BCL-2 Modulates IRE1α Activation to Attenuate Endoplasmic Reticulum Stress and Pulmonary Fibrosis.

Area of Science:

• Cellular Biology
• Pulmonary Medicine
• Molecular Biology

Background:

• BCL-2 family proteins are crucial regulators of cell survival.
• Endoplasmic reticulum (ER) stress and extracellular matrix (ECM) accumulation are implicated in lung injury and fibrosis.

Purpose of the Study:

• To investigate the role of BCL-2 in lung injury and repair processes.
• To determine BCL-2's function in attenuating ER stress and ECM accumulation following lung injury.

Main Methods:

• Intratracheal bleomycin challenge in mice to induce lung injury.
• Administration of navitoclax (a BCL-2/BCL-xL inhibitor) to assess BCL-2 inhibition effects.
• Analysis of ER stress markers (IRE1α activation), apoptosis, collagen accumulation, and MRC2 expression.
• Utilized precision-cut lung slice cultures for mechanistic studies.

Main Results:

• BCL-2 inhibition increased epithelial cell loss and ER stress markers (IRE1α activation) after bleomycin challenge.
• Navitoclax treatment led to persistent collagen accumulation and fibrosis, unlike controls.
• IRE1α's RNAase activity downregulated MRC2, a collagen turnover mediator, contributing to fibrosis.
• MRC2 deficiency mimicked the fibrotic effects of BCL-2 inhibition in lung slice cultures.

Conclusions:

• BCL-2 plays a critical role beyond anti-apoptosis in attenuating ER stress and limiting fibrosis.
• BCL-2 inhibition disrupts the association between IRE1α and BAX, promoting ER stress.
• Downregulation of MRC2 by IRE1α contributes to persistent collagen accumulation and impaired lung repair.
• Targeting BCL-2 may offer therapeutic potential for lung fibrotic diseases by modulating ER stress and ECM homeostasis.