title: Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome.
abstract: We have recently reported that antioxidant liposomes can be used as antidotes for mustard gas induced lung injury in guinea pigs. The maximum protection was achieved with a liposome composed of tocopherols (alpha, gamma, delta) and N-acetylcysteine (NAC) when administered after 5 min of exposure of 2-chloroethyl ethyl sulfide (CEES), a half sulfur mustard gas. We also reported an association of mustard gas-induced lung injury with an activation of MAPK/AP-1 signaling pathway and cell proliferation. The objective of the present study was to investigate whether CEES-induced MAPKs/AP-1 signaling pathway is influenced by antioxidant liposome therapy. A single dose (200 microl) of the antioxidant liposome was administered intratracheally after 5 min of exposure of CEES (0.5 mg/kg). The animals were sacrificed after 1h and 30 days of CEES exposure. Although the liposome treatment did not have any significant effect on the activation of the MAPKs family (ERK1/2, p38 and JNK1/2), it significantly counteracted the CEES-induced activation of AP-1 transcription factors and corresponding increase in the protein levels of Fos, ATF and Jun family members. The liposome treatment significantly blocked the CEES-induced increase in the protein levels of cyclin D1, a cell cycle protein and PCNA, a cell differentiation marker. Furthermore, it protected lung against CEES-induced inflammation and infiltration of neutrophils, eosinophils and erythrocytes in the alveolar space. This suggests that the protective effect of antioxidant liposome against CEES-induced lung damage is mediated via control of AP-1 signaling.
authors.affiliation: Department of Cancer Biology, Meharry Medical College, 1005 David Todd Blvd., Nashville, TN 37208, USA.
authors.forename: Sutapa
authors.initials: S
authors.lastname: Mukhopadhyay
authors.forename: Shyamali
authors.initials: S
authors.lastname: Mukherjee
authors.forename: William L
authors.initials: WL
authors.lastname: Stone
authors.forename: Milton
authors.initials: M
authors.lastname: Smith
authors.forename: Salil K
authors.initials: SK
authors.lastname: Das
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology*; D051696:Activating Transcription Factors / Q000378:metabolism; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000494:pharmacology*; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D019938:Cyclin D1 / Q000378:metabolism; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects; D006168:Guinea Pigs; D008081:Liposomes; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D055370:Lung Injury / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009151:Mustard Gas / Q000031:analogs & derivatives; D020556:Neutrophil Infiltration / Q000187:drug effects; D010766:Phosphorylation; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D011657:Pulmonary Eosinophilia / Q000139:chemically induced / Q000517:prevention & control; D013997:Time Factors; D024505:Tocopherols / Q000008:administration & dosage / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D051696:Activating Transcription Factors; D000931:Antidotes; D000975:Antioxidants; D001798:Blood Proteins; D008081:Liposomes; D018809:Proliferating Cell Nuclear Antigen; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019938:Cyclin D1; C031278:2-chloroethyl ethyl sulfide; D020928:Mitogen-Activated Protein Kinases; D024505:Tocopherols; D009151:Mustard Gas; D000111:Acetylcysteine