Low-dose dexamethasone alleviates lipopolysaccharide-induced acute lung injury in rats and upregulates pulmonary glucocorticoid receptors.
OBJECTIVE
The major causes of mortality among patients who survive acute lung injury/ARDS (ALI/ARDS) are due to the extensive tissue remodelling and fibrosis. Use of high-dose glucocorticoids to reduce these inflammatory and fibroproliferative responses has been shown to do more harm than good. Recently, Meduri et al. found that the early use of low-dose prolonged methylprednisolone in patients with severe ALI/ARDS significantly relieved the systemic inflammatory response and improved pulmonary and extrapulmonary organ function. This study investigated the therapeutic effect of low-dose dexamethasone (Dex) on inflammation and fibrosis in LPS-induced ALI in rats and its influence on the expression of the pulmonary glucocorticoid receptor (GR).


METHODS
Eighty Wistar rats were randomly divided into four groups: a control group (intraperitoneal normal saline injection (5 mL/kg) throughout experiment, n = 24); the LPS model group (LPS injection (5 mg/kg) for 3 days and normal saline thereafter, n = 24); the LPS + Dex group (LPS injection for 3 days and Dex solution (5 mg/kg) thereafter, n = 16); and the Dex group (normal saline injection (5 mL/kg) for 3 days and Dex solution (5 mg/kg) thereafter, n = 16). Levels of tumor necrosis factor-alpha, matrix metallopeptidase-9 and procollagen N-terminal propeptide type I in BAL fluid were examined by ELISA on the third, seventh and fourteenth days after injection. Pulmonary hydroxyproline content was measured and histological examination was performed with haematoxylin-eosin and Victoria blue-ponceau. Pulmonary distribution of GR-positive cells was examined immunohistochemically, and expression of GR mRNA and protein was determined by RT-PCR and western blot analysis.


RESULTS
Histological assessments showed that pulmonary fibrosis occurred in parallel with inflammation in the rat ALI model. Compared with the LPS group, the inflammation and fibrosis parameters were significantly improved in the LPS + Dex group at different periods after injection (P < 0.05 or P < 0.01), although parameters in the LPS + Dex group were not as good as those of the control group. GR mRNA and protein expression in the LPS + Dex group were markedly higher than that of the LPS group on the seventh and the fourteenth days (both P < 0.01). Western blotting showed that Dex also promoted the nuclear translocation of GR protein.


CONCLUSIONS
Low-dose Dex can reduce pulmonary inflammation and fibrosis after LPS-induced ALI in rats and can elevate GR expression in the lung, probably through upregulating GR levels and promoting the nuclear translocation of GR protein.
Wang
Xiao-Qiu
XQ
Department of Respiratory Medicine, Shanghai First People's Hospital of Shanghai Jiaotong University, Shanghai, China.
Zhou
Xin
X
Zhou
Yan
Y
Rong
Ling
L
Gao
Lei
L
Xu
Wei
W
D055371:Acute Lung Injury / Q000188:drug therapy* / Q000503:physiopathology*; D000818:Animals; D015153:Blotting, Western; D003907:Dexamethasone / Q000008:administration & dosage*; D005938:Glucocorticoids / Q000008:administration & dosage*; D006909:Hydroxyproline / Q000032:analysis; D007150:Immunohistochemistry; D008070:Lipopolysaccharides; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D010446:Peptide Fragments / Q000032:analysis; D011347:Procollagen / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011965:Receptors, Glucocorticoid / Q000008:administration & dosage* / Q000187:drug effects* / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D005938:Glucocorticoids; D008070:Lipopolysaccharides; D010446:Peptide Fragments; D011347:Procollagen; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C047202:procollagen Type I N-terminal peptide; D003907:Dexamethasone; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline