Growth Hormone Releasing Peptide-2, a Ghrelin Agonist, Attenuates Lipopolysaccharide-Induced Acute Lung Injury in Rats

Abstract

Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are the most common complications of sepsis, and the mortality of sepsis-induced ALI remains high in critically ill patients. Growth hormone releasing peptide-2 (GHRP-2), a ghrelin agonist, has been shown to exert beneficial effects on various inflammatory diseases. We therefore explored whether GHRP-2 possesses anti-inflammatory properties in the pathogenesis of lipopolysaccharide (LPS)-induced ALI. Male Sprague-Dawley rats were intratracheally instilled with LPS (2 mg/kg) to induce ALI. ALI was confirmed with lung tissue injury (histopathological examination), enhanced lung edema (wet-to-dry weight ratio), and neutrophil infiltration (myeloperoxidase activity) at 6 h after LPS exposure. The analyses of bronchoalveolar lavage fluid showed the significant increases in pulmonary permeability (total cells and protein) and the levels of proinflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). In contrast, these lung injury indexes were attenuated in rats that received a subcutaneous injection of GHRP-2 (100 microg/kg) 0.5 h prior to LPS administration. To further explore the potential anti-inflammatory mechanism of GHRP-2 in LPS-induced ALI, we assessed of nuclear factor-kappaB (NF-kappaB) activity in lung tissues at 6 h after LPS challenge. We thus found that pretreatment with GHRP-2 markedly suppressed the activation of NF-kappaB in lung tissues. These results indicate that GHRP-2 attenuated LPS-induced ALI. Early protection appears to be mediated partly through the inhibition of NF-kappaB pathway activation. The present study indicates that GHRP-2 acts as a potential therapeutic reagent for treating ALI.