitration in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 278: L961–L967, 2000.[Abstract/Free Full Text]
49. Gong MN, Thompson BT, Williams P, Pothier L, Boyce PD, Christiani DC. Clinical predictors of and mortality in acute respiratory distress syndrome: potential role of red cell transfusion. Crit Care Med 33: 1191–1198, 2005.[CrossRef][Web of Science][Medline]
50. Gong MN, Thompson BT, Williams PL, Zhou W, Wang MZ, Pothier L, Christiani DC. Interleukin-10 polymorphism in position –1082 and acute respiratory distress syndrome. Eur Respir J 27: 674–681, 2006.[Abstract/Free Full Text]
51. Gong MN, Wei Z, Xu LL, Miller DP, Thompson BT, Christiani DC. Polymorphism in the surfactant protein-B gene, gender, and the risk of direct pulmonary injury and ARDS. Chest 125: 203–211, 2004.[CrossRef][Web of Science][Medline]
52. Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Boyce P, Christiani DC. –308GA and TNFB polymorphisms in acute respiratory distress syndrome. Eur Respir J 26: 382–389, 2005.[Abstract/Free Full Text]
53. Gong MN, Zhou W, Williams PL, Thompson BT, Pothier L, Christiani DC. Polymorphisms in the mannose binding lectin-2 gene and acute respiratory distress syndrome. Crit Care Med 35: 48–56, 2007.[CrossRef][Web of Science][Medline]
54. Gorbunov NV, Asher LV, Ayyagari V, Atkins JL. Inflammatory leukocytes and iron turnover in experimental hemorrhagic lung trauma. Exp Mol Pathol 80: 11–25, 2006.[Web of Science][Medline]
55. Graca-Souza AV, Arruda MA, de Freitas MS, Barja-Fidalgo C, Oliveira PL. Neutrophil activation by heme: implications for inflammatory processes. Blood 99: 4160–4165, 2002.[Abstract/Free Full Text]
56. Grant GR, Robinson SW, Edwards RE, Clothier B, Davies R, Judah DJ, Broman KW, Smith AG. Multiple polymorphic loci determine basal hepatic and splenic iron status in mice. Hepatology 44: 174–185, 2006.[CrossRef][Medline]
57. Guenegou A, Leynaert B, Benessiano J, Pin I, Demoly P, Neukirch F, Boczkowski J, Aubier M. Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France. J Med Genet 43: e43, 2006.
58. Gutteridge JM. The antioxidant activity of haptoglobin towards haemoglobin-stimulated lipid peroxidation. Biochim Biophys Acta 917: 219–223, 1987.[Medline]
59. Gutteridge JM. Iron and oxygen: a biologically damaging mixture. Acta Paediatr Scand Suppl 361: 78–85, 1989.[Medline]
60. Gutteridge JM, Mumby S, Quinlan GJ, Chung KF, Evans TW. Pro-oxidant iron is present in human pulmonary epithelial lining fluid: implications for oxidative stress in the lung. Biochem Biophys Res Commun 220: 1024–1027, 1996.[CrossRef][Web of Science][Medline]
61. Gutteridge JM, Quinlan GJ, Mumby S, Heath A, Evans TW. Primary plasma antioxidants in adult respiratory distress syndrome patients: changes in iron-oxidizing, iron-binding, and free radical-scavenging proteins. J Lab Clin Med 124: 263–273, 1994.[Web of Science][Medline]
62. Gutteridge JM, Smith A. Antioxidant protection by haemopexin of haem-stimulated lipid peroxidation. Biochem J 256: 861–865, 1988.[Web of Science][Medline]
63. Hacker J, Hof H, Emody L, Goebel W. Influence of cloned Escherichia coli hemolysin genes, S-fimbriae and serum resistance on pathogenicity in different animal models. Microb Pathog 1: 533–547, 1986.[CrossRef][Medline]
64. Halliwell B. Phagocyte-derived reactive species: salvation or suicide? Trends Biochem Sci 31: 509–515, 2006.[CrossRef][Web of Science][Medline]
