Dexamethasone Targets Actin Cytoskeleton Signaling and Inflammatory Mediators to Reverse Sulfur Mustard-Induced Toxicity in Rabbit Corneas

Rama Kant,Neha Mishra,Kushal Kandhari,Laura Saba,Cole Michel,Richard Reisdorph,Neera Tewari-Singh,Mina B. Pantcheva,J. Mark Petrash,Chapla Agarwal,Rajesh Agarwal

Toxicology and Applied Pharmacology（2024）SCI 3区SCI 2区

Univ Colorado | Michigan State Univ

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Abstract

Purpose: Sulfur mustard (SM), a bi-functional alkylating agent, was used during World War I and the Iran -Iraq war. SM toxicity is ten times higher in eyes than in other tissues. Cornea is exceptionally susceptible to SMinjuries due to its anterior positioning and mucous -aqueous interphase. Ocular SM exposure induces blepharitis, photosensitivity, dry eye, epithelial defects, limbal ischemia and stem cell deficiency, and mustard gas keratopathy leading to temporary or permanent vision impairments. We demonstrated that dexamethasone (Dex) is a potent therapeutic intervention against SM-induced corneal injuries; however, its mechanism of action is not well known. Investigations employing proteomic profiling (LC-MS/MS) to understand molecular mechanisms behind SM-induced corneal injury and Dex efficacy were performed in the rabbit cornea exposed to SM and then received Dex treatment. PEAKS studio was used to extract, search, and summarize peptide identity. Ingenuity Pathway Analysis was used for pathway identification. Validation was performed using immunofluorescence. One -Way ANOVA (FDR < 0.05; p < 0.005) and Student's t -test (p < 0.05) were utilized for analyzing proteomics and IF data, respectively. Proteomic analysis revealed that SM-exposure upregulated tissue repair pathways, particularly actin cytoskeleton signaling and inflammation. Prominently dysregulated proteins included lipocalin2, coronin1A, actin -related protein2, actin -related protein2/3 complex subunit2, actin -related protein2/3 complex subunit4, cell division cycle42, ezrin, bradykinin/kininogen1, moesin, and profilin. Upregulated actin cytoskeleton signaling increases F -actin formation, dysregulating cell shape and motility. Dex reversed SMinduced increases in the aforementioned proteins levels to near control expression profiles. Dex aids corneal wound healing and improves corneal integrity via actin cytoskeletal signaling and anti-inflammatory effects following SM-induced injuries.

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Key words

Cornea,Sulfur mustard,Dexamethasone,Proteomics,Actin cytoskeleton signaling,Cell division cycle 42

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