Role of MAPK/AP-1 signaling pathway in the protection of CEES-induced lung injury by antioxidant liposome.
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.
Mukhopadhyay
Sutapa
S
Department of Cancer Biology, Meharry Medical College, 1005 David Todd Blvd., Nashville, TN 37208, USA.
Mukherjee
Shyamali
S
Stone
William L
WL
Smith
Milton
M
Das
Salil K
SK
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
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