65. Halliwell B, Gutteridge JM. Free Radicals in Biology and Medicine. Oxford: Oxford Univ. Press, 2007.
66. Hammerschmidt S, Buchler N, Wahn H. Tissue lipid peroxidation and reduced glutathione depletion in hypochlorite-induced lung injury. Chest 121: 573–581, 2002.[CrossRef][Web of Science][Medline]
67. Hammerschmidt S, Wahn H. Comparable effects of HOCl and of FMLP-stimulated PMN on the circulation in an isolated lung model. Am J Respir Crit Care Med 156: 924–931, 1997.[Abstract/Free Full Text]
68. Hammerschmidt S, Wahn H. The oxidants hypochlorite and hydrogen peroxide induce distinct patterns of acute lung injury. Biochim Biophys Acta 1690: 258–264, 2004.[Medline]
69. Hashimoto K, Nomura K, Nakano M, Sasaki T, Kurosawa H. Pharmacological intervention for renal protection during cardiopulmonary bypass. Heart Vessels 8: 203–210, 1993.[CrossRef][Medline]
70. He JQ, Ruan J, Connett JE, Anthonisen NR, Pare PD, Sandford AJ. Antioxidant gene polymorphisms and susceptibility to a rapid decline in lung function in smokers. Am J Respir Crit Care Med 166: 323–328, 2002.[Abstract/Free Full Text]
71. Hildebrand F, Stuhrmann M, van Griensven M, Meier S, Hasenkamp S, Krettek C, Pape HC. Association of IL-8-251A/T polymorphism with incidence of Acute Respiratory Distress Syndrome (ARDS) and IL-8 synthesis after multiple trauma. Cytokine 37: 192–199, 2007.[CrossRef][Medline]
72. Hoppe M, Hulthén L. Capturing the onset of the common cold and its effects on iron absorption. Eur J Clin Nutr 61: 1032–1034, 2007.[CrossRef][Medline]
73. Huang YT, Ghio AJ, Nozik-Grayck E, Piantadosi CA. Vascular release of nonheme iron in perfused rabbit lungs. Am J Physiol Lung Cell Mol Physiol 280: L474–L481, 2001.[Abstract/Free Full Text]
74. Hudson LD, Milberg JA, Anardi D, Maunder RJ. Clinical risks for development of the acute respiratory distress syndrome. Am J Respir Crit Care Med 151: 293–301, 1995.[Abstract]
75. Huy NT, Trang DT, Kariu T, Sasai M, Saida K, Harada S, Kamei K. Leukocyte activation by malarial pigment. Parasitol Int 55: 75–81, 2006.[CrossRef][Medline]
76. Hvidberg V, Maniecki MB, Jacobsen C, Hojrup P, Moller HJ, Moestrup SK. Identification of the receptor scavenging hemopexin-heme complexes. Blood 106: 2572–2579, 2005.[Abstract/Free Full Text]
77. Hybertson BM, Lee YM, Repine JE. Phagocytes and acute lung injury: dual roles for interleukin-1. Ann NY Acad Sci 832: 266–273, 1997.[CrossRef][Web of Science][Medline]
77. International HapMap Consortium. The International HapMap Project. Nature 426: 789–796, 2003.[CrossRef][Medline]
78. Izmerov NF, Kuzmina LP, Tarasova LA. Genetic-biochemical criteria for individual sensitivity in development of occupational bronchopulmonary diseases. Cent Eur J Public Health 10: 35–41, 2002.[Medline]
79. Jeney V, Balla J, Yachie A, Varga Z, Vercellotti GM, Eaton JW, Balla G. Pro-oxidant and cytotoxic effects of circulating heme. Blood 100: 879–887, 2002.[Abstract/Free Full Text]
80. Jeong HJ, Chung HS, Lee BR, Kim SJ, Yoo SJ, Hong SH, Kim HM. Expression of proinflammatory cytokines via HIF-1 and NF-B activation on desferrioxamine-stimulated HMC-1 cells. Biochem Biophys Res Commun 306: 805–811, 2003.[CrossRef][Medline]
81. Jerng JS, Yu CJ, Wang HC, Chen KY, Cheng SL, Yang PC. Polymorphism of the angiotensin-converting enzyme gene affects the outcome of acute respiratory distress syndrome. Crit Care Med 34: 1001–1006, 2006.[CrossRef][Web of Science][Medline]
82. Joshi PC, Guidot DM. The alcoholic lung: epidemiology, pathophysiology, and potential therapies. Am J Physiol Lung Cell Mol Physiol 292: L813–L823, 2007.[Abstract/Free Full Text]
83. Karwatowska-Prokopczuk E, Czarnowska E, Beresewicz A. Iron availability and free radical induced injury in the isolated ischaemic/reperfused rat heart. Cardiovasc Res 26: 58–66, 1992.[Abstract/Free Full Text]
