Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits.

Abstract

Bleomycin is a well known fibrogenic agent, provoking an initial adult respiratory distress syndrome-like injury with subsequent strong fibroproliferative response. Severe abnormalities of the alveolar surfactant system, which may be linked to the appearance of alveolar fibrin deposition, have been implicated in the pathogenetic sequence of events. Using a model of standardized aerosol delivery of 1.8 U bleomycin/kg body weight in rabbits, we investigated the influence of repetitive nebulization of heparin or urokinase-type plasminogen activator (u-PA) on the development of lung fibrosis. In an "early" (Days 2-12 postbleomycin) or "late" (Days 14-24 post-bleomycin) treatment protocol, approximately 3,500 U heparin or approximately 6,500 U u-PA was delivered to the bronchoalveolar space. Within four weeks, the bleomycin challenge provoked severe pulmonary fibrosis with reduction of lung compliance, marked increase in soluble collagen (bronchoalveolar lavage fluid) and hydroxyproline content (lung tissue), a typical reticular fibrosis pattern on high-resolution computed tomography, and typical histologic findings. Therapeutic intervention resulted in a far-reaching normalization of compliance, suppression of soluble collagen and hydroxyproline accumulation, and virtual abrogation of the computed tomography scan and histologic features of lung fibrosis, with most prominent effects seen in the early heparin and late u-PA administration. No bleeding complications occurred. These findings strongly support the concept that alveolar fibrin generation is an important event in the development of postbleomycin lung fibrosis. "Compartmentalized" anticoagulation and/or fibrinolysis via inhalational deposition of interventional agents in the alveolar compartment may thus offer a new therapeutic strategy for prevention of fibrosis.

• Authors: Andreas Günther, Norbert Lübke, Monika Ermert, Ralph T Schermuly, Norbert Weissmann, Andreas Breithecker, Philipp Markart, Clemens Ruppert, Karin Quanz, Leander Ermert, Friedrich Grimminger, Werner Seeger
• Journal: American journal of respiratory and critical care medicine (Am J Respir Crit Care Med) Vol. 168 Issue 11 Pg. 1358-65 (Dec 01 2003) ISSN: 1073-449X [Print] United States
• PMID: 14644925 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Bleomycin
• Heparin
• Plasminogen Activators
• Urokinase-Type Plasminogen Activator

Topics

• Administration, Inhalation
• Animals
• Antibiotics, Antineoplastic (adverse effects)
• Bleomycin (adverse effects)
• Disease Models, Animal
• Fibrinolysis (drug effects, physiology)
• Heparin (administration & dosage)
• Plasminogen Activators (administration & dosage)
• Pulmonary Alveoli (drug effects, physiopathology)
• Pulmonary Fibrosis (chemically induced, physiopathology, prevention & control)
• Rabbits
• Urokinase-Type Plasminogen Activator (administration & dosage)