Protective Effects Of Keratinocyte Growth Factor-2 On Lipopolysacchride-induced Acute Lung Injury And Its Potential Mechanisms

Background:Keratinocyte growth factor-2(KGF-2)plays an essential role in survival,proliferation, and differentiation of distal-alveolar epithelial progenitor cells during lung development.We investigated the role of recombinant human KGF-2(rhKGF-2)in protecting against acute lung injury caused by lipopolysacchride (LPS) and its potential mechanisms.Methods:LPS(5mg/kg) was administrated intratracheally to induce acute lung injury in rats.Single dose of rhKGF-2(5 mg/kg)was Intratracheally instilled 1,2,3, or 5 days before LPS challenge. Lung injury was measured by arterial blood gas analysis, lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in bronchoalveolar lavage fluid (BALF),and histological analysis.TNF-a and MIP-2 levels were measured in BALF.The mRNA expression level of IL-1βand IL-6 in lung tissue were analysed by quantitative PCR.Western blotting, quantitative PCR, and immunohistochemistry was done to assess expression of surfactant proteins and alveolar typeⅡepithelial cells proliferation.Results:LPS instillation resulted in significantly decreased PaO2,and elevated lung wet-to-dry weight ratio, total protein, number of leukocytes and neutrophils in BALF, lung injury score.Pretreatment of rhKGF-2 resulted in a significant improvement in the above lung injury parameters, and pretreatment given 2 to 3 days before LPS challenge showed evident improvement in lung injury.LPS induced significant elevation of TNF-a and MIP-2 in BALF, and mRNA expression level of IL-1βand IL-6 in lung tissue, whereas pretreatment with rhKGF-2 markedly reduced the levels of TNF-a, MIP-2,IL-1βand IL-6. LPS instillation significantly inhibited the expression of surfactant protein A (SPA),surfactant protein B (SPB),and surfactant protein C(SPC)in lung tissue, while pretreatment of rhKGF-2 partially restored SPA and SPC expression. Furthermore,the improved lung injury was accompanied by increased proportion of alveolar typeⅡepithelial cells in lung parenchyma.Conclusion:Topical administration of rhKGF-2 attenuates lung injury induced by LPS, suggesting that rhKGF-2 may be potent as a novel strategy to the treatment of acute lung injury.