84. Kasvosve I, Gomo ZA, Mvundura E, Moyo VM, Saungweme T, Khumalo H, Gordeuk VR, Boelaert JR, Delanghe JR, De Bacquer D, Gangaidzo IT. Haptoglobin polymorphism and mortality in patients with tuberculosis. Int J Tuberc Lung Dis 4: 771–775, 2000.[Web of Science][Medline]
85. Kemna E, Pickkers P, Nemeth E, van der HH, Swinkels D. Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 106: 1864–1866, 2005.[Abstract/Free Full Text]
86. Kramer-Stickland K, Edmonds A, Bair WBIII, Bowden GT. Inhibitory effects of deferoxamine on UVB-induced AP-1 transactivation. Carcinogenesis 20: 2137–2142, 1999.[Abstract/Free Full Text]
87. Kumar S, Bandyopadhyay U. Free heme toxicity and its detoxification systems in human. Toxicol Lett 157: 175–188, 2005.[CrossRef][Web of Science][Medline]
88. Labbe RF, Vreman HJ, Stevenson DK. Zinc protoporphyrin: a metabolite with a mission. Clin Chem 45: 2060–2072, 1999.[Abstract/Free Full Text]
89. Lagan AL, Quinlan GJ, Mumby S, Melley DD, Goldstraw P, Bellingan GJ, Hill MR, Briggs D, Pantelidis P, Du Bois RM, Welsh KI, Evans TW. Variation in iron homeostasis genes between patients with acute respiratory distress syndrome and healthy controls. Chest. In press.
90. Lamb NJ, Gutteridge JM, Baker C, Evans TW, Quinlan GJ. Oxidative damage to proteins of bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome: evidence for neutrophil-mediated hydroxylation, nitration, and chlorination. Crit Care Med 27: 1738–1744, 1999.[CrossRef][Web of Science][Medline]
91. Lang JD, McArdle PJ, O'Reilly PJ, Matalon S. Oxidant-antioxidant balance in acute lung injury. Chest 122: 314S–320S, 2002.[CrossRef][Web of Science][Medline]
92. Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem 42: 1589–1600, 1996.[Abstract/Free Full Text]
93. Lawson DS, Ing R, Cheifetz IM, Walczak R, Craig D, Schulman S, Kern F, Shearer IR, Lodge A, Jaggers J. Hemolytic characteristics of three commercially available centrifugal blood pumps. Pediatr Crit Care Med 6: 573–577, 2005.[CrossRef][Medline]
94. Leaver SK, Evans TW. Acute respiratory distress syndrome. BMJ 335: 389–394, 2007.[Free Full Text]
95. Lee H, Pespeni M, Roux J, Dennery PA, Matthay MA, Pittet JF. HO-1 induction restores c-AMP-dependent lung epithelial fluid transport following severe hemorrhage in rats. FASEB J 19: 287–289, 2005.[Abstract/Free Full Text]
96. Lee YM, Hybertson BM, Cho HG, Repine JE. Platelet-activating factor induces lung inflammation and leak in rats: hydrogen peroxide production along neutrophil-lung endothelial cell interfaces. J Lab Clin Med 140: 312–319, 2002.[CrossRef][Web of Science][Medline]
97. Leggett BA, Brown NN, Bryant SJ, Duplock L, Powell LW, Halliday JW. Factors affecting the concentrations of ferritin in serum in a healthy Australian population. Clin Chem 36: 1350–1355, 1990.[Abstract/Free Full Text]
98. Lenz AG, Jorens PG, Meyer B, De Backer W, Van Overveld F, Bossaert L, Maier KL. Oxidatively modified proteins in bronchoalveolar lavage fluid of patients with ARDS and patients at-risk for ARDS. Eur Respir J 13: 169–174, 1999.[Abstract]
99. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 31: 1250–1256, 2003.[CrossRef][Web of Science][Medline]
100. Lin Z, Pearson C, Chinchilli V, Pietschmann SM, Luo J, Pison U, Floros J. Polymorphisms of human SP-A, SP-B, and SP-D genes: association of SP-B Thr131Ile with ARDS. Clin Genet 58: 181–191, 2000.[CrossRef][Web of Science][Medline]
101. Liu X, Spolarics Z. Methemoglobin is a potent activator of endothelial cells by stimulating IL-6 and IL-8 production and E-selectin membrane expression. Am J Physiol Cell Physiol 285: C1036–C1046, 2003.[Abstract/Free Full Text]
