montelukast and Fibrosis

Montelukast is an antagonist of cysteinyl leukotriene receptor 1 (CysLTR1) that protects against inflammation and oxidative stress. However, the function of montelukast in liver fibrosis remains unknown. In this study, we examined whether the pharmacological inhibition of CysLTR1 could protect mice against hepatic fibrosis.. Carbon tetrachloride (CCl. Montelukast suppressed CCl

Topics: Animals; Carbon Tetrachloride; Diet; Fibrosis; Hepatic Stellate Cells; Humans; Inflammation; Liver; Liver Cirrhosis; Methionine; Mice; Racemethionine; Signal Transduction; Transforming Growth Factor beta1

Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor β (TGF-β), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-β, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 μM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.

Topics: Acetates; Animals; CHO Cells; Cricetinae; Cricetulus; Cyclopropanes; Fibrosis; Humans; Mice; Quinolines; Receptors, Leukotriene; Sulfides; Transforming Growth Factor beta

Arthrofibrosis is a major obstacle to restoring joint function after trauma. The objective of this study was to evaluate montelukast, forskolin, and triamcinolone as possible means of prophylaxis against the formation of arthrofibrosis. Forty-eight rats underwent surgical knee trauma with post-operative immobilization in full flexion. The treatment groups were: control (CTL), oral montelukast (3.75 mg/kg/day) (MLK), intra-articular forskolin injections (0.6 mg/kg) (FSK), and intra-articular triamcinolone injections (0.68 mg/kg) (STR). Rats were sacrificed after 14 days and femorotibial contracture angles were measured with the posterior capsule intact and with the posterior capsule cut. A 0.015Nm extension moment was applied to the knee. All treatment groups had significant reductions in contracture angle compared to the control. Mean contractures with the posterior capsule intact were 32°(CTL), 20° (MLK), 22° (FSK), and 7° (STR). Contractures with the posterior capsule cut were 28° (CTL), 19° (MLK), 20° (FSK), and 5° (STR). The STR group was significantly better than FSK and MLK. Triamcinolone injections provided dramatic reductions in stiffness. Both forskolin and montelukast provided significant, though lesser, reductions in stiffness. While the triamcinolone contracture angles were significantly better, the novel treatments of forskolin and montelukast provided encouraging results and should be studied further.

Topics: Acetates; Administration, Oral; Animals; Colforsin; Contracture; Cyclopropanes; Fibrosis; Hindlimb; Injections, Intra-Articular; Joint Capsule; Joints; Knee Injuries; Male; Quinolines; Range of Motion, Articular; Rats; Rats, Sprague-Dawley; Sulfides; Triamcinolone

Continuous ambulatory peritoneal dialysis (CAPD) induces structural changes in the peritoneal membrane such as fibrosis, vasculopathy and angioneogenesis with a reduction in ultrafiltration capacity. Leukotriene (LT) receptor antagonists have been found to be effective to prevent fibrosis in some nonperitoneal tissues. The aim of this study is to investigate the possible beneficial effect of montelukast, a LT receptor antagonist, on peritoneal membrane exposed to hypertonic peritoneal dialysis in uremic rats.. Of the 48 male, 5/6 nephrectomized Wistar rats 29 remained alive and were included in the study. These studied rats were divided into 3 groups: Group I (n=7) was the control group, Group II (n=8) was treated with 20 ml hypertonic PDF intraperitoneally daily and Group III was treated with montelukast and similar PDF treatment protocol. The morphological and functional changes in the peritoneal membrane as well as cytokine expression were compared between groups.. Submesothelial thickness and the severity of the degree of hyaline vasculapathy were more prominent in group III when compared to group I. There were no significant differences between group II and other groups in terms of submesothelial thickness and the severity of the degree of hyaline vasculapathy. Increased expressions of TGF-β and VEGF in parietal peritoneal membrane were found in group II and group III when compared to group I. The amount of TGF-β and VEGF expression were similar in group II and group III.. This study suggests that montelukast treatment does not prevent the peritoneal membrane from deleterious effects of hyperosmolar PDF in the uremic environment.

