Hypoxia induces IL-18 and neutrophil influx in lung parenchyma possibly mediated by MIP-2

Background: Increased levels of interleukin (IL)-18 have been found during experimental alveolar hypoxia and IL-18 have previously been shown to induce neutrophil migration, production of macrophage inflammatory protein 2 (MIP-2) and enhanced neutrophil functions (Verri, W.A. et al. Eur J Immunol 2007; 37:3373-80, Kinoshita, M. et al. Infect Immun. 2011; 79:2670-80). Aims: To study circulating levels of IL-18 during one week of hypoxia exposure in mice, and to investigate whether induction of IL-18 corresponds with inflammatory changes in lung parenchyma. Methods: IL-18 levels in blood was determined in C57Bl/6j mice (n=4 at each time point) exposed to hypoxic conditions at 6 hours (h) and 1-7 days. Lungs were harvested at each time point for histological analyses. Concentration of MIP-2 in blood was determined at 6h, 12h, 1-3 days. Results: The levels of circulating IL-18 were significantly increased at all time points peaking at day 1 (Figure 1A) compared to normoxic controls. Histology revealed perivascular infiltration of neutrophil granulocytes increasing from day 1 to day 3. At day 7 neutrophils were still present, but to a lesser extent than at day 3. The concentration of MIP-2 was significantly increased at day 1 (Figure 1B). Conclusions: The increase in IL-18 induced by alveolar hypoxia may promote the subsequent influx of neutrophils in lung parenchyma, possibly mediated through the neutrophil chemoattractant MIP-2.