102. Lu F, Zander DS, Visner GA. Increased expression of heme oxygenase-1 in human lung transplantation. J Heart Lung Transplant 21: 1120–1126, 2002.[CrossRef][Web of Science][Medline]
103. MacCallum NS, Evans TW. Epidemiology of acute lung injury. Curr Opin Crit Care 11: 43–49, 2005.[CrossRef][Web of Science][Medline]
104. Maguire GP, Handojo T, Pain MC, Kenangalem E, Price RN, Tjitra E, Anstey NM. Lung injury in uncomplicated and severe falciparum malaria: a longitudinal study in Papua, Indonesia. J Infect Dis 192: 1966–1974, 2005.[CrossRef][Web of Science][Medline]
105. Marshall RP, Webb S, Bellingan GJ, Montgomery HE, Chaudhari B, McAnulty RJ, Humphries SE, Hill MR, Laurent GJ. Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome. Am J Respir Crit Care Med 166: 646–650, 2002.[Abstract/Free Full Text]
106. Marshall RP, Webb S, Hill MR, Humphries SE, Laurent GJ. Genetic polymorphisms associated with susceptibility and outcome in ARDS. Chest 121: 68S-69S, 2002.[CrossRef][Web of Science][Medline]
107. Marzec JM, Christie JD, Reddy SP, Jedlicka AE, Vuong H, Lanken PN, Aplenc R, Yamamoto T, Yamamoto M, Cho HY, Kleeberger SR. Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J 21: 2237–2246, 2007.[Abstract/Free Full Text]
108. Matsunaga T, Kotamraju S, Kalivendi SV, Dhanasekaran A, Joseph J, Kalyanaraman B. Ceramide-induced intracellular oxidant formation, iron signaling, and apoptosis in endothelial cells: protective role of endogenous nitric oxide. J Biol Chem 279: 28614–28624, 2004.[Abstract/Free Full Text]
109. Medford AR, Keen LJ, Bidwell JL, Millar AB. Vascular endothelial growth factor gene polymorphism and acute respiratory distress syndrome. Thorax 60: 244–248, 2005.[Abstract/Free Full Text]
110. Melley DD, Quinlan GJ, Evans TW. The divergent effects of heme on neutrophil apoptosis (Abstract). Thorax 60: II80, 2005.
111. Messent M, Sinclair DG, Quinlan GJ, Mumby SE, Gutteridge JM, Evans TW. Pulmonary vascular permeability after cardiopulmonary bypass and its relationship to oxidative stress. Crit Care Med 25: 425–429, 1997.[CrossRef][Web of Science][Medline]
112. Metnitz PG, Bartens C, Fischer M, Fridrich P, Steltzer H, Druml W. Antioxidant status in patients with acute respiratory distress syndrome. Intensive Care Med 25: 180–185, 1999.[CrossRef][Web of Science][Medline]
113. Metzen E, Ratcliffe PJ. HIF hydroxylation and cellular oxygen sensing. Biol Chem 385: 223–230, 2004.[CrossRef][Web of Science][Medline]
114. Miller YI, Smith A, Morgan WT, Shaklai N. Role of hemopexin in protection of low-density lipoprotein against hemoglobin-induced oxidation. Biochemistry 35: 13112–13117, 1996.[CrossRef][Web of Science][Medline]
115. Moss M, Bucher B, Moore FA, Moore EE, Parsons PE. The role of chronic alcohol abuse in the development of acute respiratory distress syndrome in adults. JAMA 275: 50–54, 1996.[Abstract/Free Full Text]
116. Mumby S, Upton RL, Chen Y, Stanford SJ, Quinlan GJ, Nicholson AG, Gutteridge JM, Lamb NJ, Evans TW. Lung heme oxygenase-1 is elevated in acute respiratory distress syndrome. Crit Care Med 32: 1130–1135, 2004.[CrossRef][Web of Science][Medline]
117. Nath KA, Haggard JJ, Croatt AJ, Grande JP, Poss KD, Alam J. The indispensability of heme oxygenase-1 in protecting against acute heme protein-induced toxicity in vivo. Am J Pathol 156: 1527–1535, 2000.[Abstract/Free Full Text]
118. Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A, Ganz T. Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood 101: 2461–2463, 2003.[Abstract/Free Full Text]
119. Nevo Y, Nelson N. The NRAMP family of metal-ion transporters. Biochim Biophys Acta 1763: 609–620, 2006.[Medline]
