Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs

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Abstract

Pirfenidone, an antifibrotic drug with anti-inflammatory and antioxidant effects, delays fibrosis in idiopathic pulmonary fibrosis (IPF). Patients with IPF have a greater cough reflex sensitivity to inhaled capsaicin than healthy people, and cough is an independent predictor of IPF disease progression; however, the effects of pirfenidone on cough reflex sensitivity are unknown.

After challenge with an aerosolized antigen in actively sensitized guinea pigs, pirfenidone was administered intraperitoneally, and the cough reflex sensitivity was measured at 48 h after the challenge. Bronchoalveolar lavage (BAL) was performed, and the tracheal tissue was collected.

Pirfenidone suppressed the capsaicin-induced increase in cough reflex sensitivity in a dose-dependent manner. Additionally, increased levels of prostaglandin E2, substance P, and leukotriene B4, but not histamine, in the BAL fluid were dose dependently suppressed by pirfenidone. The decrease in neutral endopeptidase activity in the tracheal tissue was also alleviated by pirfenidone treatment. The total number of cells and components in the BAL fluid was not influenced.

These results suggest that pirfenidone ameliorates isolated cough based on increased cough reflex sensitivity associated with allergic airway diseases, and potentially relieve chronic cough in IPF patients who often have increased cough reflex sensitivity. Prospective studies on cough-relieving effects of pirfenidone in patients with IPF are therefore warranted.

Introduction

Chronic nonproductive dry cough is a complicating clinical feature in idiopathic pulmonary fibrosis (IPF) [1]. The cough is bothersome and has been described as “dry and nonproductive” or “hacking”, often accompanying a nagging desire to cough constantly, which is not relieved by coughing [2]. In an analysis of 242 patients with IPF, cough was present in 84% of subjects and was an independent predictor of disease progression [3]. Previous studies [4], [5], [6] have investigated the pathogenesis of cough in IPF; however, cough due to IPF is a diagnosis of exclusion after considering other common disorders. Additionally, reports have demonstrated that at least 50% of cough in IPF patients is not secondary to IPF [1], [7]. B.D. Hope-Gill et al. [8] revealed that patients with IPF in whom gastroesophageal reflux disease (GERD), airway hyper-responsiveness, and other confounding influences were excluded showed enhanced cough reflex sensitivity to capsaicin and substance P (SP) compared with healthy subjects, suggesting a functional upregulation of respiratory tract sensory nerves.

Pirfenidone (5 methyl-1-phenyl-2-[1H]-pyridone) is an antifibrotic drug which delays fibrosis in IPF. In a bleomycin-induced lung fibrosis mouse model, pirfenidone showed antifibrotic and anti-inflammatory effects [9]. A phase III trial in Japan showed that pirfenidone caused a significant reduction in the decline of vital capacity and improved progression-free survival [10]. Pirfenidone has been reported to have anti-inflammatory [11], [12] and antioxidant [13], [14] effects, in addition to antifibrotic effects [15], [16], in experimental models. Furthermore, the effects of pirfenidone on bronchial asthma have been investigated recently [17], [18], and although the effects of pirfenidone on airway hyper-responsiveness remain controversial, these data suggest the possibility that pirfenidone may be used for the treatment of acute allergic airway diseases and may reduce or prevent airway remodeling. However, only one study [19] has clarified the inhibitory effects of pirfenidone on cough in patients with IPF, and no reports of the effects of pirfenidone on cough reflex sensitivity have been published.

Here, we investigated the effects of pirfenidone on increased cough reflex sensitivity to inhaled capsaicin accompanied by eosinophilic airway inflammation in actively sensitized guinea pigs with cough reflex sensitivity. We also examined the effects of pirfenidone on cell components, levels of sensory nerve mediators and neuropeptides in the bronchoalveolar lavage fluid (BALF), and neutral endopeptidase (NEP) activity in the tracheal tissue.

Section snippets

Study animals

Male albino Hartley strain guinea pigs weighing 200–220 g were obtained from the Sankyo Laboratory Service (Toyama, Japan) and were quarantined in the Animal Research Center of Kanazawa University. All animal procedures in this study complied with the standards specified in the Guidelines for the Care and Use of Laboratory Animals at the Takara-machi Campus of Kanazawa University.

Study design

Guinea pigs (n = 8 per group) were assigned to the negative control (NC), positive control (PC), low-dose

Effects of pirfenidone on cough reflex sensitivity

The number of coughs induced following 2 min of exposure to aerosolized capsaicin (10−4 M) during the 3-min observation time was significantly (P < 0.01) increased in the PC group compared with the NC group (Fig. 2a). Pirfenidone significantly decreased the cough reflex in the PFD-high group (P < 0.01) compared with the PC group (Fig. 2a). There were no differences in the number of coughs in naïve guinea pigs, regardless of whether pirfenidone was administered (Fig. 2b).

Effects of pirfenidone on BALF cells

The number of total

Discussion

In the present study, we found that pirfenidone suppressed the increase in cough reflex sensitivity to inhaled capsaicin and the increase in PGE2, SP, and LTB4 levels in the BALF in a dose-dependent manner. We also found that pirfenidone repaired the decrease in NEP activity in the tracheal tissue.

Pirfenidone is an antifibrotic drug with anti-inflammatory and antioxidant effects. The 2011 ATS/ERS/JRS/ALAT guidelines [26] give recommendations for the use of pirfenidone only in selected patients,

Support statement

This study was supported in part by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology – Japan (No. 23591142).

Statement of interest

None declared.

Acknowledgments

We thank Luis J. Espinosa and Miki Kashiwano (Kanazawa University, Kanazawa, Japan) for their valuable technical advice.

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