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.

A NNUALLY, 750,000 cases of sepsis are reported in the United States, 1,2 and this disease is associated with a sustained high mortality rate, ranging from 15 to 50%. 3-9 Death relates to multiple organ dysfunction that involves kidneys, liver, pancreas, adrenals, coagulation system, central nervous system, cardiovascular system, and lungs. 10 Acute respiratory distress syndrome is a major remote organ pathology accompanied by sepsis. 11 Despite an increase in our knowledge of the pathogenesis of sepsis, all sepsis trials with immune-modulating drugs, most of which have targeted the sepsis-associated proinflammatory response, have reported no survival benefit. 12-14 One of the challenging issues for sepsis research is a heterogeneity of study populations; a vague definition of the disease accepts heterogeneity in microorganisms and the site of infection, 13 and genetic heterogeneity of hosts, which causes different responses to invading microorganisms. 15 Furthermore, immune status varies widely in the critically ill, usually preceding a hyperimmune state followed by subsequent immune paralysis, particularly in patients What We Already Know about This Topic • Sepsis is a leading cause of death, and targeting sepsisassociated inflammatory responses has not been shown to prove beneficial. What This Article Tells Us That Is New • In an established mouse model of sepsis (cecal ligation and perforation), severe versus mild sepsis was associated with increased mortality, less capacity of peritoneal inflammatory cells for phagocytosis, and decreased expression of focal and systemic cytokines and chemokine receptor expression on circulating neutrophils. These effects were reversed by the administration of the immune stimulant interferon-β after-but not before-severe sepsis was established. Interferon-β after the onset of peritonitis may restore impaired innate immunity and improve outcome.

Impaired signaling by granulocyte/macrophage-colony stimulating factor (GM-CSF) drives the pathogenesis of two diseases (autoimmune and hereditary pulmonary alveolar proteinosis (PAP)) representing over ninety percent of patients who develop PAP syndrome but not a broad spectrum of diseases that cause PAP by other mechanisms. We previously exploited the ability of GM-CSF to rapidly increase cell-surface CD11b levels on neutrophils (CD11bSurface) to establish the CD11b stimulation index (CD11b-SI), a test enabling the clinical research diagnosis of impaired GM-CSF signaling based on measuring CD11bSurface by flow cytometry using fresh, heparinized blood. (CD11b-SI is defined as GM-CSF-stimulated- CD11bSurface minus unstimulated CD11bSurface divided by un-stimulated CD11bSurface multiplied 100.) Notwithstanding important and unique diagnostic utility, the test is sensitive to experimental conditions that can affect test performance. The present study was undertaken to optimize and standardize CD11b-SI test for detecting impaired GM-CSF signaling in heparinized human blood specimens from PAP patients. Results demonstrated the test was sensitive to choice of anticoagulant, pretesting incubation on ice, a delay between phlebotomy and test performance of more than one hour, and the concentration GM-CSF used to stimulate blood. The standardized CD11b-SI test reliably distinguished blood specimens from autoimmune PAP patients with impaired GM-CSF signaling from those of health people with normal signaling. Intra-subject differences were smaller than inter-subject differences in repeated measures. Receiver operating characteristic curve analysis identified a CD11b-SI test result of 112 as the optimal cut off threshold for diagnosis of impaired GM-CSF signaling in autoimmune PAP for which the sensitivity and specificity were both 100%. These results support the use of this standardized CD11b-SI for routine clinical identification of impaired GM-CSF signaling in patients with autoimmune PAP. The CD11b-SI may also have utility in clinical trials of novel therapeutic strategies targeting reduction in GM-CSF bioactivity now under evaluation for multiple common autoimmune and inflammatory disorders.

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