Abstract
The immunologic responses that occur early in the acute respiratory distress syndrome (ARDS) elicit immune‐mediated damage. The mechanisms underlying the resolution of ARDS, particularly the role of signaling molecules in regulating immune cell kinetics, remain important questions. Th1‐mediated responses can contribute to the pathogenesis of acute lung injury (ALI). Interferon‐gamma (IFN‐γ) orchestrates early inflammatory events, enhancing immune‐mediated damage. The current study investigated IFN‐γ during resolution in several experimental models of ALI. The absence of IFN‐γ resulted in altered kinetics of lymphocyte and macrophage responses, suggesting that IFN‐γ present in this microenvironment is influential in ALI resolution. Genetic deficiency of IFN‐γ or administering neutralizing IFN‐γ antibodies accelerated the pace of resolution. Neutralizing IFN‐γ decreased the numbers of interstitial and inflammatory macrophages and increased alveolar macrophage numbers during resolution. Our results underline the complexity of lung injury resolution and provide insight into the effects through which altered IFN‐γ concentrations affect immune cell kinetics and the rate of resolution. These findings suggest that therapies that spatially or temporally control IFN‐γ signaling may promote ALI resolution. Identifying and elucidating the mechanisms critical to ALI resolution will allow the development of therapeutic approaches to minimize collateral tissue damage without adversely altering the response to injury.
Highlights
Events such as pneumonia, inhalational injury, trauma, or sepsis can damage the lung, which impedes its primary function of gas exchange
Measures of injury showed that peak weight loss after LPS was significantly less in the Ifng−/− mice, whereas after Streptococcus pneumoniae (Sp) and PR8, the peak loss and return to baseline were similar between genotypes
At the peak of LPS-induced injury, IFN-γ is required for full recruitment of neutrophils; this difference was only observed in Ifng−/− mice and not following IFN-γ antibody-mediated neutralization, which was initiated on day 1 after the neutrophil influx is established (D'Alessio et al, 2009; Zemans & Matthay, 2017)
Summary
Inhalational injury, trauma, or sepsis can damage the lung, which impedes its primary function of gas exchange. Two other stimuli that are important common causes of lung injury (S. pneumoniae and H1N1 influenza) were studied to identify and compare the effects of IFN-γ deficiency at a time point during resolution when mice have regained much of their weight loss (Arpaia et al, 2015; Gomez et al, 2017; Matute-Bello, Frevert, & Martin, 2008). These studies identified the contribution of IFN-γ both to lung injury and to changes in immune cell kinetics during resolution from lung injury
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