Heme oxygenase-1 upregulation improves lipopolysaccharide-induced acute lung injury involving suppression of macrophage migration inhibitory factor.
Although studies have demonstrated that heme oxygenase-1 (HO-1) prevents leukocyte infiltration and organ damage following LPS challenge, the mechanisms involved in this protection are incompletely understood. Macrophage migration inhibitory factor (MIF) is thought to play a pivotal role in modulation of inflammatory and immune response through upregulation of TLR4 expression. Activation of TLR4 results in the production of proinflammatory mediators including MIF, which induce neutrophils recruitment and subsequent tissue insults. We hypothesized that HO-1 mediates its salutary effects in lipopolysaccharide (LPS)-induced inflammatory lung injury via downregulation of MIF through modulation of TLR4-induced proinflammatory mediator production. Compared with wild-type cells, MIF-knockdown macrophages in vitro are hyporesponsive to LPS stimulation, as shown by a profound reduction in TLR4 expression and TNF-alpha production. In the murine model of LPS-induced acute lung injury, administration of CoPP, a potent HO-1 inducer, leaded to a significant reduction in LPS-induced pulmonary edema, leucocytes influx, myeloperoxidase activity as well as histopathologic insults. Most strikingly, pretreatment with CoPP markedly decreased the expression of TLR4 and MIF in lung tissues in response to LPS challenge. These findings herein suggest that the cytoprotective functions of HO-1 in LPS-induced lung injury are associated with negative regulation of lung MIF and TLR4-induced inflammatory response.
Yin
Hui
H
Department of Microbiology and Immunology, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Li
Xiangyong
X
Gong
Quan
Q
Jin
Xiaobao
X
Gu
Hongbiao
H
Yuan
Baohong
B
Zhang
Bobin
B
Zheng
Fang
F
Gong
Feili
F
Zhu
Jiayong
J
D055371:Acute Lung Injury / Q000139:chemically induced / Q000503:physiopathology*; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D007249:Inflammation; D019746:Intramolecular Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis* / Q000235:genetics; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D008070:Lipopolysaccharides; D008263:Macrophage Migration-Inhibitory Factors; D008565:Membrane Proteins; D011719:Pyrazines; D011758:Pyrroles; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C484301:cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine; C440499:lipopolysaccharide, Escherichia coli O111 B4; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D019746:Intramolecular Oxidoreductases; C076231:Mif protein, mouse