Effect Of Bpifa1 Replacement On Allergen-Induced Airway Hyperresponsiveness

Background: Bactericidal/permeability-increasing protein fold-containing family member A1 (BPIFA1) is an epithelium-derived smooth muscle relaxing factor whose levels are reduced in asthmatics. The objective of this study was to determine if BPIFA1 replacement could attenuate airway hyperresponsiveness (AHR) in mice with asthma-like disease induced by house dust mite (HDM) allergen. Methods: Female C57BL/6 mice were dosed with 25 µg of HDM intranasally for 12 days, a protocol that leads to a 3-fold reduction of BPIFA1 levels in the airway and renders mice hyperresponsive to methacholine (Mch). Seventy-two hours after the last HDM challenge, mice were treated intratracheally with recombinant BPIFA1 (rBIFA1) or vehicle and airway resistance measured in response to aerosolized Mch 1 hour later. Results: HDM-sensitized mice treated with vehicle prior to Mch challenge demonstrated AHR (peak RL 2.8+0.3). In contrast, mice treated with rBPIFA1 had a markedly attenuated response to Mch, similar to non-sensitized mice (peak RL 1.5+0.1). To determine the molecular interactions responsible for this effect, several mutant proteins were tested. The effect on AHR was independent of both alpha helices and the ENaC binding S18 region, while the ability of the BPIFA1 to reduce AHR was abolished with deletions and mutations in the N-terminal region of the protein. Interestingly, rBPIFA1 stimulated endogenous BPIFA1 secretion by epithelia both in vivo and in vitro. Conclusions: rBPIFA1 stimulates BPIFA1 release by epithelia, and reverses AHR induced by HDM sensitization. These findings suggest that BPIFA1-deficiency in asthma be further investigated, and its relation to AHR and other cardinal features of asthma explored.