Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma

Progranulin (PGRN) is a growth factor with multiple biological functions, and has been suggested as an endogenous inhibitor of TNFα-mediated signaling. TNFα is believed as one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on the TNFα-mediated signaling and the antigen-induced hyper-contractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used. The mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also received intranasal administrations of recombinant PGRN into the airways 1 hour before each antigen inhalation. In hBSMCs, PGRN inhibited both the degradation of IB-α (an index of NF-B activation) and the up-regulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNFα, indicating that PGRN has an ability to inhibit TNFα-mediated signaling also in the BSM cells. In BSMs of the repeatedly antigen-challenged mice, an augmented contractile responsiveness to acetylcholine with an up-regulation of RhoA was observed: both the events were ameliorated by the pretreatments with PGRN intranasally. Interestingly, a significant decrease in the PGRN expression was found in the airways of the repeatedly antigen-challenged mice than those of control animals. In conclusion, exogenously applied PGRN into the airways ameliorated the antigen-induced BSM hyperresponsiveness, probably by blocking TNFα-mediated response. Increasing PGRN levels might be a promising therapeutic for the AHR in allergic asthma.

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