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MUC5B Expression in IPF Is Associated with ER Stress
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A6354 - MUC5B Expression in IPF Is Associated with ER Stress
Author Block: E. Dobrinskikh1, A. D. Walts2, D. A. Schwartz3; 1Medicine, University of Colorado Denver, Aurora, CO, United States, 2Medicine, University of Colorado, Aurora, CO, United States, 3Dept of Medicine, Univ of Colorado, Aurora, CO, United States.
Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease with heterogeneous fibrosis and remodeled lungs due to poorly understood mechanisms. The gain-of-function MUC5B variant rs35705950 is the strongest risk factor for IPF. MUC5B protein expression is found in bronchoalveolar epithelial cells and honeycomb cysts in patients with IPF. In the current paradigm for IPF pathogenesis, pulmonary fibrosis develops as a final pathological outcome of impaired wound healing responses to continues lung injury and characterized by the excessive extracellular matrix (ECM) deposition in the lungs and chronic inflammatory environment. It is known that prominent endoplasmic reticulum (ER) stress in alveolar epithelial cells is seen in IPF. CHOP (a marker of ER stress) is often produced in the terminal unfolded protein response (UPR) to induce apoptosis. Thus, we hypothesize that overproduction of MUC5B in bronchoalveolar epithelia is associated with ER stress response leading to the cell death, pro-inflammatory environment and progressive lung fibrosis.
Methods: Chromogenic and fluorescent RNA Scope methods were used to investigate MUC5B, SPC, CHOP and BIP patterns of expression in human lungs taken from controls and patients with IPF. Label-free Fluorescent Lifetime Imaging Microscopy (FLIM) of free to bound NADH ratios changes was used to investigate local metabolic changes. Label-free Second Harmonic Generation (SHG) imaging was used to evaluate fibrillar collagens depositions in these lung tissues.
Results: We have found that different cell types express MUC5B, including a subset of type II epithelial cells in human lung tissues obtained from controls and patients with IPF. MUC5B has higher expression in IPF lungs than control lungs, and is strongly associated with honeycomb cysts, where we also found a subset of SPC-positive cells producing MUC5B. Moreover, MUC5B is co-expressed with CHOP in airway epithelial cells as well as in a subset of SPC-positive cells in patients with IPF. FLIM analysis showed that patients with IPF have a shift of free/bound NADH lifetime towards increased free NADH in alveolar regions, which indicates local pro-inflammatory environment. SHG showed increased fibrillar collagens depositions in patients with IPF.
Conclusions: These results indicate that excess of MUC5B is associated with ER stress in the distal lung, which may cause apoptosis, chronic inflammation, and lung fibrosis.
Author Block: E. Dobrinskikh1, A. D. Walts2, D. A. Schwartz3; 1Medicine, University of Colorado Denver, Aurora, CO, United States, 2Medicine, University of Colorado, Aurora, CO, United States, 3Dept of Medicine, Univ of Colorado, Aurora, CO, United States.
Introduction: Idiopathic Pulmonary Fibrosis (IPF) is a chronic progressive disease with heterogeneous fibrosis and remodeled lungs due to poorly understood mechanisms. The gain-of-function MUC5B variant rs35705950 is the strongest risk factor for IPF. MUC5B protein expression is found in bronchoalveolar epithelial cells and honeycomb cysts in patients with IPF. In the current paradigm for IPF pathogenesis, pulmonary fibrosis develops as a final pathological outcome of impaired wound healing responses to continues lung injury and characterized by the excessive extracellular matrix (ECM) deposition in the lungs and chronic inflammatory environment. It is known that prominent endoplasmic reticulum (ER) stress in alveolar epithelial cells is seen in IPF. CHOP (a marker of ER stress) is often produced in the terminal unfolded protein response (UPR) to induce apoptosis. Thus, we hypothesize that overproduction of MUC5B in bronchoalveolar epithelia is associated with ER stress response leading to the cell death, pro-inflammatory environment and progressive lung fibrosis.
Methods: Chromogenic and fluorescent RNA Scope methods were used to investigate MUC5B, SPC, CHOP and BIP patterns of expression in human lungs taken from controls and patients with IPF. Label-free Fluorescent Lifetime Imaging Microscopy (FLIM) of free to bound NADH ratios changes was used to investigate local metabolic changes. Label-free Second Harmonic Generation (SHG) imaging was used to evaluate fibrillar collagens depositions in these lung tissues.
Results: We have found that different cell types express MUC5B, including a subset of type II epithelial cells in human lung tissues obtained from controls and patients with IPF. MUC5B has higher expression in IPF lungs than control lungs, and is strongly associated with honeycomb cysts, where we also found a subset of SPC-positive cells producing MUC5B. Moreover, MUC5B is co-expressed with CHOP in airway epithelial cells as well as in a subset of SPC-positive cells in patients with IPF. FLIM analysis showed that patients with IPF have a shift of free/bound NADH lifetime towards increased free NADH in alveolar regions, which indicates local pro-inflammatory environment. SHG showed increased fibrillar collagens depositions in patients with IPF.
Conclusions: These results indicate that excess of MUC5B is associated with ER stress in the distal lung, which may cause apoptosis, chronic inflammation, and lung fibrosis.
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