Autophagy Protects Against Developing Increased Lung Permeability and Hypoxemia by Down Regulating Inflammasome Activity and IL-1β in LPS Plus Mechanical Ventilation-Induced Acute Lung Injury

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 cmH 2 O positive end-expiratory pressure for 2.5 h without additional oxygen application). Mice with myeloid-specific deletion of the autophagic protein ATG16L1 (Atg16l1 fl/fl LysM Cre ) 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.

Potential Fast COVID-19 Containment With Trehalose

“…The majority of trehalose administration in adults ranges from 4.8 to 10 g/day. Lung alteration of autophagy has been confirmed with the use of 1 g/kg trehalose to mice, which is equivalent to 4.8 g/day for every 60 kgs in humans (96). A diabetes study used 10 g/day (8), while an acute coronary artery clinical trial used 2.1 g/day (clinicalTrials.gov, NCT 03700424).…”

“…It is important to understand that while there is considerable research on trehalose administration in adults, there is still not sufficient data on its safety in children, adults with health-related issues, and the elderly. We have previously reported that trehalose exacerbated acute respiratory distress syndrome (ARDS) "two-hit" murine model (induced by LPS and mechanical ventilation), while other autophagy activations inhibited ARDS (96). Therefore, trehalose treatment would be inappropriate to treat intensive care patients with severe COVID-19, especially those presenting cytokine storm syndrome or ARDS.…”

Autophagy Augmentation to Alleviate Immune Response Dysfunction, and Resolve Respiratory and COVID-19 Exacerbations

“…Mechanical ventilation (MV)-induced lung injury is another severe form of ARDS, wherein the activation of inflammasome has been shown to mediate ALI symptoms. In a recent article, starvation-induced autophagy augmentation was shown to protect against LPS- and MV-induced ARDS features by reducing IL-1 β levels, decreasing lung permeability, and improving arterial oxygenation [ 133 ]. Thus, autophagy had a protective role in controlling the inflammasome activation and resolution of the MV-induced production of IL-1 β , which plays a pathogenic role through inducing hypoxemia and increasing lung permeability in LPS/MV-induced ALI/ARDS [ 133 ].…”

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview

“…Targeting of senescent cells was beneficial in in vivo models of fibrosis, improving lung function and physical health (74). A decline in cellular autophagic function has also been observed in the aging lung (18) and induction of autophagy protected against lung permeability in models of ALI (76), highlighting the importance of this process. Another potential mechanism by which aging may contribute to increased ARDS severity is through the upregulation of receptor for advanced glycation end products (RAGE), a marker of type I alveolar epithelial cell injury (77).…”