Authors: Lawrenz, J. Herndon, B. Kamal, A. Mehrer, A. Dim, D.C. Baidoo, C. Gasper, D. et. al.
Publication Name: Pulmonary Medicine
Publication Details: doi:10.1155/2012/457031
Bleomycin, a widely used antineoplastic agent, has been associated with severe pulmonary toxicity, primarily ﬁbrosis. Previous work has shown a reduction in bleomycin-induced lung pathology by long-chain omega-3 fatty acids. Treatment by short chain omega3 fatty acids, alpha linolenic acid, found in dietary ﬂaxseed oil may also reduce lung ﬁbrosis, as previously evidenced in the kidney. To test this hypothesis, 72 rats were divided between diets receiving either 15% (w/w) ﬂaxseed oil or 15% (w/w) corn oil (control). These groups were further divided to receive either bleomycin or vehicle (saline) via an oropharyngeal delivery, rather than the traditional intratracheal instillation. Lungs were harvested at 2, 7, and 21 days after bleomycin or saline treatment. Animals receiving ﬂaxseed oil showed a delay in edema formation (P = 0.025) and a decrease in inﬂammatory cell inﬁltrate and vasculitis (P = 0.04 and 0.007, resp.). At days 7 and 21, bleomycin produced a reduction in pulmonary arterial lumen patency (P = 0.01), but not in rats that were treated with ﬂaxseed oil. Bleomycin- treated rats receiving ﬂaxseed oil had reduced pulmonary septal thickness (P = 0.01), signifying decreased ﬁbrosis. Dietary ﬂaxseed oil may prove beneﬁcial against the side eﬀects of this highly eﬀective chemotherapeutic agent and its known toxic eﬀects on the lung. (Authors abstract)
Bleomycin is a group of glycopeptides that binds iron and oxygen in vivo to produce an active drug, eﬀective in cancer treatment. The chemotherapeutic mechanism results from the chelation of iron ions with oxygen, which leads to production of DNA-cleaving superoxide, and also hydroxide free radicals. It is the increased production of reactive oxygen species (ROS) that may be critical in producing proinﬂammatory eicosanoids that lead to bleomycin�s pulmonary toxicity, and may eventually lead to lung ﬁbrosis. A reduction in antioxidants has been reported in IPF lungs, and the resulting oxidant-antioxidant imbalance has been suggested in the progression of IPF (Idiopathic pulmonary fibrosis). Long chain omega3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have antioxidant properties and can protect against lung inﬂammation and pulmonary ﬁbrosis. The omega 6 fatty acid, gamma linolenic acid (GLA) has also been shown to be a potent antioxidant and has been found to attenuate bleomycin induced lung ﬁbrosis in hamsters. ALA from ﬂaxseed oil protects against ﬁbrosis in the kidney. The objective of this study was to determine the effect of ALA found in dietary ﬂaxseed oil on bleomycin induced lung ﬁbrosis. The results indicate that ﬂaxseed oil was eﬀective in protecting lung tissue from bleomycin induced pulmonary toxicity in rats indicated by increased lumen patency and reduced pulmonary septal thickness, decreased inﬂammatory cell inﬁltrate, delayed edema formation, reduced vasculitis, and pulmonary and peribronchial ﬁbrosis. ALA was found to be equally eﬀective in protecting against ﬁbrosis as long chain fatty acids. A potential mechanism to explain the anti inﬂammatory role of ﬂaxseed oil involves lung eicosanoid production. EPA and DHA eicosanoid derivatives are known to produce less active proinﬂammatory products than those of the typical omega 6 eicosanoid precursor, arachidonic acid. ALA derivatives have also been shown to have some anti-inﬂammatory action by competitively inhibiting the transformation of arachidonic acid to leukotrienes. ALA decreases production of the proﬁbrotic PGE2 series. This study was able to show a protective eﬀect of ﬂaxseed oil against the bleomycin induced ﬁbrosis within only a four week period of dietary treatment. This apparently provides suﬃcient time for the omega3 fatty acids to become incorporated into the phospholipid membranes. The four weeks of dietary treatment was half the length of time of dietary treatment that previously showed a protective eﬀect of ﬁsh oil against the ﬁbrosis. This diﬀerence in feeding time may have signiﬁcant implications in considering testing the protective eﬀects of omega3 fatty acids against ﬁbrosis in the clinical setting. (Editors comments)