Topics: Acetates; Animals; Cyclopropanes; Cytokines; Fibrosis; Kidney Failure, Chronic; Leukotriene Antagonists; Male; Membranes; Peritoneal Dialysis, Continuous Ambulatory; Peritoneum; Quinolines; Rats; Rats, Wistar; Sulfides; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A

Montelukast, a potent cysteinyl receptor antagonist, may be an antifibrotic therapeutic agent for lung fibrosis. Seven sarcoidosis patients and 10 with unusual interstitial pneumonia underwent conventional bronchoalveolar lavage, from which myofibroblasts were recovered. Myofibroblast proliferation was assayed, alpha smooth muscle actin levels were measured, TGFbeta mRNA RT-PCR transcripts were semiquantitated, and secretion was evaluated in myofibroblast supernatants. Montelukast at 10(-8) M concentration had a suppressive effect on cell proliferation (31 +/- 18%), which was significantly enhanced by LTD4 10(-8) M. No differences were found between sarcoidosis (31.28 +/- 15.9%) and unusual interstitial pneumonia (30.56 +/- 24.3%) lines. Fetal calf serum (20%) produced an enhancing effect (29.8 +/- 21.6%) in all lines. Myofibroblasts recovered from sarcoidosis patients showed lower alpha-smooth muscle actin contents than unusual interstitial pneumonia lines (0.09 +/- 0.02 vs. 0.34 +/- 0.16, p =0.039, respectively). Montelukast suppressed alpha-actin in short-term cultures in sarcoidosis myofibroblasts and in long-term unusual interstitial pneumonia myofibroblasts. Montelukast at 10(-6) M concentratin decreased the TGFbeta-induced alpha-actin expression in all lines tested. Montelukast decreased mRNA expression of TGFbeta. Montelukast may be a therapeutic agent in pathological conditions involving fibrotic and remodeling processes.

Topics: Acetates; Actins; Adult; Cell Proliferation; Cells, Cultured; Cyclopropanes; Female; Fibroblasts; Fibrosis; Humans; Lung Diseases, Interstitial; Male; Middle Aged; Quinolines; RNA, Messenger; Sarcoidosis; Sulfides; Transforming Growth Factor beta

Airway inflammation and remodeling in chronic asthma are characterized by airway eosinophilia, hyperplasia of goblet cells and smooth muscle, and subepithelial fibrosis. We examined the role of leukotrienes in a mouse model of allergen-induced chronic lung inflammation and fibrosis. BALB/c mice, after intraperitoneal ovalbumin (OVA) sensitization on Days 0 and 14, received intranasal OVA periodically Days 14-75. The OVA-treated mice developed an extensive eosinophil and mononuclear cell inflammatory response, goblet cell hyperplasia, and mucus occlusion of the airways. A striking feature of this inflammatory response was the widespread deposition of collagen beneath the airway epithelial cell layer and also in the lung interstitium in the sites of leukocytic infiltration that was not observed in the saline-treated controls. The cysteinyl leukotriene(1) (CysLT(1)) receptor antagonist montelukast significantly reduced the airway eosinophil infiltration, mucus plugging, smooth muscle hyperplasia, and subepithelial fibrosis in the OVA-sensitized/challenged mice. The presence of Charcot-Leyden-like crystals in airway macrophages and the increased interleukin (IL)-4 and IL-13 mRNA expression in lung tissue and protein in BAL fluid seen in OVA-treated mice were also inhibited by CysLT(1) receptor blockade. These data suggest an important role for cysteinyl leukotrienes in the pathogenesis of chronic allergic airway inflammation with fibrosis.

Topics: Acetates; Acute Disease; Allergens; Analysis of Variance; Animals; Asthma; Bronchoalveolar Lavage Fluid; Chronic Disease; Cyclopropanes; Disease Models, Animal; Drug Evaluation, Preclinical; Eosinophils; Fibrosis; Glycoproteins; Goblet Cells; Hyperplasia; Inflammation; Leukotriene Antagonists; Leukotrienes; Lysophospholipase; Macrophages, Alveolar; Mice; Ovalbumin; Quinolines; Respiratory Mechanics; Sulfides