Ca²⁺-Activated K⁺ Channel–3.1 Blocker TRAM-34 Attenuates Airway Remodeling and Eosinophilia in a Murine Asthma Model

Abstract

Key features of asthma include bronchial hyperresponsiveness (BHR), eosinophilic airway inflammation, and bronchial remodeling, characterized by subepithelial collagen deposition, airway fibrosis, and increased bronchial smooth muscle (BSM) mass. The calcium-activated K(+) channel K(Ca)3.1 is expressed by many cells implicated in the pathogenesis of asthma, and is involved in both inflammatory and remodeling responses in a number of tissues. The specific K(Ca)3.1 blocker 5-[(2-chlorophenyl)(diphenyl)methyl]-1H-pyrazole (TRAM-34) attenuates BSM cell proliferation, and both mast cell and fibrocyte recruitment in vitro. We aimed to examine the effects of K(Ca)3.1 blockade on BSM remodeling, airway inflammation, and BHR in a murine model of chronic asthma. BALB/c mice were sensitized with intraperitoneal ovalbumin (OVA) on Days 0 and 14, and then challenged with intranasal OVA during Days 14-75. OVA-sensitized/challenged mice received TRAM-34 (120 mg/kg/day, subcutaneous) from Days -7 to 75 (combined treatment), Days -7 to 20 (preventive treatment), or Days 21 to 75 (curative treatment). Untreated mice received daily injections of vehicle (n = 8 per group). Bronchial remodeling was assessed by histological and immunohistochemical analyses. Inflammation was evaluated using bronchoalveolar lavage and flow cytometry. We also determined BHR in both conscious and anesthetized mice via plethysmography. We demonstrated that curative treatment with TRAM-34 abolishes BSM remodeling and subbasement collagen deposition, and attenuates airway eosinophilia. Although curative treatment alone did not significantly reduce BHR, the combined treatment attenuated nonspecific BHR to methacholine. This study indicates that K(Ca)3.1 blockade could provide a new therapeutic strategy in asthma.

The potassium channel KCa3.1 constitutes a pharmacological target for neuroinflammation associated with ischemia/reperfusion stroke

“…Another question is of course whether KCa3.1 inhibition, which we and others have previously proposed for the treatment of asthma, 34 inflammatory bowel disease 35 and transplant vasculopathy 22 will increase the risk of infections. In this context, it should be kept in mind that the interactions between the brain and the immune system during and after stroke are complex.…”

Ion Channels in Innate and Adaptive Immunity

“…Inhibiting K Ca 3.1 genetically or pharmacologically reduces FcɛRI-mediated Ca 2+ influx and degranulation (344). Moreover, KCa3.1 − / − mice showed reduced passive cutaneous and systemic anaphylaxis (344), and K Ca 3.1 inhibitors attenuated airway remodeling and eosinophilia in murine and sheep asthma models (345, 346). However, while inhibition of mast cell function probably contributed to these effects, K Ca 3.1 is also expressed in T cells, fibroblasts, and proliferative airway smooth muscle cells.…”

Ion channels

“…The K Ca 3.1 knockout mouse displays an attenuated IgE-dependent systemic anaphylactic response. In a mouse model of asthma, treatment with the specific K Ca 3.1 blocker TRAM-34 attenuated OVA-dependent bronchial hyperresponsiveness, bronchoalveolar lavage eosinophilia, sub-basement membrane collagen deposition, airway smooth muscle mass and peribronchiolar fibrosis 3. Another mouse study demonstrated a role for K Ca 3.1 channels in the development of obliterative bronchiolitis following transplantation.…”