Mechanism of retinoic acid and mitogen-activated protein kinases regulating hyperoxia lung injury.
To investigate the protective effect of retinoic acid (RA) on hyperoxic lung injury and the role of RA as a modulator on mitogen-activated protein kinases (MAPKs), gastation 21 d Sprague-Dawley (SD) fetuses (term = 22 d) were delivered by hysterotomy. Within 12-24 h of birth, premature rat pups were randomly divided into 4 groups (n=12 each): air-exposed control group (group I); hyperoxia-exposed group (group II), air-exposed plus RA group (group III), hyperoxia-exposed plus RA group (group IV). Group I, III were kept in room air, and group II, IV were placed in 85 % oxygen. The pups in groups III and IV were intraperitoneally injected with RA (500 microg/kg every day). All lung tissues of premature rat pups were collected at the 4th day after birth. Terminal transferase d-UTP nick end labeling (TUNEL) staining was used for the detection of cell apoptosis. The expression of PCNA was immunohistochemically detected. Western blot analysis was employed for the determination of phosphorylated and total nonphosphorylated ERKs, JNKs or p38. Our results showed that lungs from the pups exposed to hyperoxia for 4 d exhibited TUNEL-positive nuclei increased markedly throughout the parenchyma (P<0.01), and decreased significantly after RA treatment (P<0.01). The index of PCNA-positive cells was significantly decreased (P<0.01), and was significantly increased by RA treatment (P<0.01). The air-space size was significantly enlarged, secondary crests were markedly decreased in hyperoxia-exposed animals. RA treatment improved lung air spaces and secondary crests in air-exposed pups, but had no effect on hyperoxia-exposure pups. Western blotting showed that the amounts of JNK, p38 and ERK proteins in hyperoxia-exposure or RA-treated lung tissues were same as those in untreated lung tissues (P>0.05), whereas activation of these MAPKs was markedly altered by hyperoxia and RA. After hyperoxia exposure, p-ERK1/2, p-JNK1/2 and p-p38 were dramatically increased (P<0.01), whereas p-JNK1/2 and p-p38 were markedly declined and p-ERK1/2 was further elevated by RA treatment (P<0.01). It is concluded that RA could decrease cell apoptosis and stimulate cell proliferation under hyperoxic condition. The protection of RA on hyperoxia-induced lung injury was related to the regulation of MAP kinase activation.
Li
Wenbin
W
Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Chang
Liwen
L
Rong
Zhihui
Z
Zhang
Qianshen
Q
Wang
Hua
H
Wang
Hong
H
Liu
Chunmei
C
Liu
Wei
W
D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D000860:Hypoxia / Q000150:complications*; D020287:In Situ Nick-End Labeling; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D014212:Tretinoin / Q000494:pharmacology*
D014212:Tretinoin; D020928:Mitogen-Activated Protein Kinases