Effects of pirfenidone on increased cough reflex sensitivity in guinea pigs.

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.

Role of transient receptor potential ion channels and evoked levels of neuropeptides in a formaldehyde-induced model of asthma in BALB/c mice.

OBJECTIVE: Asthma is a complex pulmonary inflammatory disease characterized by the hyper-responsiveness, remodeling and inflammation of airways. Formaldehyde is a common indoor air pollutant that can cause asthma in people experiencing long-term exposure. The irritant effect and adjuvant effect are the two possible pathways of formaldehyde promoted asthma. METHODOLOGY/PRINCIPAL FINDINGS: To explore the neural mechanisms and adjuvant effect of formaldehyde, 48 Balb/c mice in six experimental groups were exposed to (a) vehicle control; (b) ovalbumin; (c) formaldehyde (3.0 mg/m(3)); (d) ovalbumin+formaldehyde (3.0 mg/m(3)); (e) ovalbumin+formaldehyde (3.0 mg/m(3))+HC-030031 (transient receptor potential ankyrin 1 antagonist); (f) ovalbumin+formaldehyde (3.0 mg/m(3))+ capsazepine (transient receptor potential vanilloid 1 antagonist). Experiments were conducted after 4 weeks of combined exposure and 1-week challenge with aerosolized ovalbumin. Airway hyper-responsiveness, pulmonary tissue damage, eosinophil infiltration, and increased levels of interleukin-4, interleukin-6, interleukin-1ß, immunoglobulin E, substance P and calcitonin gene-related peptide in lung tissues were found in the ovalbumin+formaldehyde (3.0 mg/m(3)) group compared with the values seen in ovalbumin -only immunized mice. Except for interleukin-1ß levels, other changes in the levels of biomarker could be inhibited by HC-030031 and capsazepine. CONCLUSIONS/SIGNIFICANCE: Formaldehyde might be a key risk factor for the rise in asthma cases. Transient receptor potential ion channels and neuropeptides have important roles in formaldehyde promoted-asthma.

Tumor macrophages as a target for Capsaicin mediated immunotherapy.

Tumor microenvironment contributes to a large extent for failure of immunological destruction of antigenic tumors. Most solid tumors adapt to the microenvironment and escape the host immune system. The dramatic and systemic effectiveness of neuro-immune ligand Capsaicin (CP) in regression of established solid tumors led us to investigate its immunomodulatory role in tumor microenvironment. In this report we demonstrate that CP induced tumor cell apoptosis leads to increased sensitization of the surrounding stroma manifested by enhanced antigen presentation by stromal macrophages and its destruction by tumor specific T-cells. Further, CP injection alters the tumor microenvironment with regards to tumor-infiltrating Treg cells as well as the cytokine milieu at the tumor site. Our data collectively demonstrates that injection of CP sets in motion, a cascade of several independent innate and adaptive immunological events initiated at the tumor environment.

Nerve growth factor-induced substance P in capsaicin-insensitive vagal neurons innervating the lower mouse airway.

BACKGROUND: Nerve growth factor (NGF) is elevated in allergic diseases such as bronchial asthma and can lead to an induction of substance P (SP) and related neuropeptides in guinea-pigs large-diameter, neurofilament-positive airway neurons. OBJECTIVE: In the present study, the effect of NGF on tyrosine kinase receptor trkA and the capsaicin receptor TRPV1 expression in airway-specific vagal sensory neurons located in the jugular-nodose ganglia complex (JNC) of mice was investigated. METHODS: Using retrograde neuronal tracing in combination with double-labelling immunohistochemistry, SP, trkA- and TRPV1-receptor expression was examined in airway-specific sensory neurons of BALB/c mice before and after NGF treatment. RESULTS: NGF injected into the lower airway was able to induce SP (13.0+/-2.03% vs. 5.9+/-0.33%) and trkA expression (78+/-2.66% vs. 60+/-2.11%) in larger diameter (>25 microm), capsaicin-insensitive and trkA-positive vagal sensory neurons that were retrograde-labelled with Fast Blue dye from the main stem bronchi. CONCLUSION: Based on the extent of SP and trkA co-expression in airway-specific neurons by NGF treatment, the present study suggests that, following a peripheral activation of trkA receptor on SP afferent by NGF which is elevated in allergic inflammation, there may be trkA-mediated SP induction to mediate neurogenic airway inflammation.

Effects of acute stress, relaxation, and a neurogenic inflammatory stimulus on interleukin-6 in humans.