120. Nicolas G, Chauvet C, Viatte L, Danan JL, Bigard X, Devaux I, Beaumont C, Kahn A, Vaulont S. The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 110: 1037–1044, 2002.[CrossRef][Web of Science][Medline]
121. Ochoa TJ, Cleary TG. Epidemiology and spectrum of disease of Escherichia coli O157. Curr Opin Infect Dis 16: 259–263, 2003.[Medline]
122. Oury TD, Schaefer LM, Fattman CL, Choi A, Weck KE, Watkins SC. Depletion of pulmonary EC-SOD after exposure to hyperoxia. Am J Physiol Lung Cell Mol Physiol 283: L777–L784, 2002.[Abstract/Free Full Text]
123. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med 31: 2332–2338, 2003.[CrossRef][Web of Science][Medline]
124. Pepe PE, Potkin RT, Reus DH, Hudson LD, Carrico CJ. Clinical predictors of the adult respiratory distress syndrome. Am J Surg 144: 124–130, 1982.[CrossRef][Web of Science][Medline]
125. Pepper JR, Mumby S, Gutteridge JM. Blood cardioplegia increases plasma iron overload and thiol levels during cardiopulmonary bypass. Ann Thorac Surg 60: 1735–1740, 1995.[Abstract/Free Full Text]
126. Perianayagam MC, Liangos O, Kolyada AY, Wald R, MacKinnon RW, Li L, Rao M, Balakrishnan VS, Bonventre JV, Pereira BJ, Jaber BL. NADPH oxidase p22phox and catalase gene variants are associated with biomarkers of oxidative stress and adverse outcomes in acute renal failure. J Am Soc Nephrol 18: 255–263, 2007.[Abstract/Free Full Text]
127. Peters TJ. All About Albumin. San Diego, CA: Academic, 1996.
128. Philippe MA, Ruddell RG, Ramm GA. Role of iron in hepatic fibrosis: one piece in the puzzle. World J Gastroenterol 13: 4746–4754, 2007.[Medline]
129. Philippidis P, Mason JC, Evans BJ, Nadra I, Taylor KM, Haskard DO, Landis RC. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ Res 94: 119–126, 2004.[Abstract/Free Full Text]
130. Pietrangelo A. Iron-induced oxidant stress in alcoholic liver fibrogenesis. Alcohol 30: 121–129, 2003.[CrossRef][Web of Science][Medline]
131. Pugh C, Hathwar V, Richards JH, Stonehuerner J, Ghio AJ. Disruption of iron homeostasis in the lungs of transplant patients. J Heart Lung Transplant 24: 1821–1827, 2005.[CrossRef][Medline]
132. Quasney MW, Waterer GW, Dahmer MK, Kron GK, Zhang Q, Kessler LA, Wunderink RG. Association between surfactant protein B +1580 polymorphism and the risk of respiratory failure in adults with community-acquired pneumonia. Crit Care Med 32: 1115–1119, 2004.[CrossRef][Web of Science][Medline]
133. Quasney MW, Waterer GW, Dahmer MK, Turner D, Zhang Q, Cantor RM, Wunderink RG. Intracellular adhesion molecule Gly241Arg polymorphism has no impact on ARDS or septic shock in community-acquired pneumonia. Chest 121: 85S-86S, 2002.[CrossRef][Web of Science][Medline]
134. Quinlan GJ, Chen Y, Evans TW, Gutteridge JM. Iron signalling regulated directly and through oxygen: implications for sepsis and the acute respiratory distress syndrome. Clin Sci (Lond) 100: 169–182, 2001.[Medline]
135. Quinlan GJ, Evans TW, Gutteridge JM. Oxidative damage to plasma proteins in adult respiratory distress syndrome. Free Radic Res 20: 289–298, 1994.[Web of Science][Medline]
136. Quinlan GJ, Evans TW, Gutteridge JM. Iron and the redox status of the lungs. Free Radic Biol Med 33: 1306–1313, 2002.[CrossRef][Web of Science][Medline]
137. Quinlan GJ, Lamb NJ, Evans TW, Gutteridge JM. Plasma fatty acid changes and increased lipid peroxidation in patients with adult respiratory distress syndrome. Crit Care Med 24: 241–246, 1996.[CrossRef][Web of Science][Medline]
138. Quinlan GJ, Mumby S, Martin GS, Bernard GR, Gutteridge JM, Evans TW. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit Care Med 32: 755–759, 2004.[CrossRef][Web of Science][Medline]
139. Quinlan GJ, Mumby S, Pepper J, Gutteridge JM. Plasma 4-hydroxy-2-nonenal levels during cardiopulmonary bypass, and their relationship to the iron-loading of transferrin. Biochem Mol Biol Int 34: 1277–1282, 1994.[Web of Science][Medline]
140. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME. Global variation in copy number in the human genome. Nature 444: 444–454, 2006.[CrossRef][Medline]
141. Reeder BJ, Svistunenko DA, Cooper CE, Wilson MT. The radical and redox chemistry of myoglobin and hemoglobin: from in vitro studies to human pathology. Antioxid Redox Signal 6: 954–966, 2004.[Medline]
142. Reid D, Snell G, Ward C, Krishnaswamy R, Ward R, Zheng L, Williams T, Walters H. Iron overload and nitric oxide-derived oxidative stress following lung transplantation. J Heart Lung Transplant 20: 840–849, 2001.[CrossRef][Web of Science][Medline]
143. Ren H, Leib SL, Ferriero DM, Tauber MG, Christen S. Induction of haem oxygenase-1 causes cortical non-haem iron increase in experimental pneumococcal meningitis: evidence that concomitant ferritin up-regulation prevents iron-induced oxidative damage. J Neurochem 100: 532–544, 2007.[CrossRef][Medline]
144. Ritter C, da Cunha AA, Echer IC, Andrades M, Reinke A, Lucchiari N, Rocha J, Streck EL, Menna-Barreto S, Moreira JC, Dal Pizzol F. Effects of N-acetylcysteine plus deferoxamine in lipopolysaccharide-induced acute lung injury in the rat. Crit Care Med 34: 471–477, 2006.[CrossRef][Medline]
145. Rohde KH, Dyer DW. Mechanisms of iron acquisition by the human pathogens Neisseria meningitidis and Neisseria gonorrhoeae. Front Biosci 8: d1186–d1218, 2003.[Medline]
146. Rother RP, Bell L, Hillmen P, Gladwin MT. The clinical sequelae of intravascular hemolysis and extracellular plasma hemoglobin: a novel mechanism of human disease. JAMA 293: 1653–1662, 2005.[Abstract/Free Full Text]
147. Rubenfeld GD, Caldwell E, Peabody E, Weaver J, Martin DP, Neff M, Stern EJ, Hudson LD. Incidence and outcomes of acute lung injury. N Engl J Med 353: 1685–1693, 2005.[Abstract/Free Full Text]
148. Ryter SW, Alam J, Choi AM. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 86: 583–650, 2006.[Abstract/Free Full Text]
149. Schaer CA, Schoedon G, Imhof A, Kurrer MO, Schaer DJ. Constitutive endocytosis of CD163 mediates hemoglobin-heme uptake and determines the noninflammatory and protective transcriptional response of macrophages to hemoglobin. Circ Res 99: 943–950, 2006.[Abstract/Free Full Text]
150. Sharkey RA, Donnelly SC, Connelly KG, Robertson CE, Haslett C, Repine JE. Initial serum ferritin levels in patients with multiple trauma and the subsequent development of acute respiratory distress syndrome. Am J Respir Crit Care Med 159: 1506–1509, 1999.[Abstract/Free Full Text]
151. Sheikh N, Dudas J, Ramadori G. Changes of gene expression of iron regulatory proteins during turpentine oil-induced acute-phase response in the rat. Lab Invest 87: 713–725, 2007.[CrossRef][Medline]
152. Silverboard H, Aisiku I, Martin GS, Adams M, Rozycki G, Moss M. The role of acute blood transfusion in the development of acute respiratory distress syndrome in patients with severe trauma. J Trauma 59: 717–723, 2005.[Web of Science][Medline]
153. Sittipunt C, Steinberg KP, Ruzinski JT, Myles C, Zhu S, Goodman RB, Hudson LD, Matalon S, Martin TR. Nitric oxide and nitrotyrosine in the lungs of patients with acute respiratory distress syndrome. Am J Respir Crit Care Med 163: 503–510, 2001.[Abstract/Free Full Text]
154. Skrabal CA, Khosravi A, Choi YH, Kaminski A, Westphal B, Steinhoff G, Liebold A. Pericardial suction blood separation attenuates inflammatory response and hemolysis after cardiopulmonary bypass. Scand Cardiovasc J 40: 219–223, 2006.[CrossRef][Medline]
