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1 Pediatric Pulmonary Medicine, Pediatric Heart Lung Center, Department of Pediatrics, 3 Department of Pathology, and 4 Pulmonary Hypertension Center, University of Colorado School of Medicine, Denver, Colorado 80218; and 2 Sugen Incorporated, South San Francisco, California 94080
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.
bronchopulmonary dysplasia; congenital diaphragmatic hernia; fumagillin; lung growth; lung hypoplasia; pulmonary circulation; pulmonary hypertension; thalidomide; vascular endothelial growth factor
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NORMAL DEVELOPMENT of the human lung can be divided into five stages: embryonic (3-7 wk gestation), pseudoglandular (5-17 wk), canalicular (16-26 wk), saccular (24-38 wk), and alveolar (up to 2-3 yr of age) (7, 13, 16, 24, 29, 41, 42). Although these periods of lung development are similar across mammalian species, the relative timing and length of each stage varies between species. In the rat, alveolarization begins during late gestation but primarily occurs during the first 2 wk after birth (29). Alveoli are formed by the septation of large saccules that constitute the gas-exchange region of the immature lung during this critical period of lung growth. Secondary septae form as ridges that grow into distal air spaces, thereby increasing lung surface area and enhancing the capacity for gas exchange (7). Mechanisms that regulate alveolarization are poorly understood, but multiple stimuli modulate distal lung growth, including genetic factors, oxygen tension, nutrition, hormones, and autocrine and paracrine growth factors (5-7, 25, 29-31, 41, 42).
During the period of alveolarization, the lung also undergoes marked vascular growth as reflected by the 20-fold increase in alveolar and capillary surface areas from birth to adulthood (49). Lung vascular growth involves two basic processes: vasculogenesis, the formation of new blood vessels from endothelial cells within the mesenchyme, and angiogenesis, the formation of new blood vessels from sprouts of preexisting vessels (7, 14, 40, 41). Mechanisms that increase vascular surface area during late gestation and the early postnatal period are poorly understood, but it is clear that coordination of distal air space and vascular growth is essential for normal lung development. For example, the production and timing of the release from respiratory epithelial cells of angiogenic factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor are likely to play key roles in normal lung vascular growth (2-4, 17, 33, 36, 38, 41, 42, 48, 51).
Experimental studies (5, 7, 29-31, 39) have shown that adverse stimuli such as hypoxia, hyperoxia, or glucocorticoid treatment during the critical period of postnatal lung growth in the rat can disrupt alveolarization and cause lung hypoplasia. These models of lung hypoplasia are also associated with abnormalities of the pulmonary circulation (25, 26, 39, 44a). In the clinical setting, lung hypoplasia is frequently associated with abnormalities of the pulmonary circulation in diverse diseases, including bronchopulmonary dysplasia (BPD), congenital diaphragmatic hernia, primary lung hypoplasia, and Down's syndrome (1, 8, 11, 28, 45, 47). It is generally presumed that disruption of alveolarization is likely to cause failure of lung vascular growth; whether injury to the developing pulmonary circulation or disruption of normal angiogenesis can also contribute to impaired alveolarization is unknown.
