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

Eric P. Schmidt, Mahendra Damarla, Otgonchimeg Rentsendorj, Laura E. Servinsky, Bing Zhu, Aigul Moldobaeva, Alfredo Gonzalez, Paul M. Hassoun, David B. Pearse

Research output: Contribution to journalArticlepeer-review

Abstract

High tidal volume (HVT) ventilation causes pulmonary endothelial barrier dysfunction. HVT ventilation also increases lung nitric oxide (NO) and cGMP. NO contributes to HVT 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 VT. Ventilation with 20 ml/kg VT for 80 min increased the filtration coefficient (K f), an index of vascular permeability. The increased cGMP and K f caused by HVT 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 Kf, suggesting an injurious role for sGC-derived cGMP. sGC inhibition also attenuated lung Evans blue dye albumin extravasation and wetto-dry weight ratio in an anesthetized mouse model of HVT injury. Additional activation of sGC (1.5 μMBAY 41-2272) in isolated lungs at 40 min increased cGMP production and K f in lungs ventilated with 15 ml/kg VT. HVT 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 VT-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 HVT-induced endothelial barrier dysfunction resulted from a simultaneous increase in NO/sGC-derived cGMP and PDE2A expression causing decreased cAMP.

Original languageEnglish (US)
Pages (from-to)L1056-L1065
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume295
Issue number6
DOIs
StatePublished - Dec 2008

Keywords

  • Adenosine 3′,5′-cyclic monophosphate
  • Atrial natriuretic peptide
  • Endothelial permeability
  • Guanosine 3′,5′-cyclic monophosphate
  • Nitric oxide
  • Phosphodiesterase 2A

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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