Amelioration of bleomycin-induced pulmonary fibrosis in hamsters by combined treatment with taurine and niacin

doi:10.1016/0006-2952(91)90296-H

Biochemical Pharmacology

Volume 42, Issue 5, 8 August 1991, Pages 1115-1122

https://doi.org/10.1016/0006-2952(91)90296-H Get rights and content

Abstract

Interstitial pulmonary fibrosis induced by bleomycin (BL) involves the production of reactive oxygen species and the impairment of repair of damaged epithelial cells. We have shown previously that taurine or niacin treatment partially attenuates BL-induced lung fibrosis in hamsters and that the two agents probably act through different mechanisms. In the present investigation, we have demonstrated that taurine and niacin in combination provide nearly complete protection against BL-induced pulmonary fibrosis. Based on the findings of this investigation, it is suggested that combined treatment with taurine and niacin offers the potential for a novel pharmacological approach in the prevention of lung fibrosis in humans.

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Cited by (77)

Sinapic acid ameliorates bleomycin-induced lung fibrosis in rats
2018, Biomedicine and Pharmacotherapy
Citation Excerpt :
BLM induces the release of ROS and RNS by binding with DNA and iron, resulting in DNA damage [11]. BLM and DNA interaction is suggested to initiate inflammatory response and fibro proliferative changes via cytokines resulting in collagen augmentation in the lungs [12]. Moreover, BLM causes the depletion of endogenous antioxidant defenses, which in turn leads to ROS- and RNS-induced alveolar tissue damage [13].
Pulmonary fibrosis is a multifaceted disease with high mortality and morbidity, and it is commonly nonresponsive to conventional therapy.
We explore the possible discourse of sinapic acid (SA) against the prevention of bleomycin (BLM)-instigated lung fibrosis in rats through modulation of Nrf2/HO-1 and NF-κB signaling pathways.
Lung fibrosis was persuaded in Sprague-Dawley rats by a single intratracheal BLM (6.5 U/kg) injection. Then, these rats were treated with SA (10 and 20 mg/kg, p.o.) for 28 days. The normal control rats provided saline as a substitute of BLM. The lung function and biochemical, histopathological, and molecular alterations were studied in serum, bronchoalveolar lavage fluid (BALF), and the lungs tissues.
SA treatment significantly restored BLM-induced alterations in body weight index and serum biomarkers [lactate dehydrogenase (LDH) and alkaline phosphatase (ALP)]. SA (10 and 20 mg/kg) treatment appeared to show a pneumoprotective effect through upregulation of antioxidant status, downregulation of inflammatory cytokines and MMP-7 expression, and reduction of collagen accumulation (hydroxyproline). Nrf2, HO-1, and TGF-β expression was downregulated in BLM-induced fibrosis model, while the reduced expression levels were significantly and dose-dependently upregulated by SA (10 and 20 mg/kg) treatment. We demonstrated that SA ameliorates BLM-induced lung injuries through inhibition of apoptosis and induction of Nrf2/HO-1-mediated antioxidant enzymes via NF-κB inhibition. The histopathological findings also revealed that SA treatment (10 and 20 mg/kg) significantly ameliorated BLM-induced lung injury.
The present results showed the ability of SA to restore the antioxidant system and to inhibit oxidative stress, proinflammatory cytokines, extracellular matrix, and TGF-β. This is first report demonstrating that SA amoleriates BLM induced lung injuries through inhibition of apoptosis and induction of Nrf2 and HO-1 mediated antioxidant enzyme via NF-κB inhibition. The histopathological finding reveals that SA treatment (10 and 20 mg/kg) significantly ameliorates BLM induced lung injuries.
Arachidonic acid with taurine enhances pulmonary absorption of macromolecules without any serious histopathological damages
2017, European Journal of Pharmaceutics and Biopharmaceutics
Citation Excerpt :
Interestingly, these lung injuries were prevented by taurine (Tau) (Fig. 4D and Table 5). Tau was reported to protect against bleomycin-induced pulmonary fibrosis and endotoxin-induced acute lung inflammation [30–32]. From these results, the combined use of AA with Tau is suggested as a new formulation.
Therapeutic peptides and protein are being used in several indications; however, their poor permeability still remains to be solved. This study focused on the pulmonary route of macromolecules. First, the effects of arachidonic acid (AA) as an absorption enhancer on drug serum concentration, after intratracheal administration, were investigated in rats. Second, the safety of AA was assessed in rats in an acute toxicity study for 7 days. AA enhanced the exposure of both interferon-α (IFN-α) and fluorescein isothiocyanate 4000 (FD-4). In addition, the histopathological analysis indicated that AA caused alveolitis and bronchitis in rats. In combination with Taurine (Tau), these lung injuries were prevented through the histopathological analysis. The combined use of Tau with AA did not show any changes in the pharmacokinetics of FD-4. From these results, we suggest the combined use of AA with Tau as a novel formulation on the pulmonary route of macromolecule drugs. This formulation could improve the bioavailability of macromolecule drugs without any serious local damage to the lungs.
Protective effect of gallic acid against bleomycin-induced pulmonary fibrosis in rats
2015, Pharmacological Reports
Citation Excerpt :
Moreover, reactive oxygen species (ROS) such as hydrogen peroxide, peroxynitrite, superoxide, and hydroxyl radical are also play a pivotal role in lung inflammatory processes that can induce fibrosis [6]. Many xenobiotics that stimulate the overproduction of ROS such as paraquat [7], butylated hydroxytoluene [8] and bleomycin [9] are able to produce lung fibrosis. There is currently no Food and Drug Administration-approved drug for the treatment of pulmonary fibrosis or other fibrosing disorders [5].
Bleomycin (BLM), a chemotherapeutic agent is indicated in the management of some types of cancers. This drug produces a dose-dependent pulmonary fibrosis (PF) in most patients as well as experimental animals through oxidative injury. This study aimed to investigate the effect of gallic acid (GA), a polyphenolic compound, against PF-induce by BLM in rats.