Antiangiogenic therapy with agents such as thalidomide and fumagillin has been studied in diverse experimental settings in order to examine basic mechanisms of angiogenesis and their potential role in pathological settings such as tumor angiogenesis (17, 50). Because fumagillin and thalidomide block angiogenesis by inhibiting endothelial cell proliferation (12, 17, 21, 22, 34, 37), which is critical for angiogenesis, these drugs provide useful pharmacological tools for studying the physiological roles of angiogenesis in different experimental settings. Therefore, to study the role of angiogenesis in postnatal lung growth, we proposed the hypothesis that disruption of angiogenesis during a critical period of lung growth would decrease alveolarization. To test this hypothesis, we studied the effects of fumagillin and thalidomide treatment during a critical period of postnatal lung growth in neonatal rats and report that these agents decrease lung weight, pulmonary arterial density, and alveolarization. Because these agents may have nonspecific effects on lung growth independent of their effects on endothelial cell proliferation, we further tested this hypothesis by treating neonatal rats with an antiangiogenic agent, Su-5416, an inhibitor of the VEGF receptor kinase insert domain-containing/fetal liver kinase (KDR/flk)-1 (18, 43). As observed with fumagillin and thalidomide, we report that Su-5416 treatment also decreased alveolarization and arterial density at 2 wk of age. These findings suggest that angiogenesis is necessary for normal alveolarization during a critical period of lung development in the rat.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Animals
All procedures and protocols used in this study were approved by the Animal Care and Use Committee at the University of Colorado Health Sciences Center. Timed-pregnant, pathogen-free Sprague-Dawley rats were purchased from Harlan Laboratories (Indianapolis, IN). The pregnant rats were maintained at Denver's altitude for at least 1 wk before giving birth. Animals were fed ad libitum and exposed to 12:12-h light-dark cycles.Experimental Design
Daily injections of fumagillin, thalidomide, or vehicle (DMSO) were started 1 day after birth and continued until 13 days of age. Study group assignment was randomized for each litter. All drugs were freshly prepared on the day of study and stored at
20°C for
the remainder of the study period. Fumagillin and thalidomide (Biomol
Technologies, Plymouth Meeting, PA) were dissolved in DMSO before
treatment. In the fumagillin group (n = 22 animals), fumagillin was administered by subcutaneous injection at a dose of 2 mg/kg body wt. Thalidomide (n = 14 animals) was
administered by intraperitoneal injection at a dose of 10 mg/kg. An
equivalent volume of 100% DMSO (Sigma, St. Louis, MO) was administered
to the vehicle control study group (n = 18 animals) by
intraperitoneal injection. Doses and routes of administration were
based on published studies (12, 21, 22) on tumor angiogenesis
and preliminary data from our laboratory. Study rats were killed on
day 14 by intraperitoneal injection of pentobarbital sodium
(0.3 mg/g body weight). Body, lung, and cardiac weights were measured,
and the lungs were prepared for histology and morphometric analysis. At death, the hearts were removed and dissected to isolate the free wall
of the right ventricle from the left ventricle and septum. The ratio of
right ventricle weight to left ventricle plus septum weight (RV/LV+S)
was used as an index of right ventricular hypertrophy.
The same protocol was used to study the effects of Su-5416 (Sugen, South San Francisco, CA), a selective inhibitor of the VEGF receptor KDR/flk-1 (18, 43). Newborn rats (n = 30 animals) from each litter were randomly assigned to treatment with Su-5416 (20 mg/kg) or vehicle control (carboxymethylcellulose), administered by subcutaneous injections on alternate days, beginning on day 1 and continuing through day 13. The dose of Su-5416 was based on a previous study (18) of tumor antiangiogenesis in mice. Study animals were killed, and the lungs were studied as outlined above.
Arterial Density Measurements After Barium Sulfate-Gelatin Infusions
Pulmonary arterial density was measured from lungs that were infused with barium sulfate according to previously established methods (13, 14). Immediately after death, PBS was infused through a main pulmonary artery catheter to flush the pulmonary circulation free of blood. A barium sulfate-gelatin mixture was heated to 70°C and infused into the main pulmonary artery at 74 mmHg. Pressure was maintained for at least 5 min to ensure penetration of the barium mixture. Lung tissue was subsequently fixed for histology as described in Lung Histology and Radial Alveolar Counts or used for arteriograms. Pulmonary arterial density was measured by counting (by two blinded observers) barium-filled arteries per high-power field (×100 magnification) in 8-10 randomly selected fields taken from at least two blocks of tissue.Lung Histology and Radial Alveolar Counts
Lungs were fixed for histology by tracheal instillation of 10% buffered Formalin under constant pressure (20 cmH2O). The tracheae were ligated after sustained inflation, and the lungs were excised and immersed in Formalin overnight. Formalin-fixed lung tissue was cut into 4- to 5-mm-thick sections, placed in 10% buffered Formalin, and embedded in paraffin. Paraffin sections (5 µm thick) were serially mounted onto Superfrost Plus slides (Fisher Scientific, Fair Lawn, NJ) and stained with hematoxylin and eosin. At least three lung sections from each animal were assessed for morphometric analysis. Alveolarization was measured by the radial alveolar counts (RAC) methods of Cooney and Thurlbeck (9-11) and Emory and Mithal (16). Briefly, radial counts were performed by determining the number of septae that intersected a perpendicular line drawn from the center of a respiratory bronchiole to the distal acinus (connective tissue septum or pleura). At least 10 counts were performed on each lung section.Statistical Analysis
Data are presented as means ± SE. Statistical analysis was performed with the Statview software package (Abacus Concepts, Berkeley, CA). Statistical comparisons were made with the use of ANOVA and Fisher's protected least significant difference test. P < 0.05 was considered significant.| |
RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Effects of Thalidomide and Fumagillin Treatment
Lung, body, and cardiac weights.
