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A2250 - Role of Natriuretic Peptide Receptor C in Mediating the Protective Effect of Atrial Natriuretic Peptide on Acute Lung Injury
Author Block: A. Kumar1, C. Dado2, J. Braza1, J. R. Klinger3, E. O. Harrington4; 1Medicine, Brown University, Providence, RI, United States, 2PCCM, Providence, RI, United States, 3Rhode Island Hosp, Providence, RI, United States, 4Providence VA Med Ctr, Brown Med Sch, Providence, RI, United States.
Introduction: Atrial Natriuretic Peptide (ANP) attenuates acute lung injury (ALI) in a number of animal models, but the receptor that mediates the protective effect of ANP is not known. Previously, we found that ANP blunted thrombin-induced lung injury in mice with genetic deletion of natriuretic peptide receptor-A (NPR-A), suggesting that ANP may act through NPR-C. The present study investigated the protective effect of ANP on ALI in mice with genetic deletion of NPR-C.
Methods: ALI was induced by intra-tracheal (IT) administration of Pseudomonas aeruginosa (PA103) (107 CFU/mice). Four hours later, ALI was evaluated by measuring a) lung wet/dry weight ratio (W/D), b) protein concentration and c) inflammatory cell counts in bronchoalveolar lavage fluid (BALF). ANP was administered by intravenous (IV) infusion starting 30 min before lung injury and continuing for 30 or 120 min after administration of PA103 or saline vehicle using different protocols. Wild-type (WT), heterozygous (HET), or knockout mice (KO) mice, i.e. mice with 2, 1, or 0 functional genes for Npr3 ( the gene that encodes for NPR-C in mice) were subjected to four different treatments: a) Saline (IT)/Saline (IV), b) Saline (IT)/ANP (IV), c) PA103 (IT)/saline (IV), or d) PA103 (IT)/ANP (IV). In separate groups of animals, plasma ANP levels were measured 4 hours after starting one of the following a) no ANP infused, or ANP infusion for b) 60 min, c) 90 min, or d) 150 min.
Results: Compared to saline vehicle alone, PA103-induced significant increases in W/D and BALF protein and cell concentration in all 3 genotypes. ANP infusion for 60 min did not blunt the PA103-induced increase in W/D in any genotype, but reduced PA103-induced increases in BALF protein and cell concentration in WT mice. ANP infusion for 150 min blunted PA103-induced increases in W/D and BALF protein concentration in all 3 genotypes, but blunted the increased in BALF cell count only in WT mice. Plasma ANP levels 4 hrs post infusion were higher in mice given 150 min infusion than no ANP infusion, but not in mice given 60 or 90 min ANP infusion.
Conclusion: The protective effect of ANP on pulmonary edema formation (lung W/D ratio) and alveolar protein accumulation is not mediated by NPR-C. However, decreased expression of NPR-C reduces the protective effect of ANP on alveolar cellular infiltration during acute lung injury. Further studies are needed to evaluate the potential for ANP to attenuate ALI in the clinical setting.