Protection of bleomycin-induced fibrosis and inflammation by taurine
Introduction
Taurine, 2-aminoethansulfonic acid, is well known as an antioxidant and is present in most mammalian tissues and cells. It is the most abundant single amino acid in leukocytes (20–50 mM), and is present in particularly high concentrations in tissues exposed to elevated levels of oxidants [1], [2], [3]. This natural substance has been used to protect against bleomycin-induced lung injury [4], [5]. In a murine model of lung fibrosis, Gurujeyalakshmi et al. [6] showed both nitric oxide (NO) and NFKB were decreased in taurine and niacin-treated mice compared to untreated mice. Taurine has also been shown to protect against lung injury induced by various oxidants such as ozone, nitrogen dioxide, amiodarone and paraquat [4], [5], [6], [7], [8], [9]. The protective effects of taurine may be explained by its detoxification of hypochlorous acid, a potent oxidant that can cause extensive tissue damage. However, recent evidence from our laboratories [10], [11], [12], [13], [14], [15], [16] and others [17], [18], [19] demonstrates that taurine chloramine (Tau–Cl), produced from highly toxic hypochlorous acid and taurine, is thought to be pivotal in regulating inflammation. Our previous data demonstrate that Tau–Cl inhibits proinflammatory mediators such as NO and TNF-α in a variety of both primary macrophages and cultured macrophage-like lines from rodents [10], [13]. Additionally, our results demonstrate that Tau–Cl down regulates several functions of both the adherent and non-adherent population of human peripheral blood leukocytes [15], [16]. Previously, we demonstrated that MMP-9 was inhibited by Tau–Cl in LPS-activated murine peritoneal macrophages [20].
Bleomycin treatment results in dysregulated matrix remodeling, leading to thickened alveolar walls, alveolar collapse and scarring (interstitial fibrosis) [21]. Fibrosis culminates in the overproduction of interstitial collagen as a reparative response to injury. Data from this study show that fibrosis is strikingly absent from the lung of rats pretreated with taurine in the drinking water ten days prior to bleomycin instillation.
Section snippets
Animals and bleomycin treatment
Female Sprague-Dawley rats, ages 8–12 weeks (Taconic Farms, Germantown, NY), were kept in Thoren ventilated racks and cages for protection from airborne infection and given water or water with 5% taurine for 10 days prior to instillation of 1 U (1 U/200 g) bleomycin via direct intratracheal injection (i.t.) with cervical cut-down with Nembutal anesthesia (Abbott Labs, North Chicago, Ill.). Animals were divided into the following 4 groups with at least 4 rats per group: saline and water (SW),
Taurine levels, inflammatory cell counts and hydroxylproline in BALF
Our laboratory has established animal models to study the protective role of taurine in ozone- and bleomycin-induced lung injury [7]. In this study, female Sprague-Dawley rats (180–210 g) (4 rats/group) were injected i.t. with bleomycin (1 U/rat) with (BT) or without (BW) taurine supplementation. Taurine supplementation consisted of 5% taurine in the drinking water for 10 days prior to bleomycin i.t. with Nembutal anesthesia (Abbott Labs., North Chicago, IL). Taurine concentrations were
Discussion
Previous studies from our laboratory have shown that pretreating rats for 10 days with 5% taurine in the drinking water prior to exposure to 2 ppm ozone for 3 h protected the bronchioles from acute lung inflammation and hyperplasia [7]. When bleomycin is administered to rodents, a multifocal inflammatory response occurs that progresses to fibrosis [21]. The present studies show that pretreatment of rats with 5% taurine prevents fibrosis and decreases the inflammatory infiltrate in the lungs of
Acknowledgments
This work was supported by the National Institutes of Health (Grant HL-49942) and the New York State Office of Mental Retardation and Developmental Disabilities. We would like to thank Dr. William Levis for reviewing this manuscript and Vanessa DeBello for typing this manuscript.
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