Preventive effect of melatonin on bleomycin‐induced lung fibrosis in rats

Abstract

Oxidative stress has an important role in the pathogenesis of idiopathic pulmonary fibrosis. Melatonin has direct and indirect free radical-detoxifying activity. The present study investigated whether melatonin treatment attenuates bleomycin-induced lung fibrosis in rats. A group of rats was given one dose of bleomycin while the control animals were given saline. The first dose of melatonin (4 mg/kg/day) was given 2 days before the bleomycin injection. At day 14, fibrotic changes were evaluated using Aschoft's criteria and lung hydroxyproline content. Bleomycin produced a 2.7-fold rise in the fibrosis score that was decreased 65% by melatonin (P < 0.05) and a 1.4-fold increase in hydroxyproline content which was completely prevented by melatonin. Protein carbonyl and thiobarbituric acid reactive substances levels, which were significantly elevated in the bleomycin treated rats, were significantly attenuated by melatonin. Bleomycin administration significantly reduced the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in lung tissue. The reduction in CAT activity was prevented by melatonin but SOD and GSH-Px were not influenced. These results revealed that melatonin may prevent the development of bleomycin-induced lung fibrosis via the repression of protein and lipid peroxidation.

The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis?

“…J. Wang, Giri, Hyde, Nakashima, & Javadi, 1990), Taurin (Blaisdell & Giri, 1995;Gurujeyalakshmi, Hollinger, & Giri, 1998;Gurujeyalakshmi, Iyer, Hollinger, & Giri, 1996;Gurujeyalakshmi, Wang, & Giri, 2000;Q. J. Wang, Giri, Hyde, & Nakashima, 1989), N-Acetylcysteine (Cortijo et al, 2001;Hagiwara, Ishii, & Kitamura, 2000;Mata et al, 2003;Serrano-Mollar et al, 2003;Shahzeidi, Sarnstrand, Jeffery, McAnulty, & Laurent, 1991;Yildirim et al, 2005), Vitamin E (Kilinc et al, 1993), Curcumin (Punithavathi, Venkatesan, & Babu, 2000), Aminoguanidine (X. L. Chen, Huang, Li, Wang, & Wang, 2001; X. L. Chen, Li, Zhou, Ai, & Huang, 2003;de Rezende, Martinez, Capelozzi, Simoes, & Beppu, 2000;Giri, Biring, Nguyen, Wang, & Hyde, 2002;Hu, Xu, & Li, 1999;Yildirim et al, 2004), Melatonin (Arslan, Zerin, Vural, & Coskun, 2002;Genovese, Di Paola et al, 2005;Yildirim et al, 2006), Bilirubin (H. D. , CAPE = caffeic acid phenethyl ester , Erdosteine (Boyaci et al, 2006;Sogut et al, 2004;Yildirim et al, 2005;Yildirim et al, 2004) etc. ), Angiotensin converting enzyme inhibitors (Captopril (R. Wang, Ibarra-Sunga, Verlinski, Pick, & Uhal, 2000), Ramipril (Marshall et al, 2004) etc.…”

Assessment of Respiratory Physiology of C57BL/6 Mice following Bleomycin Administration Using Barometric Plethysmography

“…Analyses of lung function in animal studies of respiratory disease are frequently overlooked as investigators primarily focus on utilizing the outcome of biochemical analyses of lung tissue as indicators of disease suppression and/or regression [30,33,56,57,58,59,60,61,62]. The results from this study on C57BL/6 mice illustrate that the inclusion of whole-body barometric plethysmography would benefit any study utilizing the bleomycin animal model of pulmonary fibrosis, particularly if potential therapies are being investigated, as this technique is appropriate for the longitudinal assessment of disease progression, regression and restoration of respiratory function.…”

Effects of Recombinant Activated Protein C Derived From Drotrecogin-Alpha on Bleomycin-Induced Pulmonary Fibrosis in Rats Compared with Methyl-Prednisolone

“…Bleomisin+APC grubunda sıçanlara bleomisin uygulamasından 2 gün önce intraperitoneal rekombinant APC derivesi (drotrekogin alfa, Xigris flakon, Lilly, Almanya) 100 µg/kg/gün dozunda günde bir kez olmak üzere başlandı, 16 gün boyunca devam edildi. Tedavi prosedürü, sıçanlarda bleomisin aracılı akciğer fibrozisi oluş-turulan diğer çalışmalar temel alınarak planlandı [8,[12][13][14][15][16]. Bleomisin injeksiyonundan önce başlanan steroid ve APC tedavisine bleomisin enjeksiyonundan sonra devam edilerek koruyucu etki araştırıldı.…”

“…Örnekler, sitospinde işlem gördükten sonra May-Grünwald-Giemsa ile boyandı, her bir smearda 100 hücre x 100 büyütmede sayıl-dı. Buna göre alveoler makrofaj, nötrofil ve lenfosit ve eozinofil oranları değerlendirildi [14].…”

“…Reaktif eklenmiş numuneler 60°C su banyosunda 25 dakika inkübe edildikten sonra 558 nm'de köre karşı okundu. Sonuçlar mg/g kuru doku olarak verildi [14].…”