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Mechanisms of Apoptosis and Pulmonary Fibrosis Resulting From Sulfur Mustard-Induced Acute Pulmonary Injury in Rats
Xiaoxuan Hu1,2, Na Zhang3, Yuxu Zhong2
1Weifang No. 2 People's Hospital, Weifang Respiratory Disease Hospital, Weifang, China.
Abstract:
Sulfur mustard (SM) is a highly toxic bifunctional alkylating agent that inflicts severe damage on the respiratory tract. Although numerous studies have examined the mechanisms underlying SM-induced pulmonary injury, the exact pathways involved remain unclear. This study aims to investigate an acute pulmonary injury model, with SM administered as a single intraperitoneal injection (8 mg/kg) or single intratracheal instillation (2 mg/kg) at equal toxicity doses (1LD50). The results revealed that epithelial cells in the alveolar septa of the intraperitoneal SM group exhibited a significantly higher expression of apoptotic markers, including pro-apoptotic protein Bax, caspase-3, and caspase-9 proteins, than those in the tracheal SM group. Conversely, the expression of the anti-apoptotic protein Bcl-2 was significantly lower in the intraperitoneal SM group than in the tracheal SM group, as confirmed by TUNEL staining and immunohistochemical staining. The intraperitoneal SM group exhibited markedly higher expression of fibrosis-related proteins, including MMP-2, MMP-9, TIMP-1, TIMP-2, collagen type I, collagen type III, TGF-β1, and Smad7, than the tracheal SM group. These markers, detected through immunohistochemical immunolabeling, indicate a more significant fibrotic response in the intraperitoneal group. In summary, this study demonstrates that intraperitoneal exposure to SM results in increased apoptosis, elevated expression of pro-apoptotic proteins, and fibrosis-related proteins in the alveolar epithelial cells compared with intratracheal exposure, even at equivalent toxicity levels. Our findings highlight the suitability of the intraperitoneal route for further investigation and identify apoptotic and fibrosis-related proteins as potential targets for intervention in SM-induced pulmonary injury.
Insights
Intraperitoneal sulfur mustard (SM) exposure causes greater lung cell apoptosis and fibrosis than intratracheal exposure. This highlights SM
Area of Science:
- Toxicology
- Pulmonary Medicine
- Cellular Biology
Background:
- Sulfur mustard (SM) is a potent chemical warfare agent causing severe respiratory tract damage.
- Mechanisms of SM-induced pulmonary injury are not fully understood.
- Investigating different exposure routes is crucial for understanding SM toxicity.
Purpose of the Study:
- To compare the effects of intraperitoneal versus intratracheal sulfur mustard exposure on acute pulmonary injury.
- To identify key molecular pathways involved in SM-induced lung damage.
- To evaluate potential therapeutic targets for SM poisoning.
Main Methods:
- Acute pulmonary injury model using intraperitoneal injection or intratracheal instillation of SM at equivalent toxicity doses (1 LD50).
- TUNEL staining and immunohistochemical staining to assess apoptosis and protein expression.
- Analysis of apoptotic markers (Bax, caspase-3, caspase-9, Bcl-2) and fibrosis-related proteins (MMP-2, MMP-9, TIMP-1, TIMP-2, collagen I, collagen III, TGF-β1, Smad7).
Main Results:
- Intraperitoneal SM exposure led to significantly higher expression of pro-apoptotic proteins (Bax, caspase-3, caspase-9) and lower expression of anti-apoptotic protein (Bcl-2) in alveolar epithelial cells compared to intratracheal exposure.
- The intraperitoneal group showed markedly higher expression of fibrosis-related proteins, indicating a more pronounced fibrotic response.
- TUNEL and immunohistochemical staining confirmed increased apoptosis and fibrosis in the intraperitoneal SM group.
Conclusions:
- Intraperitoneal sulfur mustard exposure induces greater apoptosis and fibrosis in the lungs than intratracheal exposure, even at equivalent toxicity levels.
- Apoptotic and fibrosis-related proteins are key mediators of SM-induced pulmonary injury.
- The intraperitoneal route is suitable for further research, and identified proteins are potential therapeutic targets.
