# Cold Exposure Exacerbates Allergic Airway Inflammation via Ferroptosis: Evidence from a Murine Model

## TL;DR

Cold exposure worsens allergic airway inflammation in mice by causing a type of cell death called ferroptosis, which can be reduced using a specific inhibitor.

## Contribution

This study identifies ferroptosis as a novel mechanism linking cold exposure to worsened allergic airway inflammation in a murine model.

## Key findings

- Cold exposure increased Th2 cytokines, impaired lung function, and caused airway remodeling in mice with allergic airway inflammation.
- Ferroptosis was induced by cold exposure, marked by changes in GPX4, FTL, ACSL4, iron levels, and mitochondrial damage.
- Treatment with ferrostatin-1 reduced inflammation, improved lung function, and mitigated histological damage in cold-exposed mice.

## Abstract

Recently, extreme weather has been regarded as a risk factor for exacerbating allergic airway inflammation (AAI), but its underlying mechanism remains unclear. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has been implicated in various lung diseases. This study investigated whether cold exposure aggravated OVA-induced AAI by promoting ferroptosis. A murine AA model was established using OVA sensitization and challenge. Mice were exposed to cold temperatures (10 °C or 4 °C) for 4 h daily. Ferroptosis was assessed by measuring ferroptosis-related markers (GPX4, ACSL4, FTL), iron deposition (Alcian Blue-Periodic Acid-Schiff Staining), lipid peroxidation (MDA), antioxidant levels (GSH), and mitochondrial ultrastructure (TEM). The ferroptosis inhibitor ferrostatin-1 (Fer-1) was administered to evaluate its protective effects. Airway inflammation, lung function, and histopathology were also analyzed. Cold exposure significantly worsened AA symptoms, including increased Th2 cytokine levels (IL-4, IL-5, IL-13, IL-33), impaired lung function, and enhanced airway remodeling and mucus production. These effects were more pronounced at 4 °C. Cold exposure also induced ferroptosis, as evidenced by decreased GPX4 and FTL, increased ACSL4, elevated iron and MDA levels, reduced GSH, and mitochondrial damage. Treatment with Fer-1 mitigated these changes, alleviating inflammation, improving lung function, and reducing histological damage. Cold exposure exacerbated AAI by inducing ferroptosis in lung tissues. Inhibition of ferroptosis with Fer-1 attenuated these aggravation effects, suggesting ferroptosis as a potential mechanistic link between cold exposure and AAI severity. Targeting ferroptosis might offer a novel therapeutic strategy for mitigating AAI under cold conditions.