ABSTRACT
BACKGROUND/AIMS: Inhaled corticosteroids are the most effective treatment currently available for asthma, but their beneficial effect against airway remodeling is limited. The tyrosine kinase inhibitor nilotinib has inhibitory activity against c-kit and the platelet-derived growth factor receptor. We compared the effects of fluticasone and nilotinib on airway remodeling in a chronic asthma model. We also examined whether co-treatment with nilotinib and fluticasone had any synergistic effect in preventing airway remodeling. METHODS: We developed a mouse model of airway remodeling, including smooth muscle thickening, in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice per week for 3 months. Mice were treated with fluticasone and/or nilotinib intranasally during the OVA challenge. RESULTS: Mice chronically exposed to OVA developed eosinophilic airway inflammation and showed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Both fluticasone and nilotinib attenuated airway smooth muscle thickening. However, only nilotinib suppressed fibrotic changes, demonstrating inhibition of collagen deposition. Fluticasone reduced pro-inflammatory cells, such as eosinophils, and several cytokines, such as interleukin 4 (IL-4), IL-5, and IL-13, induced by repeated OVA challenges. On the other hand, nilotinib reduced transforming growth factor ß1 levels in bronchoalveolar lavage fluid and inhibited fibroblast proliferation significantly. CONCLUSIONS: These results suggest that fluticasone and nilotinib suppressed airway remodeling in this chronic asthma model through anti-inflammatory and anti-fibrotic pathways, respectively.
Subject(s)
Airway Remodeling/drug effects , Anti-Inflammatory Agents/administration & dosage , Asthma/drug therapy , Bronchodilator Agents/administration & dosage , Fluticasone/administration & dosage , Lung/drug effects , Muscle, Smooth/drug effects , Protein Kinase Inhibitors/administration & dosage , Pulmonary Fibrosis/drug therapy , Pyrimidines/administration & dosage , Administration, Intranasal , Animals , Asthma/metabolism , Asthma/pathology , Asthma/physiopathology , Cell Line , Cell Proliferation/drug effects , Chronic Disease , Collagen/metabolism , Cytokines/metabolism , Disease Models, Animal , Drug Therapy, Combination , Female , Inflammation Mediators/metabolism , Lung/metabolism , Lung/pathology , Lung/physiopathology , Mice, Inbred BALB C , Muscle, Smooth/metabolism , Muscle, Smooth/pathology , Muscle, Smooth/physiopathology , Ovalbumin , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/physiopathology , Transforming Growth Factor beta1/metabolismABSTRACT
Although neutropenia recovery is associated with deterioration of preexisting acute lung injury (ALI), there are few reports of the preventive strategies. Statins have been found to attenuate inflammatory responses in murine models of lipopolysaccharide (LPS)-induced ALI. The aim of this study was to determine whether pravastatin could attenuate ALI during neutropenia recovery in mice. Cyclophosphamide was administered to mice to induce neutropenia. Mice were given intratracheal LPS 7 days after cyclophosphamide administration, after which pravastatin was administered by intraperitoneal injection. In order to study the effects of pravastatin, mice were killed on day 5. Pravastatin attenuated the pulmonary edema and histopathological changes of LPS-induced lung injury. The accumulation of neutrophils and the concentrations of TNF-α, IL-1ß, IL-6, and MPO in BAL fluids were also effectively inhibited by pravastatin. The expression levels of Toll-like receptor 4, nuclear factor kappa B, tumor growth factor-ß and matrix metalloproteinase-9 were significantly reduced by pravastatin. Taken together, pravastatin significantly attenuated LPS-induced ALI during neutropenia recovery. These results provide evidence for the potential of pravastatin in the treatment of ALI during neutropenia recovery.
Subject(s)
Acute Lung Injury/etiology , Acute Lung Injury/prevention & control , Lipopolysaccharides/pharmacology , Neutropenia/complications , Neutropenia/drug therapy , Pravastatin/pharmacology , Acute Lung Injury/chemically induced , Animals , Bronchoalveolar Lavage Fluid , Cyclophosphamide/pharmacology , Disease Models, Animal , Female , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Immunosuppressive Agents/pharmacology , Interleukin-1beta/metabolism , Interleukin-6/metabolism , Mice , Mice, Inbred ICR , NF-kappa B/metabolism , Neutropenia/chemically induced , Pulmonary Edema/chemically induced , Pulmonary Edema/etiology , Pulmonary Edema/prevention & control , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/etiology , Respiratory Distress Syndrome/prevention & control , Toll-Like Receptor 4/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Airway smooth muscle growth contributes to the mechanism of airway hyperresponsiveness (AHR) in asthma. Although current steroid use demonstrates anti-inflammatory activity, there is little reported on the action of corticosteroid on smooth muscle of the asthmatic airway. The present study investigated the effect of inhaled corticosteroid on the thickening of airway smooth muscle in bronchial asthma. We developed a mouse model of airway remodeling including smooth muscle thickening in which ovalbumin (OVA)-sensitized female BALB/c-mice were repeatedly exposed to intranasal OVA administration twice a week for 3 months. Mice were treated intranasally with fluticasone during the OVA challenge. Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation compared with control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling, including thickening of the peribronchial smooth muscle layer. Intranasal administration of fluticasone inhibited the development of eosinophilic inflammation, and importantly, thickening of the smooth muscle layer. Moreover, intranasal fluticasone treatment reduced the transforming growth factor (TGF)-beta 1 level in bronchoalveolar lavage fluid and regulated active TGF-beta 1 signaling with a reduction in the expression of phospho-Smad2/3 and the concomitant up-regulation of Smad7 in lung tissue sections. These results suggest that intranasal administration of fluticasone can modulate the remodeling of airway smooth muscle via regulation of TGF-beta 1 production and active TGF-beta 1 signaling.
