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Silica Promotes Endoplasmic Reticulum Stress and Induces Alveolar Epithelial Apoptotic Cell Death in the Lung FREE TO VIEW

Freddy Romero; Dilip Shah; Gautam George; Michelle Duong; William Stafstrom; Ross Summer
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Division of Pulmonary and Critical Care Medicine, Thomas Jefferson University, Philadelphia, PA

Chest. 2014;146(4_MeetingAbstracts):974A. doi:10.1378/chest.1988601
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SESSION TITLE: Topics in ILD and Lung Transplantation

SESSION TYPE: Original Investigation Slide

PRESENTED ON: Wednesday, October 29, 2014 at 02:45 PM - 04:15 PM

PURPOSE: Alveolar epithelial type II (AEII) apoptotic cell death is believed to play a pathogenic role in the development of lung fibrosis. The activation of apoptotic pathways is mechanistically linked to the induction of endoplasmic reticulum (ER) stress responses in many tissues. Silica induces apoptotic cell death in the fibrotic lung but its relationship to ER stress has yet to be evaluated. The goal of this study was to determine whether silica induces ER stress in the lung and to evaluate its relationship to AEII cell apoptotic cell death.

METHODS: Lung fibrosis was induced in male C57BL6 mice with a one-time intra-tracheal instillation of silica dioxide (20 mg). Broncho-alveolar lavage (BAL) and whole lung tissue were harvested at baseline, 3, 7 and 14 days after silica administration. Lung fibrosis was assessed by measuring TGF-β1 levels in BAL fluid, by quantifying transcripts and protein levels for TGF-β1, transcript levels for collagen1alpha1 in whole lung tissue, and by histological analysis. The activation of the unfolded protein response was assessed by quantifying transcripts and protein levels for IRE1α, pPERK, peIF2 and CHOP in whole lung tissues. Apoptotic cell death was assessed in whole lung by TUNEL staining and by evaluating caspase 3 cleavage. Alveolar epithelial MLE-12 cells were used for evaluating silica-induced ER stress and apoptotic cell death in culture.

RESULTS: Intra-tracheal instillation of silica induced ER stress in the lung. Increased levels of peIF2, pPERK, CHOP and IRE1α were observed at 3 days after silica administration. This early time point coincided with the initial increase in TGF-β1 but preceded apoptotic cell death (caspase 3 cleavage), biochemical and histological onset of lung fibrosis. On day 14, when fibrosis was readily apparent, ER stress and apoptotic cell death (TUNEL staining and caspase 3 cleavage) were both evident. Similarly, ER stress preceded the activation of apoptotic death pathways in AEII cells that exposed to silica in culture, suggesting a temporal relationship between these two events.

CONCLUSIONS: Intra-tracheal administration of silica induces ER stress in the lung and sustained activation of the ER stress response was associated with the induction of AEII apoptotic cell death.

CLINICAL IMPLICATIONS: This study suggests that ER stress plays an important role in the pathogenesis of silica-induced lung fibrosis and implies that therapeutic interventions blocking ER stress may be effective for reducing AEII cell death and attenuating fibrotic responses.

DISCLOSURE: The following authors have nothing to disclose: Freddy Romero, Dilip Shah, Gautam George, Michelle Duong, William Stafstrom, Ross Summer

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