Activation of MAPK/AP-1 signaling pathway in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard gas analog.

Abstract

We reported earlier that the activation of free-radical-mediated tumor necrosis factor-alpha (TNF-alpha) cascade is the major pathway in the inflammatory lung disease induced by 2-chloroethyl ethyl sulfide (CEES), a mustard gas analog. TNF-alpha induces activating protein 1 (AP-1) activation via phosphorylation of mitogen activated protein kinases (MAPKs). The present study examines the relationship between CEES induced lung injury and MAPKs signaling pathway. Adult guinea pigs received single intratracheal injection of different doses of CEES and were sacrificed at different time points. CEES exposure caused lung injury with evidence of fibrosis. The optimum activation of all members of the MAPKs family (ERK1/2, p38 and JNK1/2) was achieved at 0.5 mg/kg dose and at 1h. No significant change was observed beyond that time point. This led to an activation of AP-1 transcription factors associated with an increase in the protein levels of Fos, activating transcription factor (ATF) and Jun family members. To explore the involvement of AP-1 in cell proliferation, we determined the protein levels of cell cycle protein cyclin D1 and cell differentiation marker proliferating cell nuclear antigen (PCNA). An up regulation of these proteins was observed. Hence it is suggested that CEES exposure causes accumulation of TNF-alpha, which is associated with an activation of MAPK/AP-1 signaling pathway and cell proliferation. Further studies are needed to clarify whether the observed effects are the adaptive responses of the lung or they contribute to the lung injury.

• Authors: Sutapa Mukhopadhyay, Shyamali Mukherjee, Milton Smith, Salil K Das
• Journal: Toxicology letters (Toxicol Lett) Vol. 181 Issue 2 Pg. 112-7 (Sep 26 2008) ISSN: 0378-4274 [Print] Netherlands
• PMID: 18675330 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Proliferating Cell Nuclear Antigen
• Transcription Factor AP-1
• Tumor Necrosis Factor-alpha
• Cyclin D1
• 2-chloroethyl ethyl sulfide
• DNA
• Mustard Gas

Topics

• Animals
• Blotting, Western
• Cyclin D1 (analysis)
• DNA (metabolism)
• Guinea Pigs
• Lung (drug effects)
• MAP Kinase Signaling System (drug effects)
• Male
• Mustard Gas (analogs & derivatives, toxicity)
• Proliferating Cell Nuclear Antigen (analysis)
• Signal Transduction (drug effects)
• Transcription Factor AP-1 (physiology)
• Tumor Necrosis Factor-alpha (biosynthesis)