The functional role and mechanisms of cereblon in chronic obstructive lung disease ; 만성폐쇄성 폐질환에서의 cereblon의 역할 및 조절 기전 규명

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의학과, 2021. 2. 유철규. ; Background Chronic obstructive pulmonary disease (COPD) is associated with chronic inflammation manifesting as emphysema and chronic airway obstruction. Although the nature of this inflammation has been heavily studied, there is no proven treatment to prevent emphysema progression due to the complexity of inflammatory mechanisms. Cereblon (CRBN) is a substrate receptor for the CRL4A E3 ubiquitin ligase complex. CRBN has been identified to play an essential role in regulating inflammatory response, oxidative stress, and endoplasmic reticulum(ER) stress, mediating the development of various diseases. However, little is known about the actions of CRBN in the lung. Objective The role of CRBN in modulating elastase-induced emphysema and its regulatory mechanisms were evaluated. Methods The correlation between CRBN expression and clinical parameters were evaluated in human lung tissues. Mouse lungs were analyzed for inflammation and emphysema after intratracheal administration of porcine pancreatic elastase (PPE). Bronchial epithelial cells and bone marrow derived macrophages (BMDM) were used after relevant siRNA transfection. With neutrophil elastase (NE), cigarette smoke extract (CSE) or lipopolysaccharide (LPS) treatment, protein expressions related to inflammation, oxidative stress and protease activity were evaluated by immunoblotting and immunohistochemistry. LPS-induced scavenger receptor expression was determined by flow cytometry. Results The level of CRBN expression was decreased in the lung tissue of COPD patients which correlated with the FEV1/FVC ratio. CRBN KO aggravated PPE-induced emphysema, and neutrophilic inflammation was predominantly observed preceding emphysema development in mice lungs. CSE or LPS-induced inflammatory cytokines such as KC, MIP-2, TNF-α, and IL-6 were increased in CRBN KO macrophages. In these cells, NE/CSE-induced mitogen-activated protein kinase (MAPK) activation was not affected, while CSE-induced nuclear factor-kappa B ...