TRPV1 and TRPM8 in Treatment of Chronic Cough

Abstract

Chronic cough is common in the population, and among some there is no evident medical explanation for the symptoms. Such a refractory or idiopathic cough is now often regarded as a neuropathic disease due to dysfunctional airway ion channels, though the knowledge in this field is still limited. Persistent coughing and a cough reflex easily triggered by irritating stimuli, often in combination with perceived dyspnea, are characteristics of this disease. The patients have impaired quality of life and often reduced work capacity, followed by social and economic consequences. Despite the large number of individuals suffering from such a persisting cough, there is an unmet clinical need for effective cough medicines. The cough treatment available today often has little or no effect. Adverse effects mostly follow centrally acting cough drugs comprised of morphine and codeine, which demands the physician’s awareness. The possibilities of modulating airway transient receptor potential (TRP) ion channels may indicate new ways to treat the persistent cough “without a reason”. The TRP ion channel vanilloid 1 (TRPV1) and the TRP melastin 8 (TRPM8) appear as two candidates in the search for cough therapy, both as single targets and in reciprocal interaction.

Aspectos fisiopatológicos do reflexo da tosse: uma revisão de literatura

“…Além das células neuronais, o TRPV1 é um canal catiónico não seletivo presente no músculo liso e epitélio do trato respiratório e na membrana plasmática dos neurônios sensoriais que inervam as vias aéreas superiores e inferiores 24 . O TRPV1 pode ser ativado por uma gama diversificada de ligantes químicos endógenos e exógenos, compostos vanilóides como a capsaicina, metabolitos de ácido araquidônico endógeno, pH baixo e temperaturas acima de 43°C [25][26][27][28][29][30][31][32][33] . Nesse sentido, estudos constataram que os receptores TRPV1 são superexpressados em pacientes com tosse crônica 34 .…”

Activation of Human Transient Receptor Potential Melastatin-8 (TRPM8) by Calcium-Rich Particulate Materials and Effects on Human Lung Cells

“…TRP channels are also directly activated by environmental particulate pollutants. For example, TRP ankyrin-1 (TRPA1) and vanilloid-1 (TRPV1), which are expressed by airway neurons and epithelial cells, are activated by and regulate responses to diesel exhaust, cigarette smoke and wood smoke particles, coal fly ash (CFA), and oxidants, as well as the pulmonary irritants allyl isothiocyanate (TRPA1) and capsaicin (TRPV1) (Veronesi et al, 1999a(Veronesi et al, ,b, 2002Johansen et al, 2006;Deering-Rice et al, 2011, 2012, 2016Shapiro et al, 2013). Activation of C-fiber neurons expressing TRPA1 and V1 triggers the cough reflex, [(2,sulfonyl]amino}-3-hydroxypropanoyl)-1-piperazinyl]carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide; HEK-293, human embryonic kidney 293; HEK-GCaMP6s, HEK-293 GCaMP6s-overexpressing cells; hTRPM8, human TRPM8; IL, interleukin; LHC-9, Lechner and LaVeck media; LJO-328, (N-(4-t-butylbenzyl)-N9-{1-[3-fluoro-4-(methylsulfonylamino)phenyl]ethyl}thiourea); NHBE, normal human bronchial epithelial cells; PIP 2 , phosphatidylinositol 4,5-bisphosphate; PM, particulate material; qPCR, quantitative real-time polymerase chain reaction; SEM-EDS, scanning electron microscopy and energy dispersive X-Ray spectroscopy; shRNA, short hairpin RNA; TRP, transient receptor potential; TRPA1, transient receptor potential ankyrin-1; TRPM8, transient receptor potential melastatin-8; TRPM8-KO, TRPM8 knockout; TRPM8-OE, human TRPM8 over-expressing cells; TRPV1, transient receptor potential vanilloid-1; TRPV4, transient receptor potential vanilloid-4.…”

“…suppresses respiratory drive, and stimulates neurogenic edema, whereas activation of these channels in epithelial cells stimulates proinflammatory cytokine responses Deering-Rice et al, 2015, 2016De Logu et al, 2016). Collectively, these events could negatively impact respiratory health.…”

“…TRPM8, a cold-sensing ion channel, is activated by temperature ,16°C, as well as by "cooling" chemicals (e.g., menthol) often found in breath mints, toothpaste, VICK's vapor rub, and menthol cigarettes (McKemy, 2007). In the lung, TRPM8 is expressed by cold-sensitive neurons that are distinct from TRPV1-and TRPA1-expressing neurons (McKemy, 2007;Teichert et al, 2014;Millqvist, 2016;Memon et al, 2017), and in human lung epithelial cells as an N-terminally truncated variant (TRPM8-D801) (Sabnis et al, 2008a,b). TRPM8 has been shown to regulate bronchial tone (Kaneko and Szallasi, 2014), suppress the cough reflex (Millqvist, 2016), and reduce irritation and bronchoconstriction caused by cigarette smoke (Willis et al, 2011;Ha et al, 2015).…”

“…In the lung, TRPM8 is expressed by cold-sensitive neurons that are distinct from TRPV1-and TRPA1-expressing neurons (McKemy, 2007;Teichert et al, 2014;Millqvist, 2016;Memon et al, 2017), and in human lung epithelial cells as an N-terminally truncated variant (TRPM8-D801) (Sabnis et al, 2008a,b). TRPM8 has been shown to regulate bronchial tone (Kaneko and Szallasi, 2014), suppress the cough reflex (Millqvist, 2016), and reduce irritation and bronchoconstriction caused by cigarette smoke (Willis et al, 2011;Ha et al, 2015). Activation of the TRPM8-D801 variant by either cold or menthol in bronchial epithelial cells regulates the expression of multiple cytokines and chemokines (Sabnis et al, 2008b).…”