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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 [ABSTRACT FROM AUTHOR]

The discovery that some selective serotonin transporter- (SSRI) and norepinephrine transporter- (NSRI) targeting antidepressants have the potential to act as anticancer agents adds greatly to their diverse pharmacological application. We report that the SSRI fluoxetine and the NSRI maprotiline are potent antiproliferative agents against human Burkitt lymphoma (BL), having little effect on normal blood cells. The results of this study show that although there is low-level expression of the norepinephrine transporter (NET) in some BL cells, NET is not involved in fluoxetine- or maprotiline-mediated cell death, as neither norepinephrine nor other NET inhibitors prevented this death. Of other NET ligands investigated for activity, only desipramine was found to have a similar effect to maprotiline and fluoxetine, suggesting the existence of a common selective structural modality for cell death and aiding in the future development of more potent analogs. In this study, we also show evidence to support previous reports that the serotonin transporter (SERT) has no involvement in antidepressant-mediated cell death, as SERT-specific ligands were unable to prevent fluoxetine or maprotiline cell death and not all SERT ligands could induce cell death. Although no target has yet been identified for the action of these compounds, the cell death elicited is potent, selective, and worthy of future investigation. [ABSTRACT FROM AUTHOR]