The rats were given GA orally at doses (50, 100, and 200 mg/kg/day) for 7 consecutive days before the administration of single intratracheal (it) instillation of BLM at 7.5 IU/kg. GA doses were continued for 21 days after BLM exposure. The regulatory effects of GA on BLM-induced pulmonary toxicity were determined by assaying oxidative stress biomarkers, lung and serum cytokine levels, and by histopathological examination of lung tissue.
The results showed that intratracheal BLM administration significantly increased the inflammatory or fibrotic changes, collagen content, levels of malondialdehyde (MDA), and pro-inflammatory cytokines such as TNF-α and IL1β in lung. Also, it significantly decreased non-enzymatic (total thiol) and enzymatic (glutathione peroxidase (GPx)) antioxidant contents in the rats’ lung tissue. However, oral administration of GA reversed all of these biochemical indices as well as histopathological alterations induced by BLM.
Results of the present study demonstrate that GA, by its antioxidant properties, attenuates oxidative damage and fibrosis induced by BLM. Thus, an effective supplement with GA as an adjuvant therapy may be a very promising compound in reducing the side effects of BLM.
Evaluating the inhibitory potential of sulindac against the bleomycin-induced pulmonary fibrosis in wistar rats
2013, Environmental Toxicology and Pharmacology
Citation Excerpt :
Bleomycin is a commonly used chemotherapeutic agent that can cause dose-dependent pulmonary fibrosis (Jules-Elysee and White, 1990). Bleomycin-induced pulmonary injury and lung fibrosis has been documented in several animal species (Wang et al., 1991; Tzurel et al., 2002). This model has been widely used for studying the mechanisms involved in the progression of human pulmonary fibrosis and the impact of various drugs on this progression (Yara et al., 2001; El-Khatib, 2002).
The present study examined the protective effect of sulindac on bleomycin-induced lung fibrosis in rats. Animals were divided into saline group, bleomycin group (single intra-tracheal instillation of bleomycin) and bleomycin + sulindac (orally from day 1 to day 20). Bleomycin administration reduced the body weight, altered antioxidant status (such as superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione) while it increased the lung weight, hydroxyproline content, collagen deposition and lipid peroxidation. However, simultaneous administration of sulindac improved the body weight, antioxidant status and decreased the collagen deposition in lungs. Moreover, the levels of inflammatory cytokine tumour necrosis factor-α increased in bleomycin-induced group, whereas, on treatment with sulindac the levels of tumour necrosis factor-α were found reduced. Finally, histological evidence also supported the ability of sulindac to inhibit bleomycin-induced lung fibrosis. The results of the present study indicate that sulindac can be used as an agent against bleomycin-induced pulmonary fibrosis.
Regulation of myofibroblast differentiation by poly(ADP-ribose) polymerase 1
2013, American Journal of Pathology
Poly(ADP-ribosyl)ation (PARylation) is a post-translational protein modification effected by enzymes belonging to the poly(ADP-ribose) polymerase (PARP) superfamily, mainly by PARP-1. The key acceptors of poly(ADP-ribose) include PARP-1 itself, histones, DNA repair proteins, and transcription factors. Because many of these factors are involved in the regulation of myofibroblast differentiation, we examined the role of PARylation on myofibroblast differentiation. Overexpression of PARP-1 with an expression plasmid activated expression of the α-SMA gene (Acta2), a marker of myofibroblast differentiation in lung fibroblasts. Suppression of PARP-1 activity or gene expression with PARP-1 inhibitors or siRNA, respectively, had the opposite effect on these cells. PARP-1–deficient cells also had reduced α-SMA gene expression. DNA pyrosequencing identified hypermethylated regions of the α-SMA gene in PARP-1–deficient cells, relative to wild-type cells. Interestingly, and of potential relevance to human idiopathic pulmonary fibrosis, PARP activity in lung fibroblasts isolated from idiopathic pulmonary fibrosis patients was significantly higher than that in cells isolated from control subjects. Furthermore, PARP-1–deficient mice exhibited reduced pulmonary fibrosis in response to bleomycin-induced lung injury, relative to wild-type controls. These results suggest that PARylation is important for myofibroblast differentiation and the pathogenesis of pulmonary fibrosis.
Antifibrosis effects of total glucosides of Danggui-Buxue-Tang in a rat model of bleomycin-induced pulmonary fibrosis
2011, Journal of Ethnopharmacology
Citation Excerpt :
Pulmonary fibrosis is characterized by excessive synthesis and deposition of extracellular matrix (ECM) in the distal airspace, and is thought to be initiated by acute or chronic lung injury (Crouch, 1990; Thannickal et al., 2004; Garantziotis et al., 2004). Bleomycin-induced pulmonary injury and pulmonary fibrosis has been documented in several animal species (Wang et al., 1991; Tzurel et al., 2002). This model has been widely used for studying the mechanisms involved in the progression of human pulmonary fibrosis and the impact of various drugs on this progression (Yara et al., 2001; El-Khatib, 2002).
The present study examined the antifibrosis effects of DBTG (total glucosides of Danggui–Buxue–Tang) on bleomycin-induced pulmonary injury and fibrosis in rats.
Animals were randomly divided into six groups: (1) saline control group; (2) Bleomycin group in which rats were endotracheally instillated with bleomycin (5 mg/kg); (3–5) Bleomycin and DBTG group, in which DBTG were given to rats daily (16.32 or 64 mg/kg/day, i.g.) one day after bleomycin injection for 4 weeks until the end of the treatment; (6) Bleomycin and positive control group. Animals were sacrificed at 7, 14, and 28 days post bleomycin administration and lungs were removed. Lung specimens were stained with hematoxylin and eosin (HE) and Masson trichrome for histological evaluation of lung injury and fibrosis by light microscopy. Body weight and lung index from various groups were measured, as well as TNF-α, TGF-β1 and type I collagen concentrations in lung homogenates.
DBTG reduced bleomycin-induced weight loss, decreased the lung index and histological evidence supported the ability of DBTG to attenuate bleomycin-induced lung fibrosis and consolidation. DBTG could partly dose-dependently decrease TNF-α and TGF-β1 activity, as well as it decrease type I collagen expression in lung tissues.
The findings of the present study provide evidence that DBTG may serve as a novel target for potential therapeutic treatment of lung fibrosis.

