Pharmacologic differentiation of inflammation and fibrosis in the rat bleomycin model.
BACKGROUND
The model most often used to study the pathogenesis of pulmonary fibroses is the bleomycin (BLM)-induced lung fibrosis model. Several treatments have been efficacious in this model, but not in the clinic.


OBJECTIVE
To describe the time course of inflammation and fibrosis in the BLM model and to study the effect of timing of antiinflammatory and antifibrotic treatments on efficacy.


METHODS
Rats were given single intratracheal injections of BLM on Day 0. At specified time points, 10 rats were killed and their lungs studied for proinflammatory cytokines and for profibrotic growth factor mRNA. After a single intratracheal injection of BLM on Day 0, rats were treated from Day 1 or 10 daily with oral prednisolone (10 mg/kg) or oral imatinib mesylate (50 mg/kg) for 21 d.


RESULTS
After BLM administration, the expression of inflammatory cytokines was elevated and returned to background levels at later time points. Profibrotic gene expression peaked between Days 9 and 14 and remained elevated till the end of the experiment, suggesting a "switch" between inflammation and fibrosis in this interval. Antiinflammatory treatment (oral prednisolone) was beneficial when commenced at Day 1, but had no effect if administered from Day 10 onward. However, imatinib mesylate was effective independently of the dosing regime.


CONCLUSIONS
The response of the BLM model to antifibrotic or antiinflammatory interventions is critically dependent on timing after the initial injury.
Chaudhary
Nveed I
NI
Department of Pulmonary Research, Boehringer Ingelheim Pharma GmbH & Co., KG, Biberach an der Riss, Germany.
Schnapp
Andreas
A
Park
John E
JE
D000818:Animals; D001549:Benzamides; D015415:Biomarkers / Q000378:metabolism; D001761:Bleomycin / Q000633:toxicity*; D004359:Drug Therapy, Combination; D005500:Follow-Up Studies; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000627:therapeutic use*; D000068877:Imatinib Mesylate; D008168:Lung / Q000187:drug effects / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000627:therapeutic use*; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011239:Prednisolone / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D016212:Transforming Growth Factor beta / Q000235:genetics; D053773:Transforming Growth Factor beta1; D016896:Treatment Outcome
D001549:Benzamides; D015415:Biomarkers; D005938:Glucocorticoids; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D000068877:Imatinib Mesylate; D011239:Prednisolone; D011505:Protein-Tyrosine Kinases