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Epithelium-dependent contraction of airway smooth muscle caused by eosinophil MBP
Abstract:
We have identified two distinct functions of the epithelium of guinea pig airways that modulate airway smooth muscle contractility in the presence of the major basic protein (MBP) of human eosinophilic granules: 1) active force generation resulting less than 1 min after epithelial contact with MBP; and 2) sustained, augmented force generation that does not depend on cytotoxic interference with the synthesis of an epithelial-derived inhibitory factor. To evaluate these influences, an in situ preparation of guinea pig trachea was developed that permitted direct, on-line measurement of isometric force generation in the underlying muscle. Direct application of 10(-8) mol/cm2 MBP to the surface of the epithelium elicited force generation that did not require the presence of a contractile agonist. Force generation began less than 1 min after MBP application and reached maximum active tension (AT) of 0.97 +/- 0.38 g/cm at 30 min (P less than 0.05 vs. baseline). Denatured MBP did not elicit active tension. MBP also caused augmented contraction to intravenous acetylcholine (ACh); 30 min after topical application of MBP, AT generated by 3 x 10(-7) mol/kg iv ACh was 0.85 +/- 0.14 vs. 0.55 +/- 0.08 g/cm in control animals (P less than 0.05). Threshold response to ACh (-8.1 +/- 0.3 log mol/kg) also decreased significantly after MBP (-9.1 +/- 0.4 log mol/kg) vs. baseline (P less than 0.01). Removal of the epithelium (confirmed histologically) abolished both direct contraction and augmented force generation to ACh caused by topical application of MBP to the airway muscle. These data suggest actions of MBP that have not been demonstrated previously: 1) activation of epithelial function that causes direct contraction of airway smooth muscle; and 2) independence of the MBP-induced effects from active tone elicited by other agonists. We also demonstrate that augmented contraction that does not depend on MBP blockade of tonic inhibitory secretion from the epithelium.