The pivotal role of HIF-1α in lung inflammatory injury induced by septic mesenteric lymph

Hypoxia inducible factor-1α (HIF-1α) plays an essential role in hypoxia and inflammatory response. Oxygen metabolic dysfunction and cascade amplification of inflammatory response are prominent pathophysiological characteristics in sepsis induced acute lung injury (ALI).In this study, we started with septic mesenteric lymph injection model to investigate whether HIF-1α played a role in the pathogenesis of ALI induced by septic lymph. The data demonstrated that rats injected with septic lymph showed a significant higher Lung Injury Scale and MPO(myeloperoxidase) levels than that of rats injected with normal saline/lymph. ALI was associated with a higher degree of HIF-1α expression in the lungs infused by septic lymph. Intratracheal delivery of YC-1(3-(5′-hydroxymethyl-2′-furyl)-1-benzylindazole) significantly attenuated lung inflammatory damages.Furthermore, in vitro studies, human alveolar type II epithelial cell (A549)/human pulmonary microvascular endothelial cell (HPMEC) incubated by septic lymph showed dramatically decreased cell viability, higher levels of inflammatory cytokines (TNF-α, IL-6 and IL-1β) and excitation of HIF-1α expression (Immunofluorescence localization/RT-PCR test) simultaneously. Nevertheless, compared with the non-silencing cell lines, A549/HPMEC with HIF-1α gene silencing manifested increased viability and restrained cytokines' expression after incubation with septic lymph.These results indicate that HIF-1α expression can be induced and activated in rats during the acute lung inflammatory damages triggered by septic lymph injection and that lung inflammatory injuries occur via a HIF-1α-dependent pathway.