4.6 Article

IFN-beta Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome-related Mortality

Journal

Publisher

AMER THORACIC SOC
DOI: 10.1165/rcmb.2017-0261OC

Keywords

bacterial pneumonia; innate immunity; acute lung injury; immune suppression; IFN-beta

Funding

  1. Ministry of Education, Culture, Sports, Science and Technology-Japan
  2. Japan Society for the Promotion of Science [A232490720001, B24390364, C26462747, 15H06176, 17K17043]
  3. Japan Ministry of Health, Labor and Welfare [H24-Nanchitou [Nanchi]-Ippan-035, H24-Rinkensui-Ippan-003]
  4. National Heart, Lung, and Blood Institute [HL085453]

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IFN-beta is reported to improve survival in patients with acute respiratory distress syndrome (ARDS), possibly by preventing sepsis-induced immunosuppression, but its therapeutic nature in ARDS pathogenesis is poorly understood. We investigated the therapeutic effects of IFN-beta for postseptic ARDS to better understand its pathogenesis in mice. Postseptic ARDS was reproduced in mice by cecal ligation and puncture to induce sepsis, followed 4 days later by intratracheal instillation of Pseudomonas aeruginosa to cause pneumonia with or without subcutaneous administration of IFN-beta 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-alpha and IL-10 concentrations and innate immune reprogramming; specifically, it reduced alveolar macrophage (AM) phagocytosis and KC (CXCL1) secretion. Ex vivo AM exposure to TNF-alpha or IL-10 duplicated cytokine release impairment. Compared with sepsis or pneumonia alone, pneumonia after sepsis was associated with blunted alveolar KC responses and reduced neutrophil recruitment into alveoli despite increased neutrophil burden in lungs (i.e., incomplete alveolar neutrophil recruitment), reduced bacterial clearance, increased lung injury, and markedly increased mortality. Importantly, IFN-beta reversed the TNF-alpha/IL-10-mediated impairment of AM cytokine secretion in vitro, restored alveolar innate immune responsiveness in vivo, improved alveolar neutrophil recruitment and bacterial clearance, and consequently reduced the odds ratio for 7-day mortality by 85% (odds ratio, 0.15; 95% confidence interval, 0.03-0.82; P = 0.045). This mouse model of sequential sepsis -> pneumonia infection revealed incomplete alveolar neutrophil recruitment as a novel pathogenic mechanism for postseptic ARDS, and systemic IFN-beta improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

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