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Comparison of fibrotic and emphysematous alterations in the lungs of bleomycin-treated rats and hamsters

: Hoymann, Heinz-G.; Schaudien, Dirk; Hansen, Tanja; Müller, Meike; Braun, Armin

American Journal of Respiratory and Critical Care Medicine 191 (2015), Art. A3454
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2015, Denver/Colo.>
Fraunhofer ITEM ()

Rationale: The bleomycin-induced pulmonary fibrosis in rodents is a standard model to test efficacy of drugs to be developed for idiopathic pulmonary fibrosis (IPF). We have modified this model and compared the manifestation of lung injury and fibrosis in rats and hamsters using histological, biochemical and physiological techniques.
Methods: To induce lung fibrosis, male Wistar rats and male Golden Syrian hamsters were treated with 1 U bleomycin (= ca. 4 U/kg in rats, ca. 10 U/kg in hamsters) intratracheally by means of a MicroSprayer® aerosolizer on Day 0. The bleomycin was given in two doses with positioning of the animal on the left and then on the right side. In contrast, a control group was sham-treated with the vehicle (saline). On Day 21, the rats were anaesthetized, orotracheally intubated and lung function was measured in the spontaneously breathing animal (no measurements in hamsters). On Day 21 (hamsters: day 28), the animals were sacrificed painlessly, a bronchoalveolar lavage (BAL) was performed and the left lung was preserved for histological and histomorphometrical investigations, the right lung was shock-frozen for biochemical analysis.
Results: On Day 21 or 28, in bleomycin-groups versus controls, pronounced interstitial lung fibrosis (rats: score 2.9 vs. 0.0, hamsters: 1.9 vs.0.0; both p<0.01), multifocal alveolar emphysema (rats: 3.2 vs. 0.0, hamsters: 0.6 vs. 0.0; both p<0.01) and in hamsters pleural fibrosis (1.45vs. 0.0, p<0.01) were detected histologically. Morphometric analysis revealed an elevated area of collagen-positive lung tissue (relative area units, rats: 0.231 vs. 0.145, hamsters: 0.107 vs. 0.064; both p<0.01). Furthermore, increased hydroxyproline concentrations in lung tissue (rats: 0.81 vs. 0.44 mg/g lung, hamsters: 1.39 vs. 0.90; both p<0.01) and BAL (rats: 1.10 vs. 0.75 µg/lung; p<0.01) were measured. Lung function measurements in rats at day 21 revealed a marked decrease in Cdyn indicating loss of distensibility of the lungs (0.109 vs 0.264ml/cmH2O; p<0.01) and an increase in R indicating elevated tissue and/or airway resistance (1.09 vs. 0.67 cmH2O/ml/s; p<0.01). Increasedtotal cell counts, macrophages, and lymphocytes were found in the BAL of rats and hamsters.
Conclusions: The extent of lung injury and fibrosis induced by aerosolized bleomycin was compared by quantitative morphometric analysis, semiquantitative histological scoring, hydroxyproline analysis and BAL. The rat as well as the hamster model have yielded comparable marked fibrosis with emphysematous alterations, increased hydroxyproline levels, macrophage accumulations and collagen-positive area. Therefore, both species have been proven as a valid model for IPF.