[Cross-talk between calcineurin and protein kinases in airway remodeling in asthma]

To determine the role of cross-talk between calcineurin-dependent signal transduction pathway and protein kinase C (PKC), mitogen-activated protein kinase (MAPK) and protein kinase A (PKA) in airway remodeling in asthma.

Male guinea pigs were sensitized with intraperitoneal injections of ovabumin (OVA), then treated with cyclosporin A (CsA, 5 mg/kg), an inhibitor of calcineurin, then inhaled OVA for 2 weeks 14 days later. Activities of calcineurin, PKC, MAPK, and PKA were was analyzed by phosphorylation and dephosphorylation. In primary cultures of rat airway smooth muscle cells (ASMC), activities of calcineurin, PKC, MAPK, and cross-talk induced by urotensin II (UII ), a recently identified strong mitogen, were measured.

(1) The activities of calcineurin, MAPK and PKC increased by 19% (P<0.01), 28% (P<0.01) and 35% (P<0.05), respectively, in the asthmatic group compared with controls but decreased by 52% (P<0.01), 18% (P<0.05) and 52% (P<0.01), respectively, in the CsA group compared with asthmatic group. PKA activity in the asthma group decreased by 53% (P<0.01) compared with controls but increased by 2.65-fold (P<0.01) in the CsA group compared with the asthma group. (2) UII 10(-7) mol/L stimulated ASMC PKC and MAPK activities by 44% and 24% (P<0.01), respectively, after incubating for 20 min. It increased CaN activity in a time-dependent manner, being 1.67 times that of the control for 24 h (P<0.01). (3) CsA 10(-6) mol/L and H(7) 50 micromol/L, an inhibitor of PKC, inhibited UII-stimulated CaN activity by 45% (P<0.01) and 21% (P<0.05), respectively, while PD(98059) 50 micromol/L, an inhibitor of MAPK, had no effect on CaN activity (P>0.05). (4) CsA 10(-6) mol/L inhibited UII-stimulated PKC activity by 14% (P<0.05), while having no effect on MAPK activity (P>0.05).

The signal transduction pathways between calcineurin and other protein kinases such as PKC, MAPK and PKA have cross-talk in airway remodeling in asthma.