Lymphocyte-derived microparticles induce apoptosis of airway epithelial cells through activation of p38 MAPK and production of arachidonic acid.
The airway epithelium is critical for the normal integrity and function of the respiratory system. Excessive epithelial cell apoptosis contributes to cell damage and airway inflammation. We previously demonstrated that lymphocyte-derived microparticles (LMPs) induce apoptosis of human bronchial epithelial cells. However, the underlying mechanisms contributing to LMPs-evoked epithelial cell death are largely unknown. Here we used bronchial and lung tissue cultures to confirm the pro-apoptotic effects of LMPs. In cell culture experiments, we found that LMPs induced human airway epithelial cell apoptosis with associated increases in caspase-3 activity. In addition, LMPs treatment triggered oxidative stress in epithelial cells by enhancing production of malondialdehyde, superoxide, and reactive oxygen species (ROS), and by inhibiting production of the antioxidant glutathione. Moreover, decreasing cellular ROS with the antioxidant N-acetylcysteine rescued epithelial cell viability. Together, these results demonstrate an important role for oxidative stress in LMPs-induced cell death. In epithelial cells, LMPs treatment induced phosphorylation of p38 MAPK and arachidonic acid accumulation. Moreover, arachidonic acid was significantly cytotoxic towards LMPs-treated epithelial cells, whereas inhibition of p38 MAPK was protective against these cytotoxic effects. Similarly, inhibition of arachidonic acid production led to decreased caspase-3 activity, thus rescuing airway epithelial cells from LMPs-induced cell death. In conclusion, our results show that LMPs induce airway epithelial cell apoptosis by activating p38 MAPK signaling and stimulating production of arachidonic acid, with consequent increases in oxidative stress and caspase-3 activity. As such, LMPs may be regarded as deleterious markers of epithelial cell damage in respiratory diseases.
Department of Respiratory Medicine, Chongqing Southwest Hospital, Third Military Medical University, 30 Gaotanyan Street, Chongqing, 400038, China.
Qian
Q
Qiu
Wei
W
Xiong
Chun
C
Yang
Xiaotian
X
Dai
Xiaoping
X
Dan
Zaixing
Z
Yang
Yan
Y
Jiao
Yang
Y
Xiang
Guoxiang
G
Liu
Pierre
P
Hardy
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016718:Arachidonic Acid / Q000378:metabolism*; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055252:Cell-Derived Microparticles / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D016718:Arachidonic Acid; D048051:p38 Mitogen-Activated Protein Kinases; D000111:Acetylcysteine