Targeting PLA2G7 ameliorates high-fat diet–induced pulmonary injury in obese mice, uncovering a key mechanistic link to obesity-associated COPD

TL;DR

This study shows that obesity can cause COPD-like lung damage in mice, and targeting the PLA2G7 gene helps reduce this damage.

Contribution

The study identifies PLA2G7 as a key driver of obesity-related COPD and reveals its mechanism involving arachidonic acid and NLRP3.

Findings

Obesity alone causes COPD-like lung changes in mice, including alveolar injury and reduced lung function.

PLA2G7 upregulation in macrophages increases arachidonic acid, leading to ROS accumulation and NLRP3 activation.

Genetic or pharmacological inhibition of PLA2G7 reduces obesity-induced COPD-like pathology.

Abstract

Obesity is a major risk factor for chronic obstructive pulmonary disease (COPD); however, the precise molecular pathways remain poorly defined, and it is uncertain whether severe obesity by itself can trigger COPD-like pathology. PLA2G7 has been identified as a pathogenic gene in COPD, yet the molecular mechanisms by which PLA2G7 contributes to disease development remain to be elucidated.

To investigate the role of PLA2G7 in obesity-related chronic obstructive pulmonary disease (COPD), we employed clinical specimens as well as in vivo and in vitro models, integrating multi-omics approaches with genetic and pharmacological interventions. Key methodologies included protein and gene expression analyses (Western blotting,, immunohistochemistry, ELISA assay, qRT-PCR), assessment of oxidative stress and lipid peroxidation (ROS and BODIPY staining), histological evaluation (H&E Staining, Oil Red O Staining, AB-PAS staining), transmission electron microscopy, micro-computed tomography (micro-CT), and pulmonary function tests in mice. Furthermore, molecular docking and molecular dynamics simulations were performed to explore potential molecular interactions of PLA2G7.

Using a diet-induced obesity model, this study revealed that obesity alone elicits COPD-like pulmonary changes, defined by weight-dependent alveolar injury, elevated airway mucus secretion, and reduced lung function. Transcriptomic analysis of lung tissues from obesity-associated COPD patients and obese mice identified macrophage-derived phospholipase A2 group VII (PLA2G7) as a key regulator of disease pathogenesis. Genetic deletion or pharmacological suppression of PLA2G7 was found to reduce obesity-associated COPD-like pathology. Mechanistically, high-fat stimulation induced upregulation of PLA2G7 in macrophages, leading to increased release of arachidonic acid (AA). The higher AA levels promoted the accumulation of lipid-derived reactive oxygen species (ROS) and stabilized NLRP3 mRNA by reducing its degradation. This process activated the inflammasome and triggered pyroptosis, thus driving pulmonary inflammation and contributing to COPD development.

PLA2G7 acts as a key mediator of obesity-associated COPD and represents a promising therapeutic target for preventing obesity-related lung injury.

1. Obese mice exhibit body weight–dependent COPD-like pulmonary alterations.

2. PLA2G7 acts as a key regulator in obesity-driven COPD

3. Upregulation of PLA2G7 enhances the generation of arachidonic acid

4. Arachidonic acid slows NLRP3 mRNA degradation

5. NLRP3 activation promotes pyroptosis, mediating obesity-related COPD pathogenesis.

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