Keywords

1 Introduction

Chronic obstructive pulmonary disease (COPD) is usually caused by multiple factors, and it is the fourth leading cause of death worldwide [1]. COPD disease pathology is heterogeneous in nature, and it includes chronic bronchitis, bronchiolitis and emphysema. The condition is presented by chronic airway inflammation [2], and the disease pathology is associated with obstruction of airflow into the lung [3,4,5]. The condition is not fully reversible at the onset of the disease and is usually progressive in nature, causing debilitating disability and finally death.

Asthmatic condition is often treated with glucocorticoids, but it is unsuccessful in treating COPD-related inflammation. Until now, no effective therapeutic and pharmacological intervention is available to reduce COPD-associated mortality [6, 7]. Extensive research performed in this specific subject area has identified oxidative damage to lung epithelial cells is directly linked to the COPD disease pathology [8,9,10]. Several factors, including smoking, domestic smoke exposure, outdoor pollution, socio-economic status, and ethnicity, have been identified as major contributors towards developing COPD [11].

Reactive oxygen species (ROS) are known causative agents for cellular oxidative stress and tissue damages. Oxidative stress in pathological condition causes oxidant burden. Free dioxygen radical (O2−.) in oxidative stress condition may function as signal transduction molecule in initiation and progression of the COPD disease state. Transient receptor potential (TRP) channels have been widely implicated in relation to COPD initiation and progression [12,13,14,15]. TRP channels are polymodal cation selective ion channels that sense and respond to environmental changes and stimuli such as pH, temperature, osmolarity and exposure to chemical agents. TRP channels also play a significant role in several cellular processes, including apoptosis and neural functions. The mechanism of calcium influx through ROS-sensitive channel and subsequent cellular signaling mechanisms are still largely unknown.

In recent past, scientists put significant effort in order to inhibit ROS-activated TRP channels by antioxidant treatment. TRPM2, one subgroup of the TRP channels, have been reported to be ROS-sensor [16]. Recent development in this specific area has identified TRPM2 channel as a potential candidate in order to modulate the antioxidant enzyme glutathione peroxidase activity [17].

TRPA1, expressed in the chemosensory C-fibers, has been reported to be activated by most of the oxidizing and electrophilic chemicals including but not limited to chlorine, acrolein, isocyanates and tear gas. The chemical stimuli exert their toxic effects by activating TRPA1 through covalent protein modification [18].

COPD disease pathology is not only restricted to lungs, but it has been established as a systemic disease that significantly affects multiple organ systems. Smoking cigarette is directly linked to developing COPD-associated morbidities, and the beneficial effect of quitting smoking has been emphasized as a first line of correcting measure to treat the disease [19].

Human body is constantly exposed not only to oxidants from exogenous sources but also to the reactive oxidant species (ROS) produced endogenously. Glutathione-S-transferase (GST) and superoxide dismutase (SOD) are two main antioxidant enzymes responsible for scavenging ROS activity and play pivotal roles in maintaining redox homeostasis. Cigarette smoke and other environmental pollutants irritate various immune cells located in the lung and cause oxidative stress. Epithelial cells being first line of defense is usually worse affected. This phenomenon ultimately leads to a disruption in redox homeostasis and cause severe damage, which in turn contributes toward developing COPD [20].

Different experimental approaches have identified TRP channels respond to several exogenous stimuli to the airway sensory neurons. The stimuli include harmful chemicals, stimuli causing pain, glandular secretion, depression, cough and other protective responses.

Till date, about 30 TRP channels have been identified. These are further subdivided into seven main subfamilies on the basis of sequence homology. These are TRPC (canonical), TRPV (vanniloid), TRPM (melastatin), TRPP (polycystein), TRPML (mucolipin), TRPA (ankyrin) and TRPN (NOMPC-like). TRPN channels are found only in invertebrates and fish, and the expression of other six subfamilies has been confirmed in human. The subsequent effect of TRP channel activation leads to either neurogenic inflammatory and/or brain-mediated responses of the airways. If undiagnosed and left untreated, these responses mature into severe breathing problem, and eventually COPD disease pathology sets in. The exact and specific roles of individual TRP channels in specific disease conditions are still largely unknown.

2 TRP Channel-Mediated Chemosensation and Associated Responses

Trigeminal chemosensory nerve endings located in the nasal mucosa is the first line of defense in combating exposure of toxic chemical-induced pathological events in the airway [21]. Release of calcitonin gene-related peptide (CGRP), neurokinin A (NKA) and tachykinins substance P (SP) occurs from the nerve ending because of chemical stimulation. The associated downstream signaling events include neurogenic inflammatory vasodilation and leakage, leading to constriction and obstruction of the nasal passage [22, 23].

