title: Leukemia inhibitory factor signaling is required for lung protection during pneumonia.
abstract: 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.
authors.affiliation: Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Lee J
authors.initials: LJ
authors.lastname: Quinton
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mizgerd
authors.forename: Kristie L
authors.initials: KL
authors.lastname: Hilliard
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Jones
authors.forename: Candice Y
authors.initials: CY
authors.lastname: Kwon
authors.forename: Eri
authors.initials: E
authors.lastname: Allen
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000276:immunology; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D015151:Immunoblotting; D007150:Immunohistochemistry; D053605:Leukemia Inhibitory Factor / Q000276:immunology / Q000378:metabolism*; D008168:Lung / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000276:immunology / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse