Lung
infections represent a tremendous disease burden and a leading cause of
acute lung injury. STAT3 signaling is essential for controlling
lung injury during
pneumonia. We previously identified LIF as a prominent STAT3-activating
cytokine expressed in the airspaces of pneumonic lungs, but its physiological significance in this setting has never been explored. To do so, Escherichia coli was intratracheally instilled into C57BL/6 mice in the presence of neutralizing anti-LIF
IgG or control
IgG. Anti-LIF completely eliminated lung LIF detection and markedly exacerbated
lung injury compared with control mice as evidenced by airspace
albumin content, lung liquid accumulation, and histological analysis. Although lung bacteriology was equivalent between groups,
bacteremia was more prevalent with anti-LIF treatment, suggestive of compromised barrier function rather than impaired antibacterial defense as the cause of dissemination. Inflammatory
cytokine expression was also exaggerated in anti-LIF-treated lungs, albeit after injury had ensued. Interestingly, alveolar neutrophil recruitment was modestly but significantly reduced compared with control mice despite elevated
cytokine levels, indicating that inflammatory injury was not a consequence of excessive neutrophilic alveolitis. Lastly, the lung transcriptome was dramatically remodeled during
pneumonia, but far more so following LIF neutralization, with gene changes implicating cell death and epithelial homeostasis among other processes relevant to tissue injury. From these findings, we conclude that endogenous LIF facilitates tissue protection during
pneumonia. The LIF-STAT3 axis is identified in this study as a critical determinant of
lung injury with clinical implications for
pneumonia patients.