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Am J Physiol Lung Cell Mol Physiol 293: L883-L891, 2007. First published July 20, 2007; doi:10.1152/ajplung.00093.2007
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CAT-2 amplifies the agonist-evoked force of airway smooth muscle by enhancing spermine-mediated phosphatidylinositol-(4)-phosphate-5-kinase- activity

Inflammation Department, Wyeth Research, Cambridge, Massachusetts

Submitted 16 March 2007 ; accepted in final form 17 July 2007

We investigated the effect the loss of the CAT-2 gene (CAT-2–/–) has on lung resistance (R_L) and tracheal isometric tension. The R_L of CAT-2–/– mice at a maximal dose of acetylcholine (ACh) was decreased by 33.66% (P = 0.05, n = 8) compared with that of C57BL/6 (B6) mice. The isometric tension of tracheal rings from CAT-2–/– mice showed a significant decrease in carbachol (CCh)-induced force generation (33.01%, P < 0.05, n = 8) compared with controls. The isoproterenol- or the sodium nitroprusside-induced relaxation was not affected in tracheal rings from CAT-2–/– mice. The activity of iNOS and arginase in lung tissue lysates of CAT-2–/– mice was indistinguishable from that of B6 mice. Furthermore, the expression of phospholipase-C (PLC-) and phosphatidylinositol-(4)-phosphate-5-kinase- (PIP-5K-) was examined in the lung tissue of CAT-2–/– and B6 mice. The expression of PIP-5K- but not PLC- was significantly reduced in CAT-2–/– compared with B6 mice. The reduced airway smooth muscle (ASM) contractility to CCh seen in the CAT-2–/– tracheal rings was completely reversed by pretreating the rings with 100 µM spermine. This increase in the CAT-2–/– tracheal ring contraction upon spermine pretreatment correlated with a recovery of the expression of PIP-5K-. Our data indicates that CAT-2 exerts control over ASM force development through a spermine-dependent pathway that directly correlates with the expression level of PIP-5K- in the lung.

lung resistance; tracheal isometric tension