Autophagy in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation

Abstract

in pulmonary macrophages mediates lung inflammatory injury via NLRP3 inflammasome activation during mechanical ventilation. Am J Physiol Lung Cell Mol Physiol 307: L173-L185, 2014. First published May 16, 2014 doi:10.1152/ajplung.00083.2014.-The inflammatory response is a primary mechanism in the pathogenesis of ventilator-induced lung injury. Autophagy is an essential, homeostatic process by which cells break down their own components. We explored the role of autophagy in the mechanisms of mechanical ventilation-induced lung inflammatory injury. Mice were subjected to low (7 ml/kg) or high (28 ml/kg) tidal volume ventilation for 2 h. Bone marrow-derived macrophages transfected with a scrambled or autophagy-related protein 5 small interfering RNA were administered to alveolar macrophage-depleted mice via a jugular venous cannula 30 min before the start of the ventilation protocol. In some experiments, mice were ventilated in the absence and presence of autophagy inhibitors 3-methyladenine (15 mg/kg ip) or trichostatin A (1 mg/kg ip). Mechanical ventilation with a high tidal volume caused rapid (within minutes) activation of autophagy in the lung. Conventional transmission electron microscopic examination of lung sections showed that mechanical ventilation-induced autophagy activation mainly occurred in lung macrophages. Autophagy activation in the lungs during mechanical ventilation was dramatically attenuated in alveolar macrophage-depleted mice. Selective silencing of autophagyrelated protein 5 in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury. Pharmacological inhibition of autophagy also significantly attenuated the inflammatory responses caused by lung hyperinflation. The activation of autophagy in macrophages mediates early lung inflammation during mechanical ventilation via NLRP3 inflammasome signaling. Inhibition of autophagy activation in lung macrophages may therefore provide a novel and promising strategy for the prevention and treatment of ventilator-induced lung injury. lung injury; autophagy; mechanical ventilation; inflammasome; macrophage MECHANICAL VENTILATION not only saves the lives of patients with respiratory failure but also initiates and exacerbates lung injury known as ventilator-induced lung injury (VILI), which in turn contributes to patient morbidity and mortality (11). VILI is characterized by an influx of inflammatory cells, increased pulmonary vascular permeability, and endothelial and epithelial cell death. The release of proinflammatory cytokines by lung cells in response to mechanical stretch is a crucial event for initiation and/or potentiation of VILI and may cause systemic inflammatory response and multiple system organ failure (4,22,35). The alveolar macrophages (AMs) (5, 7, 26), neutrophils (42), alveolar epithelium (35), and endothelium (10) are all involved in the production of proinflammatory cytokines during mechanical ...

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

“…It is recognized that NLRP3 inflammasome activation in AM mediates lung inflammatory responses during MV (13). The role of autophagy in ALI, including VILI, has been controversial with some studies suggesting a protective and others a detrimental role of autophagy (17,18). In this study we found that autophagy in myeloid cells plays a protective role in the experimental LPS/MV-induced "two-hit" ALI model.…”

“…Autophagy is a highly conserved, fundamental intracellular system associated with cellular homeostasis, recycling, and elimination of defective organelles, and intracellular pathogens (14,15). The role of autophagy in the mechanism of ALI has been controversial with studies that have suggested both protective and detrimental effects of autophagy (14,(16)(17)(18). On the other hand, numerous studies have demonstrated in various settings that autophagy plays an inhibitory role in secretion of IL-1β through downregulation of the NLRP3 activation (15).…”

Silymarin attenuates cigarette smoke extract-induced inflammation via simultaneous inhibition of autophagy and ERK/p38 MAPK pathway in human bronchial epithelial cells

“…Rescue of dysfunctional autophagy has been shown to play a protective role against hyperinflammatory responses from cystic fibrosis cells39, while autophagy deficiency in alveolar macrophages resulted in greater silica-induced inflammation40. In contrast, inhibition of autophagy in lung macrophages abolished mechanical ventilation-induced nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome activation and lung inflammatory injury41. In avian influenza A-infected lung epithelial cells, blocking autophagy not only reduced the cell death4243, but also decreased the production of proinflammatory cytokines43.…”

Role of monocytes and macrophages in regulating immune response following lung transplantation

“…Mechanistic studies have revealed the response to be inflammasome-mediated, where the stretch injury causes NLR-containing pyrin domain 3 (NLRP3) activation and induces the release of IL-1β from alveolar macrophages (42–44). Additional studies showed alveolar macrophage high-mobility group box-1 (HMGB1) and possibly transient receptor potential vanilloid 4 (TRPV4) to be involved in neutrophil recruitment to the alveolar space and lung vascular permeability and lung edema (45–47).…”