Pulmonary Chemoreflex Responses Are Potentiated by Chronic Treatment of Tumor Necrosis Factor Alpha (TNFα) in Mice

Abstract

TNFα, a pro‐inflammatory cytokine, is involved in the pathogenesis of asthma and also known for its sensitizing effect on somatic nociceptive afferents. This study was carried out to test whether chronic treatment of TNFα enhances pulmonary chemoreflex responses. Mice were divided into two matching groups (n=9 each), TNFα (10.08 μg/kg; 1μg = ~105 units) and vehicle were administered by intratracheal (i.t.) instillation in treated and control group, respectively, during a brief anesthesia. 24 h later, the dose‐related responses of apnea to right atrial injection of capsaicin (a TRPV1 activator; 0.25–1.0 μg/kg), allyl isothiocyanate (a TRPA1 activator; 0.3–1.2 mg/kg) and phenylbiguanide (a 5‐HT3 activator; 30–120 μg/kg) were all markedly elevated in TNFα‐treated group as compared to that in the control group. Furthermore, the elevated sensitivity was absent when the same TNFα treatment was applied to p55/p75‐null mice, in which both types of TNFα receptors were mutated. These results suggest a positive interaction between TNFα and pulmonary C‐fiber receptors, which is responsible for elevating the pulmonary chemoreflex sensitivity. (Supported by NIH grant HL96914)