Oxidative stress and other noxious chemical compounds activate unmyelinated bronchopulmonary C-fibers and initiate action potentials that conduct centrally to evoke unpleasant sensations (e.g. coughing, dyspnea and chest tightness) and to stimulate/modulate reflexes (e.g. cough, bronchoconstriction, respiratory rate and inspiratory drive) [24].

Key components of this pathological event are highly sensitive to regulation of intracellular calcium concentration ([Ca2+]i) and play a significant role in nociception and other exogenous stimuli-induced responses. This finding actually emphasizes the importance of cellular calcium mobilization and calcium-mediated signal transduction. As COPD pathology is usually associated with cellular signaling mechanisms initiated by an increase of [Ca2+]i as a result of cellular calcium influx, TRP channels draw wide attention due to its cation selective gating properties with a focused interest of calcium influx, specifically through these channels [25].

Localization of different subtypes of TRP channels was confirmed in the epithelium and smooth muscle of the lung tissue. Cigarette smoke, industrial pollutants, aldehyde, chlorine and fragrances are the known activators of TRP channels in the human lung epithelium and in the airways. During signal transduction event, calcium is released into the cytoplasm from endoplasmic reticulum (ER), and the immediate effect is store-operated calcium entry through store-operated calcium influx channels, including TRP channels [18]. TRP channels are mostly plasma membrane (PM)-bound (except nuclear membrane and mitochondrial membrane) and selectively allow influx of cations including of Ca2+, Mg2+ and trace metal ions [26].

One of the important mechanisms of cellular calcium influx happens through Store-Operated Calcium Entry (SOCE) [27]. ER calcium store is usually replenished by such a mechanism in a faster way after store depletion. Stromal Interaction Molecule 1 (STIM1) with PM localization has been discovered as critical communicating protein that controls SOCE [28] when the store becomes empty. Immediately after STIM1 discovery, ER Ca2+ sensor Orai1 has been identified as the pore-forming subunit of the Ca2+ release-activated Ca2+ (CRAC) channels [29,30,31]. STIM1 mediated activation of SOC channels require Orai and TRPC1 interaction [32,33,34,35,36,37,38,39,40]. The role of STIM1 and Orai1 variants in SOCE has been reviewed extensively in Ref. [41].

3 Oxidative Damage and COPD

COPD pathogenesis mainly happens due to oxidative stress in the lung tissue. Exposure of lung to inhaled exogenous oxidants along with endogenously produced oxidative stress in the lung due to ageing and various metabolic processes creates significant oxidative damage. Oxidant and COPD-associated pathology includes but not limited to cell membrane damage due to destruction of membrane lipid bilayer, proteins and nucleic acids [42].

Cigarette smoke (CS) has long been identified as a major cause of COPD due to oxidative stress produced in the lower airways [43]. CS-induced damage to the lung tissue and the development of COPD depends on the extent of inhaled cigarette smoke exposure. Hydroxyl radical (OH−.) in the inhaled CS causes lipid peroxidation of the cell membrane proteins. OH−., upon reacting with unsaturated fatty acids of the membrane phospholipid, generates organic acid free radicals and causes membrane damage [44]. The secondary metabolite formed due to rapid degradation of the unstable intermediate oxidant molecules causes further lipid peroxidation. The intermediate oxidants molecules include alkanes (e.g. ethane/pentane) and aldehydes (e.g. malondialdehyde). The concentration of thiobarbituric acid reactive substance (TBARS) has been found in higher quantities in smoker lungs with COPD [45].

Non smoking-associated COPD development and progression of the disease has been linked to several factors. Deficiency of α1 antitrypsin, presence of chronic asthma, ROS-exposure due to polluted air, biomass smoke (BS) exposure, etc. has been found to be the major cause of nonsmoking-associated COPD [45].

Smoker lungs have been shown to have elevated high granular density alveolar macrophages, which has been identified as a major contributor for increased ROS production [46, 47]. The deadly association among H2O2, O2−. and OH−. radicals results in bronchial hyper responsiveness in COPD patients [48].

Endogenous cell-derived ROS produced in metabolically active cells is a result of enzymatic reactions involving a group of oxidant enzymes. Three main members of such an oxidant enzymes are NADPH oxidase, eosinophil peroxidase (EPO) and myeloperoxidase (MPO) [49]. Mitochondria are the source of reactive nitrogen species (RNS), O2−. and H2O2 production [50, 51]. Sources of exogenously produced ROS are CS [52] and the lipid peroxidation in inflammation of airway epithelium due to environmental ozone exposure [53].

