montelukast and Hyperplasia

Topics: Acetates; Cyclopropanes; Diagnosis, Differential; Female; Follow-Up Studies; Humans; Hyperplasia; Infant; Lung; Lung Diseases, Interstitial; Methylprednisolone; Neuroendocrine Cells; Quinolines; Sulfides; Tomography, X-Ray Computed

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

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