Body weights were not reduced by fumagillin or thalidomide treatment
compared with weights of control rats (25.3 ± 2.0 g with fumagillin; 30.7 ± 0.6 g with thalidomide; 26.3 ± 1.8 g with vehicle). Lung weights were 0.44 ± 0.02 g
for the fumagillin-treated, 0.41 ± 0.03 g for the
thalidomide-treated, and 0.55 ± 0.06 g for control rats.
Compared with the control group, lung-to-body weight ratios were
reduced by 30 and 38% in the fumagillin and thalidomide treatment groups, respectively (0.017 ± 0.001 with fumagillin; 0.015 ± 0.001 with thalidomide; 0.023 ± 0.002 with vehicle control;
P < 0.05 for control vs. other groups; Fig.
1). Right ventricular mass or hypertrophy
as determined by the RV/LV+S was not different between the drug
treatment and vehicle control groups (0.39 ± 0.01 with
fumagillin; 0.38 ± 0.02 with thalidomide; 0.38 ± 0.02 with
vehicle).
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Pulmonary arterial density after barium sulfate-gelatin infusion.
To determine whether treatment with antiangiogenic agents during a
critical period of lung development could decrease arterial density, we
infused the main pulmonary artery with a barium sulfate-gelatin suspension. Arteriograms from the left lungs of thalidomide- and fumagillin-treated rats showed a decrease in the filling of small pulmonary vessels (a decrease in background haze) compared with arteriograms of control animals (Fig. 2).
The major conduit pulmonary arteries and their branches also appeared
narrow compared with those in control rats, and lung histology revealed
a reduction in the number of barium-filled arteries in the fumagillin-
and thalidomide-treated rats (Fig.
3A). Pulmonary arterial
density, as determined by barium-filled arteries per high-power field, was reduced by 20 and 36% in the fumagillin- and thalidomide-treated rats, respectively, compared with that in control animals (32.0 ± 0.2 with fumagillin; 29.0 ± 0.8 with thalidomide; and 44 ± 0.3 with vehicle; P < 0.05 vs. control group; Fig.
3B).
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Lung histology and RAC.
Lung histology revealed striking differences in lung structure between
the fumagillin and thalidomide groups and the control group. Compared
with vehicle control rat lungs, fumagillin and thalidomide treatment
caused a histological pattern of alveolar simplification
characterized by the presence of larger and fewer distal air spaces
(Fig. 4A). To quantify the
apparent decreases in alveolar number, we measured RAC in the
fumagillin-, thalidomide-, and vehicle-treated groups. Compared with
lungs from control rats, RAC were reduced by 22% in both the
fumagillin- and thalidomide-treated rats (Fig. 4B).
