tranilast and Pulmonary-Disease--Chronic-Obstructive

Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β. In the current study, we examine the contribution of TGF-β activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-β.

Topics: Anti-Inflammatory Agents; Antiviral Agents; Asthma; Benzamides; Cell Line; Dioxoles; Drug Resistance, Viral; Enzyme Activation; Epithelial Cells; Glucocorticoids; Humans; Influenza A virus; Influenza, Human; ortho-Aminobenzoates; Picornaviridae Infections; Poly I-C; Protein Serine-Threonine Kinases; Pulmonary Disease, Chronic Obstructive; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta; Respiratory Mucosa; Respiratory Syncytial Virus Infections; Respiratory Syncytial Viruses; Rhinovirus; Transforming Growth Factor beta

Tranilast (TL), an antiallergic agent, has been clinically used in the treatment of bronchial asthma, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder (RP) of TL for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). In the CSD/TL, wet-milled crystalline TL particles with a mean diameter of 122 nm were dispersed, and there was a marked improvement in dissolution behavior of the CSD/TL-RP compared with that of a physical mixture of TL and carrier. Laser diffraction and cascade impactor analyses on the CSD/TL-RP demonstrated high dispersibility and deposition in the respiratory organs with emitted dose and fine particle fraction of ca. 98 and 60%, respectively. Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by histochemical analyses and inflammatory biomarkers such as lactate dehydrogenase, eosinophil peroxidase, and myeloperoxidase. The CSD/TL-RP seemed to be more potent than the physical mixture in inhibiting inflammatory responses, possibly due to the improved dissolution behavior. Systemic exposure of TL after intratracheal administration of CSD/TL-RP at a pharmacologically effective dose (100 μg of TL/rat) was found to be fivefold less than that of the oral TL dosage form at clinical dose (1.67 mg/kg). Given the improved pharmacodynamics and lower systemic TL concentration, the inhalable TL formulation might provide an interesting alternative to oral therapy with a better safety margin for the treatment of asthma and other airway inflammatory diseases.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents, Non-Steroidal; Asthma; Crystallization; Lung; Male; Nanoparticles; ortho-Aminobenzoates; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; Solubility

Tranilast (TL) has been clinically used for the treatment of airway inflammatory diseases, although the clinical use of TL is limited because of its poor solubility and systemic side effects. To overcome these drawbacks, a novel respirable powder of TL (CSD/TL-RP) for inhalation therapy was developed using nanocrystal solid dispersion of TL (CSD/TL). Stability study on CSD/TL-RP was carried out with a focus on inhalation performance. Even after 6 months of storage at room temperature, there were no significant morphological changes in micronized particles on the surface of carrier particles as compared with that before storage. Cascade impactor analyses on CSD/TL-RP demonstrated high inhalation performance with emitted dose and fine particle fraction (FPF) of ca. 98% and 60%, respectively. Long-term storage of CSD/TL-RP resulted in only a slight decrease in FPF value (ca. 54%). Inhaled CSD/TL-RP could attenuate antigen-induced inflammatory events in rats, as evidenced by marked reduction of granulocytes in bronchoalveolar lavage fluid and inflammatory biomarkers such as eosinophil peroxidase, myeloperoxidase, and lactate dehydrogenase. These findings were consistent with decreased expression levels of mRNAs for nuclear factor-kappa B and cyclooxygenase-2, typical inflammatory mediators. Given these findings, inhalable TL formulation might be an interesting alternative to oral therapy for the treatment of asthma and other airway inflammatory diseases with sufficient dispersing stability.

Topics: Administration, Inhalation; Animals; Anti-Allergic Agents; Asthma; Biomarkers; Bronchoalveolar Lavage Fluid; Cyclooxygenase 2; Drug Compounding; Drug Stability; Dry Powder Inhalers; Granulocytes; Inflammation Mediators; Lung; Male; Nanoparticles; NF-kappa B; ortho-Aminobenzoates; Ovalbumin; Powders; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Sprague-Dawley; RNA, Messenger