Preventive Effect of Tranilast on Oleic Acid-Induced Lung Injury in Guinea Pigs

Abstract

Acute respiratory distress syndrome (ARDS) or acute lung injury (ALI) are among the most severe forms of acute lung injuries with severe pulmonary edema and hypoxemia, which are seen in patients with sepsis, severe trauma, fat embolism and so on.1) The mortality of ARDS/ALI is still high (approximately 40%), despite recent advances in intensive care, because there are only a few drugs available for the prevention and treatment of ARDS/ALI. 1,2) Therefore, the development of new available drugs against ARDS/ALI is very important.In ARDS/ALI, non-cardiogenic edema develops as a result of pulmonary vascular hyper-permeability induced by inflammatory reactions. Recent studies have suggested that ARDS/ALI arises from multiple inflammatory mediators, such as cytokines, reactive oxygen species, proteases and eicosanoids, which are released from inflammatory cells (e.g. polymorphonuclear leukocytes (PMN)), possibly through complex mechanisms. 3) Tranilast (N-3,4-demethoxycinnamoyl-anthranilic acid) has been used clinically to treat allergic diseases, such as bronchial asthma, allergic rhinitis, atopic dermatitis, and hypertrophic scarring and keloid formation. Tranilast seems to have multiple anti-inflammatory effects, through inhibiting the production or releasing cytokines (e.g. tumor necrosis factor-a, interleukin-1b, and -8) or prostanoids (thromboxane A 2 and prostaglandin E 2 ) from monocytes 4) and superoxide 5) from PMNs. Nagai et al. 6) reported that tranilast ameliorated the pulmonary vascular hyper-permeability in lipopolysaccharide (LPS)-induced lung injury, one of the animal models of ARDS/ALI. Therefore, these anti-inflammatory effects of tranilast may work against ARDS/ALI caused by LPS. To extend the application of tranilast to the ARDS/ALI caused by factors other than LPS, it is necessary to examine the effects of tranilast on other animal models of acute lung injury.The injection of oleic acid (OA), an endogenous unsaturated fatty acid, can produce lung injury with pulmonary vascular hyper-permeability and hypoxemia as well as ARDS/ALI. Since pathophysiological changes induced by OA are similar to those in patients with ARDS/ALI, OA-induced lung injury is known as one of the models of these diseases.7) OA-induced lung injury resembles specific forms of ARDS/ALI that follow pancreatitis, 8) long bone fractures 9) and meconium aspiration, 10) all of which are thought to be caused by the toxicity of fatty acids. However, no research has been done to examine the effect of tranilast on lung injury induced by OA. The purpose of this study was to determine whether tranilast ameliorates pulmonary vascular hyper-permeability and hypoxemia induced by OA. MATERIALS AND METHODS AnimalsHartley strain guinea pigs (male, 650Ϯ85 g) were used. This study was approved by the Animal Care and Use Committee of Kumamoto University, and was performed in accordance with National Institutes of Health guidelines for the care and handling of animals. An operation was performed as described before. 11)Animal Treatment Animals wer...

Tranilast: A review of its therapeutic applications

“…Two cases of LMDF were treated with tranilast orally [197] ARDS/ALI Oral administration of the drug in an animal model of ARDS/ALI prevented vascular permeability and hypoxemia [198] Crohn's disease Twelve patients were given tranilast three times in day (200 mg) and tranilast affected the strictures in a positive way [199] Annular elastolytic giant cell granuloma (AEGCG)…”

Protection afforded by a herbal medicine, Sho-seiryu-to (TJ-19), against oleic acid-induced acute lung injury in guinea-pigs

“…Promptly, 1 ml/kg saline was used to push out the oleic acid from the catheter into the vein. All operations and measurements mentioned below were performed as described previously 20–25 …”

“…We have developed a system of acute lung injury induced by oleic acid in guinea‐pigs to screen drugs against ARDS/ALI 20–22 . Using this screening system, we have found some candidate drugs effective against ARDS/ALI and clarified some of the mechanisms of oleic acid‐induced lung injury 23–25 …”

Protection afforded by a herbal medicine, Sho-seiryu-to (TJ-19), against oleic acid-induced acute lung injury in guinea-pigs

“…All operations and measurements mentioned below were performed as described previously. [20][21][22][23][24][25]…”

“…[20][21][22] Using this screening system, we have found some candidate drugs effective against ARDS/ALI and clarified some of the mechanisms of oleic acid-induced lung injury. [23][24][25] Building upon our earlier studies, this study was conducted to examine whether Sho-seiryu-to could be a drug candidate against ARDS/ALI. We used TJ-19 (Shoseiryu-to extract granules for ethical use), which is an extract from a mixture of eight herbal components, Pinellia Tuber, Glycyrrhiza Root, Cinnamon Bark, Schisandra Fruit, Asiasarum Root, Paeony Root, Ephedra Herb and Ginger Rhizome.…”