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^☆: This paper was presented in part at the World Conference on Lung Health, Boston, MA, May 20–24, 1990, and in part at the meeting of the American Society for Pharmacology and Experimental Therapeutics, Milwaukee, WI, August 12–15, 1990, and published as abstracts in Am Rev Respir Dis (Suppl) 141: A138, 1990, and in Pharmacologist32: 173, 1990, respectively.

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Amelioration of bleomycin-induced pulmonary fibrosis in hamsters by combined treatment with taurine and niacin☆

Abstract

Toxicol Appl Pharmacol

Exp Mol Pathol

Exp Med Pathol

Exp Mol Pathol

Fundam Appl Toxicol

Mutat Res

Anal Biochem

Anal Biochem

J Biol Chem

Arch Biochem Biophys

Arch Biochem Biophys

Biochem Pharmacol

Toxicology

Prostaglandins Leukotrienes Essent Fatty Acids

J Biol Chem

Biochem Biophys Res Commun

Biochem Pharmacol

Pathol Res Pract

A clinical, radiographie, and physiologie scoring system for the longitudinal assessment of patients with idiopathic pulmonary fibrosis

Am Rev Respir Dis

Unraveling pulmonary fibrosis: The bleomycin model

Lab Invest

Chronic interstitial pulmonary fibrosis produced in hamsters by endotracheal bleomycin

Am Rev Respir Dis