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Senescence and Stress Signaling Pathways in Corneal Cells After Nitrogen Mustard Injury
Khandaker N Anwar1, Mohammad Soleimani1, Mohammad Javad Ashraf1
1Department of Ophthalmology and Visual Sciences, University of Illinois Chicago, Chicago, IL 60612, USA.
Abstract:
Mustard gas keratopathy (MGK), a complication of exposure to sulfur mustard, is a blinding ocular surface disease involving key cellular pathways, including apoptosis, oxidative stress, and inflammation. Recent studies indicate that cellular senescence contributes to the pathophysiology of mustard gas toxicity. This study aimed to assess senescence and stress-related pathways-particularly mitogen-activated protein kinase (MAPK) signaling-in nitrogen mustard (NM)-induced corneal injury. In vitro, primary human corneal epithelial (P-HCECs), primary human corneal mesenchymal stromal cells (hcMSCs), and human corneal-limbal epithelial cell (HCLE) lines were exposed to varying concentrations of NM. The results demonstrated a dose-dependent increase in cellular senescence, characterized by reduced Ki67 expression, elevated p16, and p21 mRNA levels, as well as activation of the MAPK pathway activation. Treatment with a selective p38-MAPK inhibitor significantly reduced senescence markers and improved cell proliferation following exposure to NM. Overall, these studies indicate that NM exposure triggers cellular senescence and stress-related MAPK signaling, while p38-MAPK inhibition mitigates these effects, suggesting a potential therapeutic strategy.
Insights
Nitrogen mustard (NM) exposure causes cellular senescence and activates stress pathways in the cornea. Inhibiting p38-MAPK reduces these effects, offering a potential treatment for mustard gas keratopathy.
Area of Science:
- Ocular toxicology
- Cellular senescence
- Molecular biology
Background:
- Mustard gas keratopathy (MGK) is a severe ocular complication of sulfur mustard exposure.
- Cellular senescence is increasingly recognized as a contributor to mustard gas toxicity.
- Mitogen-activated protein kinase (MAPK) signaling is implicated in stress responses.
Purpose of the Study:
- To investigate cellular senescence and MAPK signaling in nitrogen mustard (NM)-induced corneal injury.
- To evaluate the therapeutic potential of p38-MAPK inhibition in NM-induced corneal damage.
Main Methods:
- In vitro exposure of human corneal cells (P-HCECs, hcMSCs, HCLE) to varying NM concentrations.
- Assessment of senescence markers (Ki67, p16, p21) and MAPK pathway activation.
- Treatment with a selective p38-MAPK inhibitor post-NM exposure.
Main Results:
- NM exposure induced a dose-dependent increase in cellular senescence.
- Elevated p16 and p21 mRNA levels and reduced Ki67 expression were observed.
- MAPK pathway, specifically p38-MAPK, was activated by NM.
- p38-MAPK inhibition significantly reduced senescence markers and enhanced cell proliferation.
Conclusions:
- Nitrogen mustard exposure triggers cellular senescence and stress-related MAPK signaling in corneal cells.
- p38-MAPK inhibition demonstrates a protective effect, mitigating senescence and promoting cell recovery.
- Targeting p38-MAPK represents a promising therapeutic strategy for managing NM-induced ocular injury.
