montelukast and Pulmonary-Fibrosis

Montelukast, a leukotriene receptor antagonist, is used commercially as a maintenance treatment for asthma and to relieve allergic symptoms. In this study, we evaluated the protective effects of montelukast against the airway inflammation and fibrosis using a murine model of ovalbumin (OVA) induced chronic asthma. The animals received OVA challenge three times a week for 4 weeks. Montelukast (30 mg/kg) was administrated orally once a day for 4 weeks. The administration of montelukast caused a reduction in elevated interleukin (IL)-4, IL-13, eotaxin, immunoglobulin (Ig), inflammatory cell infiltration into the airways, and mucus production after repeated OVA challenges. To investigate the antifibrotic mechanism of montelukast, we examined the expression of profibrotic mediators, including vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-β1, and Smad3 proteins in the lung tissue using western blotting and immunohistochemistry. The administration of montelukast reduced the overexpression of profibrotic proteins in the lung tissue, which was confirmed by immnunohistochemistry. These results are consistent with a histopathological examination of lung tissue with Masson's trichrome stain. In conclusion, the administration of montelukast reduced airway inflammation and pulmonary fibrosis by reducing the release of Th2 cytokines and the expression of VEGF, TGF-β1/Smad3 in the lung tissue.

Topics: Acetates; Allergens; Animals; Anti-Asthmatic Agents; Asthma; Bronchoalveolar Lavage Fluid; Cyclopropanes; Cytokines; Disease Models, Animal; Female; Immunoglobulin E; Leukotriene Antagonists; Lung; Mice; Mice, Inbred BALB C; Mucus; Ovalbumin; Pulmonary Fibrosis; Quinolines; Smad3 Protein; Sulfides; Transforming Growth Factor beta1; Vascular Endothelial Growth Factor A

Airway remodeling in bronchial asthma results from chronic, persistent airway inflammation. The effects of the reversal of airway remodeling by drug interventions remain to be elucidated. We investigated the effects of ONO-1301, a novel prostacyclin agonist with thromboxane inhibitory activity, on the prevention and reversibility of airway remodeling in an experimental chronic asthma model. Mice sensitized and challenged to ovalbumin (OVA) three times a week for 5 consecutive weeks were administered ONO-1301 or vehicle twice a day from the fourth week of OVA challenges. Twenty-four hours after the final OVA challenge, airway hyperresponsiveness (AHR) was assessed, and bronchoalveolar lavage was performed. Lung specimens were excised for staining to detect goblet-cell metaplasia, airway smooth muscle, and submucosal fibrosis. Mice administered ONO-1301 showed limited increases in AHR compared with mice administered the vehicle. The histological findings of airway remodeling were improved in ONO-1301-treated mice compared with vehicle-treated mice. Presumably, these therapeutic effects of ONO-1301 are attributable to the up-regulation of production of hepatocyte growth factor (HGF) in lung tissue, because the neutralization of HGF by antibodies prevented the effects of ONO-1301 on AHR and airway remodeling. Mice administered ONO-1301 showed similar levels of AHR and airway remodeling as mice administered montelukast, a cysteinyl-leukotriene-1 receptor antagonist, and lower levels were observed in mice administered dexamethasone. These data suggest that ONO-1301 exerts the effect of reversing airway remodeling, at least in part through an elevation of HGF in the lungs, and may be effective as an anti-remodeling drug in the treatment of asthma.

Topics: Acetates; Airway Remodeling; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cyclopropanes; Dexamethasone; Epoprostenol; Female; Goblet Cells; Hepatocyte Growth Factor; Inflammation; Lung; Metaplasia; Mice; Mice, Inbred BALB C; Muscle, Smooth; Ovalbumin; Pulmonary Fibrosis; Pyridines; Quinolines; Receptors, Leukotriene; Sulfides; Thromboxanes; Up-Regulation

Cysteinyl-leukotrienes are potent mediators involved in various inflammatory diseases and lung disorders such as asthma. However, their precise role in the pathogenesis of pulmonary fibrosis is unknown. In the present study, we investigated the effect of montelukast, a cysteinyl-leukotriene type 1 receptor antagonist, on bleomycin-induced pulmonary fibrosis in mice. Montelukast (10mg/kg/day) was orally administered to the bleomycin-induced pulmonary fibrosis mice for 3days before and 14days after intratracheal instillation of bleomycin. We evaluated the effects of montelukast on the development of pulmonary fibrosis in these mice and investigated the expression of various cytokines and two cysteinyl-leukotriene receptors. Treatment with montelukast significantly attenuated the increased fibrotic area and hydroxyproline content in the fibrotic lungs of bleomycin-instilled mice. Montelukast treatment also decreased mRNA levels of IL-6, IL-10, IL-13, and TGF-β1, all of which were elevated in fibrotic lungs. In fibrotic lungs, TNF-α and IL-1β mRNA levels were increased and IFN-γ mRNA levels were decreased, but montelukast did not affect these mRNA levels. Furthermore, cysteinyl-leukotriene type 1 receptor mRNA levels were increased, whereas cysteinyl-leukotriene type 2 receptor mRNA levels were decreased in fibrotic lungs. Montelukast treatment induced the recovery of cysteinyl-leukotriene type 2 receptor mRNA levels to normal control levels but did not change cysteinyl-leukotriene type 1 receptor mRNA levels. These results suggest that montelukast exhibits its beneficial effects by inhibiting the overexpression of IL-6, IL-10, IL-13, and TGF-β1 and by modulating the homeostatic balance between the cysteinyl-leukotriene type 1 and type 2 receptors.

