**7. Conclusions**

phatidylinositol 3-kinase (PI3K), p70S6 kinase, and glycogen synthase kinase-3 (GSK-3) [150, 152]. The involvement of the Rho family (RhoA, Rac and Cdc42) in the control mechanisms of airway smooth muscle cell proliferation has not been sufficiently clarified. EGF- and PDGFinduced cell proliferation is not suppressed by inactivation of RhoA/Rho-kinase signaling [126]; in contrast, the activation of RhoA, not Rac or cdc42, causes the proliferation of human bronchial smooth muscle cells that have been stimulated with serum. This proliferative reaction is suppressed by Y-27632, C3 exoenzyme, and simvastatin, a HMG-CoA reductase inhibitor, which attenuate proliferation via the geranylgeranylation of RhoA [153]. Another factor, M2 muscarinic receptor, facilitates the proliferation of airway smooth muscle cells [154, 155]. A recent clinical trial has demonstrated that an antagonist of VDC channels inhibits airway remodeling in patients with severe asthma [156]. Therefore, Ca2+ influx via VDC

airway smooth muscle [7, 8]. These results indicate that both Ca2+ dynamics and Ca2+ sensiti‐

Cell migration is a characteristic function of inflammatory cells, fibroblasts and smooth muscle cells, and it plays an important role in various pathophysiological environments, such as inflammatory cell infiltration and airway smooth muscle hyperplasia [157]. Migration of airway smooth muscle cells is enhanced by the extracellular matrix [158]. Cell migration occurs due to contraction involving actin, myosin reactions and actin reorganization. Since RhoA/ Rho-kinase signaling is the most important factor controlling the cytoskeleton of airway smooth muscle cells and other cells [159], this pathway may control the migration of airway smooth muscle cells via changes in the cytoskeleton. Hence, RhoA/Rho-kinase may be involved in airway remodeling mediated not only by cell proliferation but also by cell migration. Urokinase, PDGF, leukotriene and lysophosphatidic acid facilitate the migration of human airway smooth muscle cells [160, 161, 162, 163]. Moreover, heat shock protein, PI3K, p38 mitogen-activated protein kinase, prostaglandin D2, and IL-13 facilitate airway smooth muscle migration [160, 164, 165]. Y-27632 significantly suppresses the increased migration of airway smooth muscle cells, due to PDGF or leukotriene stimulation [161, 162], indicating that RhoA/Rho-kinase signaling (Ca2+ sensitization) plays an important role in controlling cell migration (Figure 5). On the other hand, Ca2+ dynamics regulate the migration of airway smooth muscle cells and inflammatory cells. Ca2+ influx via SOC channels contributes to PDGF-

when MCh is applied to

via other

channels is enhanced since KCa channel activity is attenuated by Gi

*6.4.2. Cell migration*

314 Muscle Cell and Tissue

zation contribute to the proliferation of airway smooth muscle cells (Figure 5).

induced cell migration of airway smooth muscle [166], and increasing [Ca2+]i

induced by IL-13 may be regulated by Ca2+ dynamics [168].

*6.4.3. Interaction between airway smooth muscle and inflammatory cells*

mechanisms also causes substance P–induced cell migration of airway smooth muscle [167] (Figure 5). Since IL-13 enhances Ca2+ oscillation in airway smooth muscle cells, cell migration

As described earlier, contractility of airway smooth muscle is altered by tryptase and S1P, which are released from mast cells, and Lyso-PC, which is synthesized in the membrane of various inflammatory cells [108, 112, 140, 141]. Ca2+ sensitization by RhoA/Rho-kinase

Ca2+ signaling, which is due to Ca2+ dynamics and Ca2+ sensitization, contributes to alterations of contractility that lead to airway disorders (airflow limitation, airway hyperresponsiveness, and β2-adrenergic desensitization), which are characteristic features of asthma and COPD. Ca2+ dynamics and Ca2+ sensitization also facilitate the proliferation and migration of airway smooth muscle via changing to proliferative phenotype. A recent report has indicated that bitter taste receptor stimulation causes relaxation of airway smooth muscle via activation of KCa channels [177]. Hence, Ca2+ dynamics due to G proteins/KCa/VDC channels and Ca2+ sensitization due to RhoA/Rho-kinase processes may be therapeutic targets for asthma and COPD, and research in these areas may provide novel strategies in the development of bronchodilators for these diseases.