155. Slebos DJ, Ryter SW, van der Toorn M, Liu F, Guo F, Baty CJ, Karlsson JM, Watkins SC, Kim HP, Wang X, Lee JS, Postma DS, Kauffman HF, Choi AM. Mitochondrial localization and function of heme oxygenase-1 in cigarette smoke-induced cell death. Am J Respir Cell Mol Biol 36: 409–417, 2007.[Abstract/Free Full Text]
156. Sun J, Hoshino H, Takaku K, Nakajima O, Muto A, Suzuki H, Tashiro S, Takahashi S, Shibahara S, Alam J, Taketo MM, Yamamoto M, Igarashi K. Hemoprotein Bach1 regulates enhancer availability of heme oxygenase-1 gene. EMBO J 21: 5216–5224, 2002.[CrossRef][Web of Science][Medline]
157. Suttner DM, Dennery PA. Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 13: 1800–1809, 1999.[Abstract/Free Full Text]
158. Svenmarker S, Engstrom KG. The inflammatory response to recycled pericardial suction blood and the influence of cell-saving. Scand Cardiovasc J 37: 158–164, 2003.[CrossRef][Web of Science][Medline]
159. Sznajder JI, Fraiman A, Hall JB, Sanders W, Schmidt G, Crawford G, Nahum A, Factor P, Wood LD. Increased hydrogen peroxide in the expired breath of patients with acute hypoxemic respiratory failure. Chest 96: 606–612, 1989.[CrossRef][Web of Science][Medline]
160. Tampo Y, Kotamraju S, Chitambar CR, Kalivendi SV, Keszler A, Joseph J, Kalyanaraman B. Oxidative stress-induced iron signaling is responsible for peroxide-dependent oxidation of dichlorodihydrofluorescein in endothelial cells: role of transferrin receptor-dependent iron uptake in apoptosis. Circ Res 92: 56–63, 2003.[Abstract/Free Full Text]
161. Tanaka K, Kanamori Y, Sato T, Kondo C, Katayama Y, Yada I, Yuasa H, Kusagawa M. Administration of haptoglobin during cardiopulmonary bypass surgery. ASAIO Trans 37: M482–M483, 1991.[Medline]
162. Tavill AS, Qadri AM. Alcohol and iron. Semin Liver Dis 24: 317–325, 2004.[CrossRef][Medline]
163. Taylor C, Rogers G, Goodman C, Baynes RD, Bothwell TH, Bezwoda WR, Kramer F, Hattingh J. Hematologic, iron-related, and acute-phase protein responses to sustained strenuous exercise. J Appl Physiol 62: 464–469, 1987.[Abstract/Free Full Text]
164. Taylor JG, Ackah D, Cobb C, Orr N, Percy MJ, Sachdev V, Machado R, Castro O, Kato GJ, Chanock SJ, Gladwin MT. Mutations and polymorphisms in hemoglobin genes and the risk of pulmonary hypertension and death in sickle cell disease. Am J Hematol 83: 6–14, 2007.[Web of Science]
165. Thomson L, Christie J, Vadseth C, Lanken PN, Fu X, Hazen SL, Ischiropoulos H. Identification of immunoglobulins that recognize 3-nitrotyrosine in patients with acute lung injury after major trauma. Am J Respir Cell Mol Biol 36: 152–157, 2007.[Abstract/Free Full Text]
166. Treggiari MM, Hudson LD, Martin DP, Weiss NS, Caldwell E, Rubenfeld G. Effect of acute lung injury and acute respiratory distress syndrome on outcome in critically ill trauma patients. Crit Care Med 32: 327–331, 2004.[CrossRef][Web of Science][Medline]
167. Tsuji Y, Torti SV, Torti FM. Activation of the ferritin H enhancer, FER-1, by the cooperative action of members of the AP1 and Sp1 transcription factor families. J Biol Chem 273: 2984–2992, 1998.[Abstract/Free Full Text]
168. Turi JL, Yang F, Garrick MD, Piantadosi CA, Ghio AJ. The iron cycle and oxidative stress in the lung. Free Radic Biol Med 36: 850–857, 2004.[CrossRef][Web of Science][Medline]
169. Upton RL, Chen Y, Mumby S, Gutteridge JM, Anning PB, Nicholson AG, Evans TW, Quinlan GJ. Variable tissue expression of transferrin receptors: relevance to acute respiratory distress syndrome. Eur Respir J 22: 335–341, 2003.[Abstract/Free Full Text]
170. Valko M, Morris H, Cronin MT. Metals, toxicity and oxidative stress. Curr Med Chem 12: 1161–1208, 2005.[CrossRef][Web of Science][Medline]
171. Wagener FA, Eggert A, Boerman OC, Oyen WJ, Verhofstad A, Abraham NG, Adema G, van Kooyk Y, de Witte T, Figdor CG. Heme is a potent inducer of inflammation in mice and is counteracted by heme oxygenase. Blood 98: 1802–1811, 2001.[Abstract/Free Full Text]
