ABSTRACT
BACKGROUND AND AIMS: Autophagy is a highly regulated, complex intracellular recycling process that is vital to maintaining cellular homeostasis in response to diverse conditions and stressors. Despite the presence of robust regulatory pathways, the intricate and multi-step nature of autophagy creates opportunity for dysregulation. Errors in autophagy have been implicated in the development of a broad range of clinical pathologies including granulomatous disease. Specifically, activation of the mTORC1 pathway has been identified as a key negative regulator of autophagic flux, prompting the study of dysregulated mTORC1 signaling in the pathogenesis of sarcoidosis. Our review: We conducted a thorough search of the extant literature to identify the regulatory pathways of autophagy, and more specifically the implication of upregulated mTORC1 pathways in the pathogenesis of sarcoidosis. We review data showing spontaneous granuloma formation in animal models with upregulate mTORC1 signaling, human genetic studies showing mutation in autophagy genes in sarcoidosis patients, and clinical data showing that targeting autophagy regulatory molecules like mTORC1 may provide new therapeutic approaches for sarcoidosis. CONCLUSIONS: Given the incomplete understanding of sarcoidosis pathogenesis and the toxicities of current treatments, a more complete understanding of sarcoidosis pathogenesis is crucial for the development of more effective and safer therapies. In this review, we propose a strong molecular pathway driving sarcoidosis pathogenesis at which autophagy is at the center. A more complete understanding of autophagy and its regulatory molecules, like mTORC1, may provide a window into new therapeutic approaches for sarcoidosis.
ABSTRACT
Ozone is a highly reactive environmental pollutant with well-recognized adverse effects on lung health. Bronchial hyperresponsiveness (BHR) is one consequence of ozone exposure, particularly for individuals with underlying lung disease. Our data demonstrated that ozone induced substantial ATP release from human airway epithelia in vitro and into the airways of mice in vivo and that ATP served as a potent inducer of mast cell degranulation and BHR, acting through P2X7 receptors on mast cells. Both mast cell-deficient and P2X7 receptor-deficient (P2X7-/-) mice demonstrated markedly attenuated BHR to ozone. Reconstitution of mast cell-deficient mice with WT mast cells and P2X7-/- mast cells restored ozone-induced BHR. Despite equal numbers of mast cells in reconstituted mouse lungs, mice reconstituted with P2X7-/- mast cells demonstrated significantly less robust BHR than mice reconstituted with WT mast cells. These results support a model where P2X7 on mast cells and other cell types contribute to ozone-induced BHR.
