Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here, we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, was higher in lungs of patients with idiopathic pulmonary fibrosis compared to control individuals and correlated with disease severity. We also found that Dio2 knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. Given after bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a or Pink1 knockout mice suggesting dependence on these pathways. We conclude that the TH anti-fibrotic properties are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and thus may represent an effective therapy for pulmonary fibrosis.

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Diabetes mellitus (DM) is a growing international concern. Considerable mortality and morbidity associated with diabetes mellitus arise predominantly from thrombotic cardiovascular events. Oxidative stress‐mediated mitochondrial damage contributes significantly to enhanced thrombosis in DM. A basal autophagy process has recently been described as playing an important role in normal platelet activation. We now report a substantial mitophagy induction (above basal autophagy levels) in diabetic platelets, suggesting alternative roles for autophagy in platelet pathology. Using a combination of molecular, biochemical, and imaging studies on human DM platelets, we report that platelet mitophagy induction serves as a platelet protective mechanism that responds to oxidative stress through JNK activation. By removing damaged mitochondria (mitophagy), phosphorylated p53 is reduced, preventing progression to apoptosis, and preserving platelet function. The absence of mitophagy in DM platelets results in failure to protect against oxidative stress, leading to increased thrombosis. Surprisingly, this removal of damaged mitochondria does not require contributions from transcription, as platelets lack a nucleus. The considerable energy and resources expended in “prepackaging” the complex mitophagy machinery in a short‐lived normal platelet support a critical role, in anticipation of exposure to oxidative stress.

Lysosomal-mediated degradation of intracellular lipids, proteins and organelles, known as autophagy, represents a inducible adaptive response to lung injury resulting from exposure to insults, such as hypoxia, microbes, inflammation, ischemia-reperfusion, pharmaceuticals (e.g., bleomycin), or inhaled xenobiotics (i.e., air pollution, cigarette smoke). This process clears damaged or toxic cellular constituents and facilitates cell survival in stressful environments. Autophagic degradation of dysfunctional or damaged mitochondria is termed mitophagy. Enhanced mitophagy is usually an early response to promote survival. However, overwhelming or prolonged mitochondrial damage can induce excessive/pathological levels of mitophagy, thereby promoting cell death and tissue injury. Autophagy/mitophagy is therefore an important modulator in human pulmonary diseases and a potential therapeutic target. This review article will summarize the most recent studies highlighting the role of autophagy/mitophagy and its molecular pathways involved in stress response in pulmonary pathologies.

OBJECTIVES Pulmonary hypertension (PH) is a process of lung vascular remodeling which can lead to right heart dysfunction and significant morbidity. The underlying mechanisms leading to PH are not well understoon and therapies are limited. Using Intermittent hypoxia (IH) as a model of oxidant-induced PH, we identified an important role for endothelial cell mitophagy via mitochondrial uncoupling protein 2 (Ucp2) in the development of IH-induced PH. APPROACH AND RESULTS Ucp2 endothelial knockout (VE-KO) and Ucp2 Flox (Flox) mice were subjected to 5 weeks of IH. Ucp2 VE-KO mice exhibited higher RVSP and worse right heart hypertrophy, as measured by increased RV/LV+S ratio, at baseline and after IH. These changes were accompanied by increased mitophagy. Primary mouse lung endothelial cells (MLEC) transfected with Ucp2 siRNA and subjected to cyclical exposures to CoCl2 (chemical hypoxia) showed increased mitophagy, as measured by Pink1 and LC3BII/I ratios, decreased mitochondrial biogenesis and increased apoptosis. Similar results were obtained in primary lung endothelial cells isolated from VE-KO mice. Moreover, silencing Pink1 in the endothelium of Ucp2 KO mice, using endothelial-targeted lentiviral silencing RNA in vivo, prevented IH-induced PH. Human pulmonary artery endothelial cells from people with PH demonstrated changes similar to Ucp2-silenced MLEC. CONCLUSION The loss of endothelial Ucp2 leads to excessive Pink1-induced mitophagy, inadequate mitochondrial biosynthesis and increased apoptosis in endothelium. An endothelial Ucp2-Pink1 axis may be effective therapeutic targets in PH.