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Effects of Su-5416 Treatment
Compared with vehicle-treated control group, treatment of neonatal rats with Su-5416, a specific inhibitor of the VEGF receptor KDR/flk-1, reduced both lung and body weight (see Table 1). Lung weight was decreased in the Su-5416-treated rats versus control animals (0.49 ± 0.02 vs. 0.33 ± 0.01 g; P < 0.05) as was body weight (33.74 ± 1.36 vs. 21.42 ± 0.77 g; P < 0.05). As demonstrated by light microscopy, Su-5416 treatment altered lung architecture, causing a histological pattern of enlarged distal air spaces ("alveolar simplification") with decreased arterial density (Fig. 5). Su-5416 treatment reduced RAC by 30% (9.8 ± 0.8 in control lungs vs. 6.8 ± 0.7 in treated lungs; P < 0.02; Fig. 6). Barium arteriograms from the left lungs of Su-5416-treated rats showed a decrease in the filling of small pulmonary vessels (Fig. 7). The major conduit pulmonary arteries and their branches were more narrowed compared with those in control animals, and pulmonary arterial density was reduced by Su-5416 treatment (Fig. 8). At the doses used in this study, Su-5416 had a more striking effect on the reduction of arterial density than fumagillin or thalidomide.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Extensive vascular growth accompanies the increase in alveolarization during the critical period of postnatal lung development in young rats, but mechanisms that coordinate alveolarization with growth of the pulmonary circulation are uncertain. We hypothesized that if vascular growth were necessary for the increase in alveolarization during this time period, then disruption of angiogenesis should cause lung hypoplasia. To test this hypothesis, we treated neonatal rats during the critical period of lung growth with three different antiangiogenic agents: thalidomide, fumagillin, and Su-5416. We report that treatment with thalidomide or fumagillin caused a histological pattern of alveolar simplification, reduced RAC and pulmonary arterial density, and decreased lung-to-body weight ratios. These findings support the hypothesis that angiogenesis may be necessary for alveolarization during normal lung development and that adverse stimuli that disrupt vascular growth may contribute to lung hypoplasia. Because thalidomide and fumagillin may have additional effects on lung growth that are independent of their well-established antiangiogenic activities and to determine the potential role of the VEGF receptor KDR/flk-1 during this critical period of postnatal lung growth, we performed a similar protocol with a KDR/flk-1 inhibitor, Su-5416. As observed with the other antiangiogenic agents, Su-5416 treatment reduced alveolarization as determined by RAC and decreased arterial density. These findings suggest that the KDR/flk-1 receptor contributes significantly to vascular growth in the postnatal rat lung and provide additional support for the hypothesis that angiogenesis is necessary for normal alveolarization during the postnatal period of rapid lung growth.
Previous studies (7, 29, 30) have demonstrated that alveoli are formed by the septation of large saccules that constitute the gas-exchange region of the immature lung. Secondary septae are formed by alternate upfolding of one of the two capillary layers on either side of the primary septum (7). The double-capillary network persists until later in maturation when focal fusions lead to the development of a single-capillary layer and thinning of the interstitium (7). This mechanism implies that the failure of capillary growth and maturation or disruption of the upfolding of the double-capillary network could limit alveolarization. Thus we speculate that failure of growth or maturation of the pulmonary circulation during the critical period of alveolarization could potentially decrease septation and cause lung hypoplasia. However, few studies have directly addressed the effects of disrupted angiogenesis on lung development during the neonatal period. Because alveolarization primarily occurs during late gestation and the early postnatal period (30), it is likely that disruption of alveolarization by abnormal intrauterine stimuli, premature birth, postnatal injury, or other mechanisms contributes to this problem. Past studies (5, 6, 29-31, 39) have shown that exposure to dexamethasone, hyperoxia, or hypoxia decreases alveolar number in neonatal rats. Premature infants with BPD and children with lung hypoplasia have distal air spaces that fail to septate, resulting in fewer alveoli and a reduced surface area for gas exchange (28, 32, 47). In BPD, lung injury occurs in premature newborns before the alveolar period of lung development. Several morphometric studies of older infants and children dying with BPD have demonstrated impaired alveolarization and abnormal lung vascular development (28, 47). Because hyperoxia, ventilator-induced stretch injury, inflammation, and hypoxia can directly injure the pulmonary circulation (15, 31, 39), we speculate that disruption of vascular growth early in development may contribute to the subsequent failure of alveolarization during infancy and childhood.
