(619.1) Loss of Club Cell Creb Mitigates IL-1B–mediated Muco-obstructive Phenotypes in Male Murine Airways

Poster Board Number: E633

Mariana Sponchiado (University of Florida), Angelina Bonilla (University of Florida), Luz Mata (University of Florida), Yan-Shin Liao (University of Florida), Amy Fagan (University of Florida), Victor Moncada (University of Florida), Leah Reznikov (University of Florida)

Goblet cell metaplasia and/or mucus hypersecretion are hallmark features of multiple lung diseases, including asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis and pulmonary fibrosis. Interleukin 1β (IL-1B) is a proinflammatory mediator that increases expression of the major gel forming mucins in the airways, Muc5b and Muc5ac, in part through activation of the cAMP response element binding protein (Creb) transcription factor. IL-1B also induces Spdef, a key regulator of goblet cell differentiation from airway club cells. Here we tested the hypothesis that elimination of murine club cell Creb mitigates muco-obstructive phenotypes induced by IL-1B. Mice with floxed Creb1 were bred to Scgb1atm1(cre/ERT)Blh to generate mice with conditional loss of Creb1 from club cells. Wild-type and transgenic male mice (7-9/group) littermates received intranasal IL-1B (0.5 ng/inhalation) or saline (control) for four consecutive days, with tamoxifen administration occurring on days 1 and 3 to induce Cre recombinase expression. Periodic acid–Schiff staining in lung samples showed that IL-1B increased the number of goblet cells in central airways compared to saline controls. This effect was blunted by conditional loss of Creb1. Similarly, flexiVent measurements demonstrated that IL-1B increased airway resistance (R), Newtonian resistance (Rn), tissue elastance (ERS), tissue damping (G) and tissue elasticity (H). Loss of club cell Creb1 mitigated all effects of IL-1B on airway mechanics. Additionally, though the percentage of granulocytes in the bronchoalveolar lung lavage fluid was not increased by IL-1B, loss of club cell Creb1 decreased the percentage of granulocytes in the bronchoalveolar lung lavage fluid independent of treatment (i.e., saline or IL-1B). These findings suggest that the muco-obstructive effects of IL-1B are dependent upon club cell Creb1 and provide novel insight for therapeutic strategies.

Funding Information: NIH (1R01HL152101 and OT2OD026582), Cystic Fibrosis Foundation (REZNIKO20I0) and Katie Rose Foundation (AWD08203).