Doxycycline reduces airway inflammation and hyperresponsiveness in a murine model of toluene diisocyanate-induced asthma.
BACKGROUND
Toluene diisocyanate (TDI) is a leading cause of occupational asthma. Although considerable controversy remains regarding its pathogenesis, TDI-induced asthma is an inflammatory disease of the airways characterized by airway remodeling caused, at least in part, by an excess of extracellular matrix deposition in the airway wall. Matrix metalloproteinases (MMPs) are major proteolytic enzymes that are involved in extracellular matrix turnover because of their ability to cleave all proteins constituting extracellular matrix. Previous studies have reported that MMP-9 might play a role in chronic airway inflammation and remodeling in asthma.


OBJECTIVE
An aim of the current study was to evaluate the effects of MMP-inhibiting antibiotic, doxycycline, and MMP inhibitors on hyperresponsiveness and inflammation of the airways in TDI-induced asthma.


METHODS
We used a murine model for TDI-induced asthma to examine the effect of doxycycline or MMP inhibitors on bronchial inflammation and airway hyperresponsiveness.


RESULTS
The following typical pathophysiologic features are observed in the lungs of the mice: airway inflammation, airway hyperresponsiveness, and increased expression of MMP-9 mRNA and protein. Administration of doxycycline and MMP inhibitors reduced all of these pathophysiologic findings. In addition, the increased phosphorylated Akt but not Akt protein levels in lung tissues after TDI inhalation were significantly reduced by the administration of doxycycline and MMP inhibitors.


CONCLUSIONS
These findings suggest that doxycycline may reduce airway inflammation and hyperresponsiveness through phosphatidylinositol 3-kinase pathway in a murine model of TDI-induced asthma.
Lee
Kyung S
KS
Department of Internal Medicine, Research Center for Allergic Immune Diseases, Chonbuk National University Medical School, 634-18 Keumamdong, Jeonju 561-712, South Korea.
Jin
Sun M
SM
Kim
Seung S
SS
Lee
Yong C
YC
D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D004195:Disease Models, Animal; D004318:Doxycycline / Q000627:therapeutic use*; D005260:Female; D007249:Inflammation / Q000188:drug therapy; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011480:Protease Inhibitors / Q000627:therapeutic use; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014051:Toluene 2,4-Diisocyanate / Q000633:toxicity
D000900:Anti-Bacterial Agents; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D012333:RNA, Messenger; D014051:Toluene 2,4-Diisocyanate; D010047:Ovalbumin; D020780:Matrix Metalloproteinase 9; D004318:Doxycycline