Knockdown of placental growth factor (PLGF) mitigates hyperoxia-induced acute lung injury in neonatal rats: Suppressive effects on NFκB signaling pathway.
Although supplemental high-level oxygen treatment can promote the survival of premature infants, hyperoxia may adversely induce acute lung injury (ALI) in newborns. Our prior work illustrated that hyperoxic exposure could enhance the release of placental growth factor (PLGF) in the lungs of neonatal rats. We therefore postulated that PLGF contributed to hyperoxic ALI in newborns and evaluated the anti-PLGF treatment mediated by systematic delivery of lentivirus in hyperoxic ALI in this study. Lentivirus particles containing PLGF specific shRNA were injected into neonatal rats prior to hyperoxic exposure (90% oxygen for 72h) to inhibit PLGF expression. Hyperoxia induced oxidative damages in lung tissues as evidenced by the increased malondialdehyde and myeloperoxidase, and the decreased antioxidant superoxide dismutase. Also, hyperoxia caused excessive infiltration of inflammatory cells and overproduction of proinflammatory cytokines (tumor necrosis factor-α, interleukin-1β and interleukin-6) in rat lung tissue. These pathological alterations were partly reversed by PLGF shRNA delivery. The expression levels and activities of metalloproteinase (MMP)-2 and MMP9 were up-regulated in response to hyperoxia, whereas down-regulated when PLGF was inhibited. Moreover, PLGF shRNA inhibited nuclear factor kappa B (NFκB) signaling delivery in hyperoxic rat lungs. Additionally, exogenous PLGF-induced activation of MMPs in rat RLE-6TN alveolar epithelial cells was suppressed by NFκB inhibitor pyrrolidine dithiocarbamate. These results suggest that therapy targeting PLGF may be beneficial for infants with hyperoxic ALI.
Department of Neonatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China. Electronic address: lzhang@cmu.edu.cn.
Liang
L
Zhang
Department of Pediatrics, Shenyang Fourth People's Hospital, Shenyang, Liaoning 110003, People's Republic of China.
Shuang
S
Zhao
Department of Biochemistry and Molecular Biology, Harbin Medical University (Daqing Campus), Daqing, Heilongjiang 163319, People's Republic of China.
Lijie
L
Yuan
Department of Neonatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Hongmin
H
Wu
Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Hong
H
Jiang
Department of Pediatrics, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Gang
G
Luo
Department of Neonatology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, People's Republic of China.
Shimeng
S
Zhao
D055371:Acute Lung Injury / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002460:Cell Line; D016207:Cytokines / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D018496:Hyperoxia / Q000378:metabolism*; D008168:Lung / Q000473:pathology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D000072483:Placenta Growth Factor / Q000235:genetics / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013482:Superoxide Dismutase / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology
D016207:Cytokines; D016328:NF-kappa B; C000608038:Pgf protein, rat; D011759:Pyrrolidines; D034741:RNA, Small Interfering; D013859:Thiocarbamates; D000072483:Placenta Growth Factor; C020972:pyrrolidine dithiocarbamic acid; D013482:Superoxide Dismutase; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
ALI; Hyperoxia; Inflammation; NFκB signaling pathway; Oxidative stress damage; PLGF