Leukemia inhibitory factor signaling is required for lung protection during pneumonia1

• Published in: The Journal of immunology (1950) 2012-05, Vol.188 (12), p.6300-6308
• Main Authors: Quinton, Lee J., Mizgerd, Joseph P., Hilliard, Kristie L., Jones, Matthew R., Kwon, Candice Y., Allen, Eri
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200256

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 leukemia inhibitory factor (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 to 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 to 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 amongst other processes relevant to tissue injury. From these findings, we conclude that endogenous LIF facilitates tissue protection during pneumonia. The LIF-STAT3 axis is here identified as a critical determinant of lung injury with clinical implications for pneumonia patients.