[Regulative mechanism of dexamethasone on Toll-like receptor 4 signal transduction of infant asthma rat].
OBJECTIVE
Eosinophilic airway inflammation is one of the basic characteristics of allergic asthma. Toll-like receptor is one of the most important innate immunity pattern recognition receptors. Glucocorticoids (GCS) are still the most effective treatment for asthma. However, few reports of studies on regulatory mechanism of GCS on the innate immunity system are available. The mechanism of effects of GCS on TLR4 is unclear. The present study aimed at understanding the effect of dexamethasone (DXM) on change of TLR4 and mechanism of regulatory effect of TLR4 on eosinophil (EOS) apoptosis.


METHODS
Twenty-seven Sprague-Dawley (SD) rats (age 28 to 42 days, body weight 120 to 180 gram) were randomly divided into the control group, asthma group and DXM group with 9 in each. Asthma model rats were sensitized with the mixture of ovalbumin (OVA, 1 mg) and Al (OH)(3), 100 mg on day 1 and day 8, repeatedly exposed to aerosolized OVA after day 15, once a day for three days and continued for 30 minutes at every time. During the sensitization stage, 100 microg/ml DXM were prepared with DXM group for every other day, and the same doses DXM were prepared for every day on the stage of challenge. The histopathological changes of lung tissues were observed with light microscope (LM). EOS and other inflammatory cells in bronchoalveolar lavage fluid (BALF) were counted; the concentrations of OVA-sIgE in serum were measured by using "sandwich" ELISA; The expressions of TLR4 mRNA were determined by in situ hybridization, the apoptosis of EOS was detected by TUNEL.


RESULTS
(1) LM showed many inflammatory cells infiltration around the bronchi and blood vessels, bronchus mucus increased, airway epithelium damage and desquamation, and airway mucous plugs in asthma group, whereas DXM group showed significantly milder changes. (2) Inflammationary cells count in BALF of asthma group was significantly higher as compared to control group (P < 0.01); compared with asthma group, the total cell count, EOS absolute count and EOS% were all significantly decreased in DXM group [(2.14 +/- 0.10) x 10(9)/L, (4.78 +/- 1.23) x 10(7)/L, (2.17 +/- 0.25)%]. (3) Levels of OVA-sIgE in serum of asthma group [(83.40 +/- 6.80) microg/ml] were significantly higher than those of the control group [(14.38 +/- 4.25) microg/ml] (P < 0.01), while those of DXM group [(45.02 +/- 7.47) microg/ml] were significantly lower than asthma group (P < 0.0 1). (4) There were no significant differences in TLR4 mRNA detected by in situ hybridization between control group (24.71 +/- 0.85) and asthma group (25.81 +/- 3.56) (P > 0.05); but it significantly increased in DXM group (29.86 +/- 3.92) as compared to asthma group. (5) The percentages of apoptotic EOS in asthma group [(7.39 +/- 1.93)%] were significantly lower than those in control group [(9.06 +/- 1.52)%] (P < 0.01); and significantly higher in DXM group [(13.33 +/- 1.09)%] than in asthma group (P < 0.01). There were significantly positive correlations between TLR4 mRNA and the percentage of apoptotic EOS (r = 0.612, P < 0.01).


CONCLUSIONS
DXM can decrease OVA-sIgE level, induce EOS apoptosis, which may correlate with the activation of TLR4 signal transduction.
Su
Miao-shang
MS
Department of Respiratory Diseases, Yuying Children's Hospital of Wenzhou Medical College, Wenzhou 325027, China.
Li
Chang-chong
CC
Lin
Li
L
Zheng
Ji-shan
JS
Zheng
Yang-ming
YM
Guan
Xiao-jun
XJ
Zhang
Wei-xi
WX
Luo
Yun-chun
YC
D000818:Animals; D017209:Apoptosis; D001249:Asthma / Q000139:chemically induced / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000494:pharmacology*; D004804:Eosinophils / Q000276:immunology*; D005938:Glucocorticoids / Q000494:pharmacology; D007073:Immunoglobulin E / Q000097:blood; D008168:Lung / Q000473:pathology; D010047:Ovalbumin; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D051197:Toll-Like Receptor 4 / Q000276:immunology / Q000378:metabolism*
D005938:Glucocorticoids; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E; D003907:Dexamethasone; D010047:Ovalbumin