Topics: Acetates; Animals; Bleomycin; Bronchoalveolar Lavage Fluid; Cell Count; Cyclopropanes; Cytokines; Female; Gene Expression Regulation; Hydroxyproline; Leukotriene Antagonists; Lung; Mice; Mice, Inbred C57BL; Pulmonary Fibrosis; Quinolines; Receptors, Leukotriene; RNA, Messenger; Sulfides

To compare the effects of montelukast, prednisone and the combination of both drugs in a rat model of bleomycin-induced lung fibrosis. Rats, injected intravenously with bleomycin daily for five consecutive days, were treated with either montelukast, prednisone or a combination of both drugs orally daily for 35 days starting 14 days after the commencement of the first dose of bleomycin. Montelukast-treated rats showed reduction in collagen deposition by 29% and significant reduction in lung hydroxyproline content by 32%. Prednisone produced nonsignificant difference in collagen deposition and in lung hydroxyproline content compared with the bleomycin group. There was also a significant reduction in collagen deposition and hydroxyproline content in montelukast and prednisone treated rats by 15 and 17%, respectively, compared with bleomycin group. A significant reduction occurred in the mean area percentage of myofibroblast α smooth muscle actin in montelukast and montelukast and prednisone-treated groups by 41 and 37%, respectively, with nonsignificant difference in prednisone-treated rats as compared with the bleomycin group. Montelukast may be therapeutically effective for inhibiting further progression of lung fibrosis through inhibition of α-SMA positive myofibroblasts.

Topics: Acetates; Animals; Bleomycin; Collagen; Cyclopropanes; Dose-Response Relationship, Drug; Drug Combinations; Hydroxyproline; Leukotriene Antagonists; Lung; Male; Prednisone; Pulmonary Fibrosis; Quinolines; Rats; Sulfides

Airway structural changes that occur in patients with asthma in response to persistent inflammation are termed airway remodeling. The cysteinyl leukotrienes (LTC(4), D(4) and E(4)) are known to play important roles in the pathobiology of asthma. To evaluate the effect of low dose montelukast (MK) on the development of airway remodeling using a chronic murine model of allergic airway inflammation with subepithelial fibrosis, BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on days 0 and 14, received intranasal OVA periodically on days 14-75. MK treated mice received montelukast sodium intraperitoneally on days 26-75. The OVA sensitized/challenged mice developed an extensive eosinophil cell inflammatory response, goblet cell hyperplasia, mucus occlusion, and smooth muscle hypertrophy of the airways. In addition, in OVA sensitized/challenged mice, dense collagen deposition/fibrosis was seen throughout the lung interstitium surrounding the airways, blood vessels, and alveolar septae. The cysteinyl leukotriene 1 (CysLT1) receptor antagonist, MK significantly reduced the airway eosinophil infiltration, goblet cell hyperplasia, mucus occlusion, and lung fibrosis except airway smooth muscle hypertrophy in the OVA sensitized/challenged mice. The OVA sensitized/challenged mice had significantly increased epithelial desquamation compared with control mice. MK markedly reduced epithelial desquamation of airways in OVA/MK treated animals compared with OVA sensitized/challenged mice. MK treatment did not affect the levels of CysLT in lung tissue. Our results show that the important role of cysteinyl leukotrienes in the pathogenesis of asthma. Lower dose of CysLT1 receptor antagonism has a significant anti-inflammatory effect on allergen-induced lung inflammation and fibrosis but not airway smooth muscle hypertrophy in an animal model of asthma.

Topics: Acetates; Airway Obstruction; Animals; Anti-Asthmatic Agents; Asthma; Collagen; Cyclopropanes; Cysteine; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Goblet Cells; Hyperplasia; Hypertrophy; Leukotriene Antagonists; Leukotrienes; Lung; Mice; Mice, Inbred BALB C; Mucus; Muscle, Smooth; Pulmonary Fibrosis; Quinolines; Receptors, Leukotriene; Respiratory Mucosa; Sulfides