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Soluble guanylyl cyclase and phosphodiesterase 2A contribute to lung injury from intra‐tracheal LPS in mice
Author(s) -
Rentsendorj Otgonchimeg,
Schmid Eric P,
D'Alessio Franco R,
Aggarwal Neil R,
Stephens R Scott,
Servinsky Laura E,
Pearse David P
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.lb159
Subject(s) - soluble guanylyl cyclase , lipopolysaccharide , bronchoalveolar lavage , nitric oxide , pharmacology , enos , chemistry , umbilical vein , nitric oxide synthase , phosphodiesterase , peroxynitrite , lung , immunology , medicine , in vitro , biochemistry , enzyme , superoxide , guanylate cyclase
In animal models of lipopolysaccharide‐induced acute lung injury (LPS‐ALI), increased NO production from endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) contributes to alveolitis and epithelial barrier dysfunction. The toxic effects of NO have been attributed to peroxynitrite, but NO also generates cGMP through soluble guanylyl cyclase (sGC). Cytokines have been shown to increase human umbilical vein endothelial expression of phosphodiesterase 2A (PDE2A) in vitro (Surapisitchat et al. Circ Res 2007). PDE2A is a dual‐function PDE stimulated by cGMP to hydrolyze cAMP, a potent barrier‐protective molecule. We hypothesized that sGC and PDE2A contribute to LPS‐ALI. To test this, we administered intratracheal LPS (3.75 μg/g body weight) or diluent to anesthetized C57BL6 mice pretreated with the sGC inhibitor ODQ (10 mg/kg ip 1 hr before), the PDE2A inhibitor BAY 60‐7550 (3 mg/kg 1 hr before) or intraperitoneal (ip) diluent. At 6 hrs, the mice were reanesthetized for unilateral bronchoalveolar lavage (BAL) and lung harvesting. LPS increased BAL leukocytes, LDH and protein indicating alveolitis. LPS also increased lung Ser 1177 eNOS phosphorylation, iNOS mRNA and PDE2A mRNA and protein expression. LPS did not alter sGC expression. sGC inhibition significantly attenuated the LPS‐induced increase in iNOS mRNA, BAL leukocytes and BAL LDH activity indicating an injurious role for sGC‐derived cGMP. PDE2A inhibition decreased iNOS mRNA and BAL LDH activity suggesting that PDE2A was also involved. We conclude that LPS‐induced activation of sGC in combination with LPS‐induced PDE2A expression contribute to LPS‐ALI in mice. Supported by AHA Grant‐In‐Aid