Obesity-Induced Endoplasmic Reticulum Stress Causes Lung Endothelial Dysfunction and Promotes Acute Lung Injury

Area of Science:

• Pulmonary Medicine
• Cellular Biology
• Metabolic Disorders

Background:

• Obesity is a known risk factor for acute respiratory distress syndrome (ARDS).
• The precise mechanisms linking obesity to ARDS remain unclear.
• Previous work indicated diet-induced obesity causes pulmonary vascular endothelial dysfunction and heightened susceptibility to lung injury.

Purpose of the Study:

• To investigate the role of endoplasmic reticulum (ER) stress in obesity-associated pulmonary endothelial dysfunction.
• To determine if ER stress contributes to the increased susceptibility to acute lung injury in diet-induced obese mice.
• To explore potential therapeutic strategies targeting ER stress in obese individuals at risk for ARDS.

Main Methods:

• Diet-induced obesity model in mice.
• Analysis of ER stress markers (PERK, IRE1α, ATF6) in lung tissue and primary lung endothelial cells.
• In vitro exposure of lung endothelial cells to obese mouse serum and saturated fatty acids.
• Assessment of endothelial cell-cell junction proteins and adhesion molecules.
• Treatment with 4-phenylbutyric acid (4-PBA) to reduce ER stress.
• Evaluation of protection against LPS-induced acute lung injury.

Main Results:

• Diet-induced obese mice exhibited increased ER stress markers in lung endothelial cells.
• Obese serum and saturated fatty acids induced ER stress, increased adhesion molecules, and decreased cell-cell junction proteins in endothelial cells.
• Tunicamycin-induced ER stress mimicked these endothelial dysfunction markers.
• 4-PBA treatment reduced ER stress, normalized endothelial cell markers, and protected against acute lung injury in obese mice.

Conclusions:

• Fatty acids in obese serum induce ER stress in pulmonary endothelial cells, leading to endothelial dysfunction.
• ER stress is a key mechanism linking obesity to increased ARDS susceptibility.
• Reducing ER stress in pulmonary endothelial cells may offer a protective strategy against ARDS in obese individuals.