172. Wallander ML, Leibold EA, Eisenstein RS. Molecular control of vertebrate iron homeostasis by iron regulatory proteins. Biochim Biophys Acta 1763: 668–689, 2006.[Medline]
173. Walter PB, Fung EB, Killilea DW, Jiang Q, Hudes M, Madden J, Porter J, Evans P, Vichinsky E, Harmatz P. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol 135: 254–263, 2006.[CrossRef][Medline]
174. Weiss G. Pathogenesis and treatment of anaemia of chronic disease. Blood Rev 16: 87–96, 2002.[CrossRef][Web of Science][Medline]
175. Weiss G. Modification of iron regulation by the inflammatory response. Best Pract Res Clin Haematol 18: 183–201, 2005.[Medline]
176. Wheeler AP, Bernard GR. Treating patients with severe sepsis. N Engl J Med 340: 207–214, 1999.[Free Full Text]
177. Wippermann J, Albes JM, Hartrumpf M, Kaluza M, Vollandt R, Bruhin R, Wahlers T. Comparison of minimally invasive closed circuit extracorporeal circulation with conventional cardiopulmonary bypass and with off-pump technique in CABG patients: selected parameters of coagulation and inflammatory system. Eur J Cardiothorac Surg 28: 127–132, 2005.[Abstract/Free Full Text]
178. Wright RM, Ginger LA, Kosila N, Elkins ND, Essary B, McManaman JL, Repine JE. Mononuclear phagocyte xanthine oxidoreductase contributes to cytokine-induced acute lung injury. Am J Respir Cell Mol Biol 30: 479–490, 2004.[Abstract/Free Full Text]
179. Xiong S, She H, Takeuchi H, Han B, Engelhardt JF, Barton CH, Zandi E, Giulivi C, Tsukamoto H. Signaling role of intracellular iron in NF-B activation. J Biol Chem 278: 17646–17654, 2003.[Abstract/Free Full Text]
180. Yang F, Haile DJ, Berger FG, Herbert DC, Van Beveren E, Ghio AJ. Haptoglobin reduces lung injury associated with exposure to blood. Am J Physiol Lung Cell Mol Physiol 284: L402–L409, 2003.[Abstract/Free Full Text]
181. Ye SQ, Simon BA, Maloney JP, Zambelli-Weiner A, Gao L, Grant A, Easley RB, McVerry BJ, Tuder RM, Standiford T, Brower RG, Barnes KC, Garcia JG. Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury. Am J Respir Crit Care Med 171: 361–370, 2005.[Abstract/Free Full Text]
182. Yu Y, Kovacevic Z, Richardson DR. Tuning cell cycle regulation with an iron key. Cell Cycle 6: 1982–1994, 2007.[Medline]
183. Zhai R, Gong MN, Zhou W, Thompson TB, Kraft P, Su L, Christiani DC. Genotypes and haplotypes of the VEGF gene are associated with higher mortality and lower VEGF plasma levels in patients with ARDS. Thorax 62: 718–722, 2007.[Abstract/Free Full Text]
184. Zhai R, Zhou W, Gong MN, Thompson BT, Su L, Yu C, Kraft P, Christiani DC. Inhibitor kappaB-alpha haplotype GTC is associated with susceptibility to acute respiratory distress syndrome in Caucasians. Crit Care Med 35: 893–898, 2007.[CrossRef][Medline]
185. Zhao G, Ayene IS, Fisher AB. Role of iron in ischemia-reperfusion oxidative injury of rat lungs. Am J Respir Cell Mol Biol 16: 293–299, 1997.[Abstract]
186. Zhu S, Ware LB, Geiser T, Matthay MA, Matalon S. Increased levels of nitrate and surfactant protein A nitration in the pulmonary edema fluid of patients with acute lung injury. Am J Respir Crit Care Med 163: 166–172, 2001.[Abstract/Free Full Text]

This article has been cited by other articles:

				L. Gao and K. C. Barnes Recent advances in genetic predisposition to clinical acute lung injury Am J Physiol Lung Cell Mol Physiol, May 1, 2009; 296(5): L713 - L725. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 294/2/L161    most recent 00169.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lagan, A. L. Articles by Quinlan, G. J. Search for Related Content PubMed PubMed Citation Articles by Lagan, A. L. Articles by Quinlan, G. J.