Pulmonary fibrosis is a serious medical problem that may significantly compromise respiratory functions. The aim of this work was to study the effect of linagliptin and/or calcipotriol on bleomycininduced pulmonary fibrosis and to explore the possible mechanisms underlying this effect. One hundred and twenty male C57BL/6 mice were divided into 6 equal groups as follows: control group; bleomycin group; bleomycin + carboxymethylcellulose group; bleomycin+ linagliptin group; bleomycin+ calcipotriol group and bleomycin + linagliptin + calcipotriol group. Lung weight/body weight index, lung tissue hydroxyproline, collagen, toll-like receptor 4 (TLR4), nuclear factor-like 2 (Nrf2), heme oxygenase-1 (H0-1), malondialdehyde (MDA), glutathione peroxidase (GPx) and catalase (CAT) were measured. Also, bronchoalveolar lavage fluid (BALF) was analyzed for total and differential leucocytic count, lactate dehydrogenase, tumor necrosis factor-alpha (TNF-a), interleukin-10 (IL-10) and transforming growth factor-beta 1 (TGF-(31). Vascular response to potassium chloride, phenylephrine and carbachol as well as tracheal response to carbachol were measured. Also, lung tissue was subjected to histopathological and immunohistochemical examination. Administration of linagliptin and/or calcipotriol induced significant decrease in the lung weight/body weight index, total leucocytic count, BALF lactate dehydrogenase activity, IL-10, TNF-ot and TGF-I31 associated with significant decrease in lung tissue MDA, Nrf2, HO-1, TLR4, hydroxyproline and collagen content with significant increase in tissue GPx and CAT and improvement of the pulmonary architecture, vascular and tracheal response compared to bleomycin group. These effects were significant in linagliptin/calcipotriol combination group compared to the use of each of these drugs alone. In conclusion, linagliptin/calcipotriol combination may represent an effective therapeutic modality for amelioration of bleomycin-induced pulmonary fibrosis. (C) 2017 Elsevier B.V. All rights reserved.