Search

[beta]-Adrenergic agonists ([beta]-agonists) are commonly used to treat respiratory syncytial virus (RSV) bronchiolitis but are generally ineffective for unknown reasons. We have previously shown that RSV strain A2 inhibits bronchoalveolar epithelial responses to [beta]-agonists in a BALB/c mouse model by inducing heterologous keratinocyte cytokine (KC)/CXCR2-mediated desensitization of epithelial [[beta].sub.2]-adrenergic receptors. The aim of the current study was to determine whether RSV also induces airway insensitivity to [beta]-agonists. Total lung resistance (R) was measured in anesthetized female BALB/c mice undergoing mechanical ventilation on a flexiVent computer-controlled piston ventilator. Data were analyzed using the single-compartment model. Infection with RSV A2 did not induce airway hyperresponsiveness to increasing doses of the nebulized cholinergic agonist methacholine (MCh) at any time point after RSV infection. Prenebulization with the [beta]-agonist terbutaline (100 [micro]M) significantly attenuated bronchoconstrictive responses to 20 and 50 mg/ml MCh in uninfected mice and in mice infected with RSV 4-8 days postinfection (d.p.i.). However, in mice infected with replication-competent, but not UV-inactivated, RSV for 2 days, significant terbutaline insensitivity was found. Terbutaline insensitivity at 2 d.p.i, could be reversed by systemic preinfection treatment with neutralizing anti-CXCR2 antibodies, which reduced bronchoalveolar lavage (BAL) neutrophil counts but did not alter viral replication, BAL KC levels, or lung edema. Terbutaline insensitivity was also reversed by postinfection nebulization with neutralizing anti-KC or anti-CXCR2 antibodies and could be replicated in normal, uninfected mice by nebulization with recombinant KC. These data suggest that KC/CXCR2-mediated airway insensitivity to [beta]-agonists may underlie the modest utility of these drugs as bronchodilators in therapy for acute RSV bronchiolitis. CXCL8; CXCR2; keratinocyte cytokine; airway hyperresponsiveness doi:10.1152/ajplung.00363.2009.

High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cm[H.sub.2]O P, but increased to 37.3% at 18 cm[H.sub.2]O P. AFC rate declined at 22 cm[H.sub.2]O P, which also induced lung damage. Increased AFC at 18 cm[H.sub.2]O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented [Na.sup.+] and [Cl.sup.-] absorption. PKA agonists and [beta]-agonists stimulated AFC at 10 cm[H.sub.2]O P by upregulating amiloride-sensitive Na+ transport. However, at 18 cm[H.sub.2]O P, PKA agonists and [beta]-agonists reduced AFC. At 15 cm[H.sub.2]O P, the AFC rate was intermediate (mean 26.6%), and forskolin and [beta]-agonists had no effect. Comparable P dependency of AFC and 13-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cm[H.sub.2]O was blocked by adenosine deaminase or an Azb-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cm[H.sub.2]O P. Modulation of adenosine signaling also resulted in altered responsiveness to [beta]-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to [beta]-agonists are impacted by ventilation pressure in an adenosine-dependent manner. tidal volume; epithelial sodium channel; adenosine doi: 10.1152/ajplung.00096.2009