C-C chemokines: novel mediators of the profibrotic inflammatory response to bleomycin challenge
| Autor: | Steven L. Kunkel, Robert E. Smith, Sem H. Phan, Robert M. Strieter |
|---|---|
| Rok vydání: | 1996 |
| Předmět: |
Pulmonary and Respiratory Medicine
Pathology medicine.medical_specialty Necrosis Pulmonary Fibrosis Clinical Biochemistry Bleomycin Extracellular matrix chemistry.chemical_compound Idiopathic pulmonary fibrosis Animals Humans Medicine Chemokine CCL4 Fibroblast Molecular Biology Macrophage inflammatory protein Chemokine CCL2 Lung business.industry Bleomycin Sulfate Cell Biology Macrophage Inflammatory Proteins respiratory system medicine.disease medicine.anatomical_structure chemistry Immunology Chemokines medicine.symptom business |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 15:693-702 |
| ISSN: | 1535-4989 1044-1549 |
| Popis: | Over the last 20 years, fibrotic lung diseases have been treated with corticosteroids or cytotoxic immunosuppressants with very little change in morbidity and mortality outcomes (1). In order to find more effective treatment regimens, many laboratories have developed and characterized animal models of fibrotic diseases. Since 1974, bleomycin sulfate has been used in rodents to initiate fibrotic lung lesions which have many of the histologic components of the human disease idiopathic pulmonary fibrosis (IPF) (2). In rodents, bleomycin administration results in a route, dose, and strain dependent pulmonary inflammatory response characterized by increases in leukocyte accumulation, fibroblast proliferation, and collagen content (2-7). Rodents intratracheally challenged with bleomycin typically exhibit necrosis of type I pneumocytes 0 to 1 day post-challenge, acute alveolitis 2 to 3 days post-challenge, and intense interstitial inflammation 4 to 12 days post-challenge (8-11). Additionally, fibroblast proliferation and extracellular matrix synthesis are initiated 4 to 14 days post-bleomycin challenge with collagen content elevated approximately 2-fold, 3 wk post-challenge (4-6, 9, 11). These pathologic changes in pulmonary architecture create diminished respiratory capacity due to thickening of alveolar septa and loss of lung elasticity, resulting in significant morbidity in the animal. By these criteria, the rodent pulmonary inflammatory response to intratracheal bleomycinchallenge constitutes a representative model of human IPF. Soon after the development of the rodent bleomycin model oflPF, researchers hypothesized that the drug directly stimulated collagen synthesis from fibroblasts. Supporting this contention, direct stimulation of normal or granuloma fibroblasts with bleomycin resulted in increased synthesis of type I pro-collagen and glycosaminoglycans, respectively (12, 13). However, another study demonstrated that only 1% of the total intratracheal dose of bleomycin remained in the lung 24 h post-challenge, while fibroblast proliferation and increased collagen synthesis began approximately 4 days post-challenge (4-6, 11, 14-16). Furthermore, studies of the direct effect of bleomycin on hamster lung slices demonstrated significantly reduced "Csproline uptake and hydroxylation, indicating decreased production of collagen (17). |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|