Possible limitations of this study include the potential for
nonspecific effects of thalidomide and fumagillin on the developing lung. Fumagillin, an antibiotic secreted by Aspergillus
fumigatus, and thalidomide, an immunomodulatory drug with sedative
and teratogenic effects, have been shown to inhibit angiogenesis
(12, 17, 21, 22, 34, 37). Thalidomide, known as a
teratogen for its disruption of fetal limb formation (phocomelia), has
been reintroduced as a therapeutic agent for use in macular
degeneration, leprosy, Crohn's disease, Behcet's disease, arthritis,
acquired immunodeficiency syndrome (AIDS), graft versus host lung
disease after bone marrow transplantation, and metastatic cancer
(17). Although thalidomide may inhibit the effects of
tumor necrosis factor-
, recent studies (12, 22) have
also shown that it can inhibit VEGF- and basic fibroblast growth
factor-induced neovascularization in a mouse corneal model. In addition
to thalidomide, fumagillin and its synthetic analog TNP-470 are also
antiangiogenic, and effects on vascular growth have been extensively
studied in diverse experimental settings. Fumagillin may act by binding
endothelial methionine aminopeptidase II (21). Whether
both of these drugs can also reduce alveolarization by direct
inhibition of epithelial growth, elastin production in developing
septae, or related nonvascular mechanisms is unknown.
In contrast, Su-5416 is a potent antagonist of the KDR/flk-1 receptor, has potent inhibitory effects on tumor angiogenesis, and is currently undergoing clinical trials in patients with cancer (18, 43). When used in similar treatment protocols as the other antiangiogenic agents, Su-5416 treatment also inhibits alveolarization. The exact mechanism by which inhibition of endothelial cell proliferation leads to decreased alveolar septation is uncertain; we speculate that these effects may be due to a trophic effect on vascular endothelium, altered production of endothelium-derived products such as nitric oxide or platelet-derived growth factor (PDGF), or other mechanisms (19, 23, 33, 35, 38, 46, 51). In addition to its effects on the KDR/flk-1 receptor, Su-5416 can also block the platelet-derived growth factor receptor at higher concentrations (IC50: 1.5 µm for KDR; 20 µM for PDGF receptor) (44). Whether part of the response to Su-5416 in this study is also in part due to inhibition of PDGF receptors is uncertain. However, a recent study (20) demonstrated that VEGF inhibition with the use of an inducible Cre-loxP-mediated gene-targeting approach or by treatment with a soluble VEGF receptor protein caused growth failure and high mortality in neonatal mice. In addition to reduced body and organ weights, VEGF inhibition also decreased lung weight and altered lung histology. A further study (20) revealed a marked alteration in endothelial cell appearance as viewed by electron microscopy and increased apoptosis, suggesting that VEGF is necessary for endothelial survival as well as for proliferation.
Recently, our laboratory has observed abnormal lung development in the Fawn-Hooded rat (FHR), a genetic strain that develops severe pulmonary hypertension with modest decreases in alveolar PO2 (25). Although the FHR strain has been generally considered as a genetic model of "primary" pulmonary hypertension, our laboratory (25) previously reported that FHR lungs showed a pattern of alveolar simplification and reduced pulmonary arterial density early during maturation. Similarly, in other rat models of lung hypoplasia caused by neonatal dexamethasone treatment (29) or hypoxia (5, 6, 31), pulmonary arterial density is also reduced, and there is an increased risk for late development of pulmonary hypertension (26, 44a). Whether decreased angiogenesis plays a significant role in the development of lung hypoplasia in these models is unknown, but data from this current report support the concept that inhibition of angiogenesis during a critical period of lung growth may contribute to impaired alveolarization.
In summary, we report that treatment of neonatal rats with two different inhibitors of angiogenesis during a critical period of postnatal lung growth caused lung hypoplasia as demonstrated by reduced lung-to-body weight ratios, alveolarization, and pulmonary arterial density. We also report that an inhibitor of the VEGF receptor KDR/flk-1 also reduced alveolarization, further suggesting that disruption of angiogenesis attenuates normal lung development. Based on these findings, we speculate that disruption of angiogenesis impairs alveolarization, suggesting that primary or acquired abnormalities of lung vascular growth can cause or contribute to lung hypoplasia. We further speculate that new strategies that stimulate vascular growth may provide an alternate approach to the treatment of abnormal lung growth in clinical disorders such as BPD and congenital diaphragmatic hernia.
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FOOTNOTES |
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Address for reprint requests and other correspondence: S. H. Abman, Dept. of Pediatrics, B-395, The Children's Hospital, 1056 E. Nineteenth Ave., Denver, CO 80218-1088 (E-mail: steven.abman{at}uchsc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Received 7 January 2000; accepted in final form 10 April 2000.
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TOP
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METHODS
RESULTS
DISCUSSION
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