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

Abstract

IFN-b 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-b 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-b 1 day earlier. Sepsis induced prolonged increases in alveolar TNF-a 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-a 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-b reversed the TNF-a/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-b improved survival by restoring the impaired function of AMs, mainly by recruiting neutrophils to alveoli.

Pulmonary Innate Immune Response Determines the Outcome of Inflammation During Pneumonia and Sepsis-Associated Acute Lung Injury

“…The impaired efferocytosis by AMs during the late stages of sepsis further increases the severity of ALI/ARDS due to the accumulation of dead neutrophils and other pulmonary cells ( Figure 3 ) ( 227 ). However, the IFN-β treatment reverses the impaired AM function in response to the IL-10 at the late stage of sepsis and decreases the severity of sepsis-associated ALI/ARDS and the associated mortality ( 228 ). The HMG-B1 release in the cytosol of AMs during the late sepsis indicates their necrotic cell death, which further increases the ALI severity ( Figure 3 ) ( 229 ).…”

Sepsis and Nosocomial Infection: Patient Characteristics, Mechanisms, and Modulation

“…In polymicrobial sepsis models, AM display both depressed cytokine responses to endotoxin challenge and decreased phagocytic capacity ( 82 ). Neutrophil recruitment to the alveolus is decreased ( 83 ) and recruited neutrophil ROS production is depressed ( 84 ). In an Escherichia coli pneumonia model, lung parenchymal dendritic cells demonstrated decreased antigen presenting capacity and reduced immunostimulatory responses during recovery from sepsis ( 85 ).…”

Polydatin mediates Parkin-dependent mitophagy and protects against mitochondria-dependent apoptosis in acute respiratory distress syndrome

“…Acute respiratory distress syndrome (ARDS) is a devastating disorder that occurs most frequently due to severe bacterial pneumonia or sepsis, and presents a critical health concern that results in high mortality rates [1,2].…”