Abstract
Targeting inflammasome activation to modulate interleukin (IL)-1β is a promising treatment strategy against acute respiratory distress syndrome and ventilator-induced lung injury (VILI). Autophagy is a key regulator of inflammasome activation in macrophages. Here, we investigated the role of autophagy in the development of acute lung injury (ALI) induced by lipopolysaccharide (LPS) and mechanical ventilation (MV). Two hours before starting MV, 0.2 mg/kg LPS was administered to mice intratracheally. Mice were then placed on high-volume MV (30 ml/kg with 3 cmH2O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1fl/fl LysMCre) suffered severe hypoxemia (adjusted p < 0.05) and increased lung permeability (p < 0.05, albumin level in bronchoalveolar lavage fluid) with significantly higher IL-1β release into alveolar space (p < 0.05). Induction of autophagy by fasting-induced starvation led to improved arterial oxygenation (adjusted p < 0.0001) and lung permeability (p < 0.05), as well as significantly suppressed IL-1β production (p < 0.01). Intratracheal treatment with anti-mouse IL-1β monoclonal antibody (mAb; 2.5 mg/kg) significantly improved arterial oxygenation (adjusted p < 0.01) as well as lung permeability (p < 0.05). On the other hand, deletion of IL-1α gene or use of anti-mouse IL-1α mAb (2.5 mg/kg) provided no significant protection, suggesting that the LPS and MV-induced ALI is primarily dependent on IL-1β, but independent of IL-1α. These observations suggest that autophagy has a protective role in controlling inflammasome activation and production of IL-1β, which plays a critical role in developing hypoxemia and increased lung permeability in LPS plus MV-induced acute lung injury.
Highlights
Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema caused by increased pulmonary vascular permeability [1]
We have recently demonstrated that the LPS-plus-Mechanical ventilation (MV) induced-mouse model of ARDS triggers extracellular ATP and subsequent NLRP3 activation followed by IL-1β release in the lungs that led to lung inflammation, severe hypoxemia as well as increased lung permeability [12]
Since we have shown the key role of IL-1 in the induction of hypoxemia in this LPS plus MV “two-hit” lung injury model [12], and since several other prior studies have demonstrated that autophagy inhibits NLRP3 inflammasome activation and IL-1β release by LPS/ATP-treated macrophages [28,29,30,31], we hypothesized that autophagy would play a beneficial role in the LPS plus MV acute lung injury (ALI) model
Summary
Acute respiratory distress syndrome (ARDS) is the acute onset of non-cardiogenic pulmonary edema caused by increased pulmonary vascular permeability [1]. ARDS is a major cause of respiratory failure in critically ill patients with basic inflammatory diseases, such as pneumonia, sepsis, and severe trauma [2]. Mechanical ventilation (MV) is the most critical intervention in ARDS treatment, which decreases respiratory load in ARDS patients by maintaining ability of gas exchange [3]. MV has an obvious advantage in supporting these patients, MV has been associated with significant complications aggravating lung injury which results in increased mortality [4]. This injury has been termed ventilator-induced or -associated lung injury (VILI/VALI). Reducing VILI/VALI is believed to be the key to decrease mortality in ARDS, elucidating the mechanisms of VILI/VALI remains a high priority research [4]
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