Autophagy and inflammation in chronic respiratory disease

Abstract

Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.

Keywords: asthma; autophagy; chronic obstructive pulmonary disease (COPD); inflammation; pulmonary fibrosis; pulmonary hypertension; sleep apnea; tuberculosis.

Figure 1.

Autophagy and chronic lung disease. Autophagy plays an essential role in the inflammatory response of the lung to infection and stress. Autophagy is upregulated in response to a number of pathogenic stimuli including cigarette smoke, TGFB, IL13 and chronic hypoxia. The upregulation of autophagy may initially act as a prosurvival mechanism responsible for the clearance of damaged proteins or organelles. In the chronic lung diseases IPF, PH and CF, loss of autophagy drives lung inflammation and injury, suggesting autophagy plays a protective role. However, under certain circumstances, this naturally homeostatic cellular process may become overwhelmed or dysregulated and ultimately become unable to deal with the chronic burden and clearance of excessive autophagic targets. Such a burden may lead to the accumulation of aggresomes or damaged organelles with the concurrent appearance of increased autophagosomes, which may in turn be detrimental to the cell. Such cellular damage and stress caused by dysregulated autophagy drives lung inflammation and injury in a number of chronic lung diseases including COPD and asthma.