| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥2,600,000 (Direct Cost: ¥2,600,000)
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| Research Abstract |
Predominance of Th2 cytokines compared to Th1 cytokines has been hypothesized to cause bronchial asthma. Major pathogenesis of bronchial asthma is inflammation and hyperresponsiveness of the airway. However, causal relationship between Th2 cytokines and the development of airway hyperresponsiveness has not been fully clarified. We have examined the effects of interleukin 4 (IL4) and 13 (IL13), Th2 cytokines, on the contractility of bovine tracheal smooth muscle cells (BTSMC). Pretreatment of BTSMC-embedded collagen gel lattice with IL4 suppressed ATP- and A23187-induced contraction of the gels, whereas IL13 markedly augmented the gel contraction. IL4 and IL13, however, did not affect the [Ca^<2+>]_i elevation and phosphorylation of contractile proteins induced by these stimuli in BTSMC, indicating that IL4 and IL13 do not affect the contractility of smooth muscle cells. We have observed that IL4 markedly and IL13 moderately increased the expression of matrix metalloprotease-1 (MMP-1) mRNA in BTSMC. Protein level of MMP-1 in the culture medium was also markedly increased by IL4, and moderately increased by IL13. The exogenous application of low concentration of MMP-1 induced the augmentation of the BTSMC-embedded collagen gels, and high concentration of MMP-1 leaded to the inhibition of gel contraction. Also, galardin, a non-specific inhibitor of MMP, suppressed both IL4- and IL13-induced effects on gel contraction. We have concluded from these results that Th2 cytokines induce the production of MMP-1 in airway smooth muscle cells, thereby digesting the extracellular matrix and changing tissue elasticity. We suppose these are partially responsible for the airway remodeling and hyperresponsiveness induced by Th2 cytokines. Furthermore, since airway epithelial cells are reported to generate MMP-1, we suppose that this mechanism plays a role in the possible functional interaction between epithelium and smooth muscle cells.
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