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This Article Full Text Full Text (PDF) All Versions of this Article: 295/6/L1056    most recent 90329.2008v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Schmidt, E. P. Articles by Pearse, D. B. Search for Related Content PubMed PubMed Citation Articles by Schmidt, E. P. Articles by Pearse, D. B.

Soluble guanylyl cyclase contributes to ventilator-induced lung injury in mice

¹Division of Pulmonary and Critical Care Medicine, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland; ²Center for Lung Biology, The University of South Alabama College of Medicine, Mobile, Alabama

Submitted 31 May 2008 ; accepted in final form 7 October 2008

High tidal volume (HV_T) ventilation causes pulmonary endothelial barrier dysfunction. HV_T ventilation also increases lung nitric oxide (NO) and cGMP. NO contributes to HV_T lung injury, but the role of cGMP is unknown. In the current study, ventilation of isolated C57BL/6 mouse lungs increased perfusate cGMP as a function of V_T. Ventilation with 20 ml/kg V_T for 80 min increased the filtration coefficient (K_f), an index of vascular permeability. The increased cGMP and K_f caused by HV_T were attenuated by nitric oxide synthase (NOS) inhibition and in lungs from endothelial NOS knockout mice. Inhibition of soluble guanylyl cyclase (sGC) in wild-type lungs (10 µM ODQ) also blocked cGMP generation and inhibited the increase in K_f, suggesting an injurious role for sGC-derived cGMP. sGC inhibition also attenuated lung Evans blue dye albumin extravasation and wet-to-dry weight ratio in an anesthetized mouse model of HV_T injury. Additional activation of sGC (1.5 µM BAY 41-2272) in isolated lungs at 40 min increased cGMP production and K_f in lungs ventilated with 15 ml/kg V_T. HV_T endothelial barrier dysfunction was attenuated with a nonspecific phosphodiesterase (PDE) inhibitor (100 µM IBMX) as well as an inhibitor (10 µM BAY 60-7550) specific for the cGMP-stimulated PDE2A. Concordantly, we found a V_T-dependent increase in lung cAMP hydrolytic activity and PDE2A protein expression with a decrease in lung cAMP concentration that was blocked by BAY 60-7550. We conclude that HV_T-induced endothelial barrier dysfunction resulted from a simultaneous increase in NO/sGC-derived cGMP and PDE2A expression causing decreased cAMP.

nitric oxide; guanosine 3',5'-cyclic monophosphate; phosphodiesterase 2A; adenosine 3',5'-cyclic monophosphate; atrial natriuretic peptide; endothelial permeability