- 【Updated on May 12, 2025】 Integration of CiNii Dissertations and CiNii Books into CiNii Research
- Trial version of CiNii Research Knowledge Graph Search feature is available on CiNii Labs
- Suspension and deletion of data provided by Nikkei BP
- Regarding the recording of “Research Data” and “Evidence Data”
IFN-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Postseptic Acute Respiratory Distress Syndrome–related Mortality
-
- Takahiro Hiruma
- Department of Acute Medicine
-
- Hitoshi Tsuyuzaki
- Department of Acute Medicine
-
- Kanji Uchida
- Department of Anesthesiology
-
- Bruce C. Trapnell
- Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and
-
- Yoshiro Yamamura
- Discovery Research Department, Pharmaceutical Research and Development Division, Maruishi Pharmaceutical Co., Ltd., Osaka, Japan
-
- Yoshiomi Kusakabe
- Department of Acute Medicine
-
- Tokie Totsu
- Department of Acute Medicine
-
- Takuji Suzuki
- Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio; and
-
- Shigeki Morita
- Department of Pathology, and
-
- Kent Doi
- Department of Acute Medicine
-
- Eisei Noiri
- Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
-
- Kensuke Nakamura
- Department of Acute Medicine
-
- Susumu Nakajima
- Department of Acute Medicine
-
- Naoki Yahagi
- Department of Acute Medicine
-
- Naoto Morimura
- Department of Acute Medicine
-
- Kyungho Chang
- Department of Anesthesiology
-
- Yoshitsugu Yamada
- Department of Anesthesiology
Search this article
Description
IFN-β 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-β 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-β 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-α 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-α 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-β reversed the TNF-α/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-β improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.
Journal
-
- American Journal of Respiratory Cell and Molecular Biology
-
American Journal of Respiratory Cell and Molecular Biology 59 (1), 45-55, 2018-07
American Thoracic Society
