Mechanisms of bleomycin-induced lung damage

Abstract

Bleomycins are a family of compounds produced by Streptomyces verticillis. They have potent tumour killing properties which have given them an important place in cancer chemotherapy. They cause little marrow suppression, but pulmonary toxicity is a major adverse effect. The mechanisms of cell toxicity are well described based on in vitro experiments on DNA. The bleomycin molecule has two main structural components: a bithiazole component which partially intercalates into the DNA helix, parting the strands, as well as pyrimidine and imidazole structures, which bind iron and oxygen forming an activated complex capable of releasing damaging oxidants in close proximity to the polynucleotide chains of DNA. This may lead to chain scission or structural modifications leading to release of free bases or their propenal derivatives. The mechanisms are well described based on in vitro experiments on DNA, but how they relate to intact cells in whole animals is more tenuous. Bleomycin is able to cause cell damage independent from its effect on DNA by induction lipid peroxidation. This may be particularly important in the lung and in part account for its ability to cause alveolar cell damage and subsequent pulmonary inflammation. The lung injury seen following bleomycin comprises an interstitial oedema with an influx of inflammatory and immune cells. This may lead to the development of pulmonary fibrosis, characterized by enhanced production and deposition of collagen and other matrix components. Several polypeptide mediators capable of stimulating fibroblasts replication or excessive collagen deposition have been implicated in this, but the precise role of these in bleomycin-induced fibrosis is yet to be demonstrated. Current therapy for bleomycin-induced lung damage is inadequate, with corticosteroids most often used. Given the mechanism of action described above, antioxidants and iron chelators might be beneficial. Although, studies to date are equivocal and there is insufficient evidence to promote their use clinically. Novel drugs are currently being developed and it is hoped these may be more useful.

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

“…In addition, in concert with the abundant evidence indicating that ROS is central to BLM-induced pulmonary fibrosis 25,[36][37][38] , our study demonstrate that alveolar type II epithelial cells in Elovl6 À / À mice produce more ROS than those in WT mice as assessed by staining with antibody against nitrotyrosine. These results help explain why Elovl6 À / À mice are more susceptible to BLM-induced pulmonary fibrosis.…”

Bleomycin‐induced lung injury assessed noninvasively and in spontaneously breathing rats by proton MRI

“…However, BLM produces a dosedependent pulmonary fibrosis in most patients (8). A single intratracheal instillation of BLM is commonly used to induce experimental pulmonary fibrosis in rodents (11,12). In this animal model, the single application of the antibiotic causes an acute inflammatory reaction and fibrotic changes that resemble human fibrotic lung disease both histologically and physiologically (1,13,14).…”

“…The availability of this animal model of pulmonary fibrosis provides the opportunity to investigate novel pharmacological approaches that can be used to treat and prevent this disease (12).…”

Evaluating the ameliorative potential of plant flavonoids and their nanocomposites in bleomycin induced idiopathic pulmonary fibrosis

“…Bleomycin administration is known to damage the lung epithelial cells resulting in lower cell numbers (Hay et al, 1991). The results from our colony forming assay in BALF demonstrated a reduction in colonyforming units on bleomycin treatment.…”

“…Although the exact mechanisms by which bleomycin causes pulmonary fibrosis remains unclear, it has been reported that, Reactive Oxygen Species (ROS) generated by bleomycin, causes direct injury to the lung epithelial cells (Banerjee et al, 2015;Hay et al, 1991;Wang et al, 2002). Reactive Oxygen Species such as superoxide anions, hydrogen peroxides, and hydroxyl radicals have been reported to play an important role as a mediator of bleo-induced lung fibrosis (Arslan et al, 2002;Chen and Stubbe, 2004).…”