Involvement of ER stress in the molecular mechanisms of lung injury and pulmonary fibrosis

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1.ER stress in bleomycin-induced pulmonary fibrosisEpithelial cell apoptosis is involved in pathophysiology of lung injury and pulmonary fibrosis. We previously demonstrated that accumulation of mulit-ubiqitinated protein was detected in lung tissues of bleomycin-treated mice. The accumulation of multi-ubiquitinated protein may reflect the dysregulation of ubiquitin proteasome pathway. It is known that accumulation of unfolded and malfolded proteins causes endoplasmic reticulum(ER) stress and unfolded protein response(UPR). Various stresses can impair protein folding and induce ER stress, and severe ER stress can transduce apoptotic signals. PURPOSE : The purpose of this study is to investigate whether the ER stress and UPR are involoved in pathophysiology of bleomycin-induced pulmonary fibrosis in mice. We performed western blot analysis and immunohistochemistry to assess the expression and activation of ER-resident chaperones GRP78, and ER stress-associated apoptosis factor CHOP, and … More caspase-12 in lung tissue of bleomycin-treated mice. Expression of CHOP was increased at 7 days after bleomycin injection and reduced to normal levels at 14 days. Caspase-12 was upregurated and activated at day 14. The immunoreactivity for caspase-12 was increased in alveolar epithelial cells. GRP78 expression was not increased after bleomycin instillation. These results suggest that ER stress may be involved in the pathophysiology of bleomycin-induced pulmonary fibrosis in mice via induction of apoptosis epithelial cells.2.ER stress in idiopathic pulmonary fibrosisEpithelial cell apoptosis is considered to be involved in the pathophysiology of idiopathic pulmonary fibrosis. Various stresses can induce endoplasmic reticulum stress, which can lead to apoptosis. We investigated the association between endoplasmic reticulum stress and epithelial cell apoptosis in pulmonary fibrosis. We performed western blot analysis and immunohistochemistry to assess the expression ofendoplasmic reticulum stress-associated proteins GRP78 and CHOP in lung tissues from 8 patients with idiopathic pulmonary fibrosis, 6 patients with non-specific interstitial pneumonia, and 8 controls. The expressions of ER stress-specific proapoptotic molecule CHOP and an antiapoptotic molecule GRP78 were significantly increased in the lung tissues of pulmonary fibrosis compared with normal lung parenchyma. The positive signals for GRP78 and CHOP in epithelial cells were increased in pulmonary fibrosis by immunohistochemistry. The immunoreactive grade for GRP78 and CHOP were associated with the severity offibrosis. Some of positively stained cells for CHOP appeared to be positive for TUNEL staining using serial sections. Although the number of patients examined is small, we conclude that ER stress-mediated apoptosis, at least CHOP-mediated apoptosis pathway in epithelial cells, may contribute to the development of pulmonary fibrosis. Less