Effects of three experimental manipulations: mental stress, relaxation, and a nociceptive inflammatory stimulus, capsaicin, on levels of interleukin-6 (IL-6) were examined. Fifty subjects were pre-trained in relaxation and then randomized to a stress (Stroop test), relaxation (tape), or control (video) manipulation. Subjects participated in an evening reactivity session including 20 min of stress, relaxation, or control followed by a capsaicin injection in the forearm. Cardiovascular variables and levels of IL-6 were measured before and after the manipulation, and at regular intervals up to 60 min post-capsaicin. Group assignment did not differentially affect change in IL-6 over time, either before or after capsaicin. Small but significant increases in IL-6 were seen at 60 min post-capsaicin. These findings suggest that an acute stress manipulation does not modulate IL-6 within this time frame. Although IL-6 did increase following a neurogenic inflammatory stimulus, it did so subsequent to the maximum flare, suggesting that flare mechanisms are independent of IL-6.

Effects of carbocysteine on antigen-induced increases in cough sensitivity and bronchial responsiveness in guinea pigs.

Carbocysteine is a mucoactive drug and is being used for both acute and chronic infectious airway diseases. Although carbocysteine can repair the damage of epithelial cells caused by exposure to various agents, the effects of this agent on allergic airway diseases such as asthma and eosinophilic bronchitis with an isolated chronic cough, in both of which epithelial damage may be characteristic, is not clear. We investigated the effects of carbocysteine on antigen-induced cough hypersensitivity to inhaled capsaicin at 48 h and bronchial hyperresponsiveness to inhaled methacholine at 72 h after challenge with an aerosolized antigen in actively sensitized guinea pigs. After measuring bronchial responsiveness, we examined neutral endopeptidase (NEP) activity in the tracheal tissue. Carbocysteine (10, 30, or 100 mg/kg) was given intraperitoneally every 12 h for 3 days after antigen challenge. The number of coughs elicited by an aerosol of capsaicin (10(-4) M) was significantly (p < 0.01) decreased in carbocysteine groups (6.13 +/- 0.59 at 10 mg/kg, 4.88 +/- 0.67 at 30 mg/kg, and 4.50 +/- 0.33 at 100 mg/kg during 3 min measurement) compared with the control group (9.75 +/- 0.53). Furthermore, carbocysteine dose dependently repaired the antigen-induced decrease of NEP activity in the tracheal tissue, but it did not influence the bronchial hyperresponsiveness or bronchoalveolar lavage cell component. These findings suggest that carbocysteine promotes the repair of damaged epithelium by allergic reaction and may be useful in allergic airway diseases accompanied by isolated chronic coughing, especially eosinophilic bronchitis without asthma and tracheobronchitis with cough hypersensitivity.

Efecto de la adición del acido cápsico, proveniente de la semilla de paprika (Capsicum annuum) en la dieta de pollo de engorda infectado experimentalmente por Salmonella gallinarum / Effect of Paprika seed (Capsicum annum) diet on Salmonella gallinarum infection in broiler chicks

Para evaluar el efecto del ácido cápsico en la dieta de pollos de engorda, se utilizaron 150 pollitos mixtos de un día de edad, que fueron divididos aleatoriamente en 5 grupos con 30 aves cada uno. Los grupos 1 y 2 fueron alimentados con una dieta basal, mientras que los grupos 3, 4 y 5 recibieron una dieta basal con 18, 27 y 35 ppm de ácido cáspico respectivamante. A los 15 días de edad se registraron los pesos de todos los grupos y se inocularon a las aves de los grupos 2, 3, 4 y 5 con 10 ufc/ml de Salmonella gallinarum resistente a ácido nalidíxico y novobiocina. Las aves se sacrificaron 24 h posinoculación y se realizó la lectura del pH cecal; se obtuvieron muestras de tonsilas cecales para determinar la colonización cecal y de hígado y bazo (muestra mixta) para determinar la invasión a órganos. Tanto la colonización como la invasión por S. gallinarum fue menor (P< 0.001) en los tres grupos que recibieron ácido cápsico en la dieta, en comparación con el grupo inoculado que recibió una dieta basal. El pH cecal disminuyo significativamante (P< 0.05) en los grupos tratados, en relación con los grupos testigo. Los resultados obtenidos en este estudio concuerdan con estudios previos donde se observó que la capsaicina aumentó la resistencia a la invasión de S. enteritidis en órganos. Esta resistencia estuvo asociada con el pH cecal y sugiere que la capsaicina presente en la semilla de paprika es también efectiva en la invasión causada por S. gallinarum en órganos