FIGURE 10.

Proposed mechanism of hyperoxia-induced lethality in NLRP3^−/− mice. In WT mice, hyperoxia induces infiltration of macrophages and neutrophils into the lungs via the chemokines CCL2 and CXCL1. These infiltrated inflammatory cells increase Stat3 activation through humoral factors. Activated Stat3 increases and decreases transcription of Bcl-2 and MMP-9, respectively; this may in turn attenuate lung injury. In NLRP3^−/− mice, infiltration of macrophages and neutrophils decreases because of reduced expression of CCL2 and CXCL1 and impaired migration of neutrophils. Therefore, Stat3 activation is reduced and inappropriately regulates Bcl-2 and MMP-9, thereby impairing the protective mechanism of hyperoxia-induced lung injury and increasing lethality.