4 TRP Channels and COPD

Increased TRPC6 mRNA expression in human alveolar and lung tissue macrophages has been reported in COPD patients [54]. The pathophysiological roles of non-neuronal TRPV1/TRPA1 channels have been widely studied in infection, inflammation and immunity. The sensory input of non-neuronal TRP channel mediated signal transduction mechanisms ultimately results indirect neurogenic pain or inflammation.

TRPV1/TRPA1 activation has been positively correlated with airway neurogenic inflammation. Non-neurogenic inflammatory responses produced by non-neuronal TRPA1 results inflammatory airway diseases. Thus TRPA1 has been identified as a prominent target to treat inflammatory respiratory diseases [55]. TRP channels are also involved as active removal mechanisms of foreign toxic substances in the cell. TRPV1/TRPA1 isoforms are widely expressed in lung sensory neurons, and those specific TRP channel activation causes alteration in vagal output associated with change in respiratory pattern, blood flow and coughing behavior.

TRPV2/TRPV4 expressed in the alveolar macrophages play critical roles in immune response initiation [56]. Contribution of different TRP channel family members in relation to COPD development is summarized in Fig. 10.1.

Fig. 10.1
figure 1

Summary of different TRP channels expressed in lung tissues and the exogenous toxic agents they sense and respond. Respective membrane topology, functional domain and proposed binding sites with respect to the modulators of individual TRP channels are depicted in this figure. 4α-PDD 4α -Phorbol 12,13-didecanoate, 5,6 EET 5,6-Epoxy-eicosatrienoic acid, AA arachidonic acid, A Ankyrin repeat, AITC allyl isothiocyanate, ADPR ADP-ribose, cADPr cyclic ADP-ribose, CaM calmodulin binding site, CIRB calmodulin-IP3-receptor-binding site, CIRPIB calmodulin-IP3-receptor-phospho-inositide-bindingsite, RTX Resinferatoxine, TRP TRP box, Nudix nudix box, P pore, S1–6 transmembrane segment 1–6, TRP box, PDZ, PSD95/SAP90-Discs-large-Zonula-occludentes-1 domain. (Taken from Ref. [151] with permission)

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4.1 TRPC6

TRPC6 and TRPC7 both gene expression has been detected in lung tissue [57]. TRPC6 being predominantly expressed in macrophages, lymphocytes and neutrophils [12] and also in the airway epithelium became a target gene for inflammation-induced lung diseases.

Increased TRPC6 gene expression has been reported in macrophages isolated from COPD patients [54]. In COPD patients phospholipase C (PLC), one of the important modulators of TRPC channels including TRPC6, has been found to be activated [58] as a result of CXC chemokine receptor activation. Thus TRPC6 activation and CXC chemokine receptor activation-mediated inflammation in COPD has been emerging as an interesting area of research.

4.2 TRPC4

Expression of TRPC proteins has been reported in endothelial cells, vascular smooth muscle cells and mast cells [59]. Discovery of TRPC4 knock out (KO) mouse model [60] opened up the possibility of detailed study for the role of TRPC4 in lung diseases and in COPD. Vascular endothelial cells of lungs in TRPC4 KO mice have a defective Ca2+ influx mechanism which has been found to be induced by thrombin [61]. Investing future research effort on TRPC4 in context to COPD and respiratory diseases certainly has potential to shed lights on COPD disease pathology.

4.3 TRPM2

Recently TRPM2 channel has been described as an oxidant sensor [62]. TNF-α and lipopolysaccharides (LPS) are two known potent activators of TRPM2 channels [63]. TRPM2 channel is largely expressed in inflammatory cells, including endogenous ROS-producing cells. Primary human monocytes have been shown to cause TRPM2 mRNA upregulation upon LPS or TNFα challenge [63]. Targeted gene knockdown studies of TRPM2 employing specific siRNA have been shown to reduce TNF-α, IL-6, IL-10 and [Ca2+]i rise upon LPS exposure [63].

Direct activation of TRPM2 and IL-8 production by H2O2 and subsequent cellular calcium influx have been shown in human monocyte cell line [64]. TRPM2 has been identified as an important target in oxidative damage-induced cellular inflammatory processes. The involvement of TRPM2 channel-mediated oxidative stress-induced cellular inflammatory processes has been tested in TRPM2−/− mice compared to WT counterparts [65, 66]. Further research on monocytes isolated from TRPM2−/− mice has shown reduced Ca2+ influx and reduced macrophage inflammatory protein-2α (MIP-2α or CXCL-2α) production in response to oxidative stress compared to WT mice [67].

Research from Heiner group [68] has shown involvement of TRPM2 in the neutrophil chemotaxis in human. Yamammoto group [64] also has provided the evidence for the existence of similar TRPM2-mediated mechanisms in experimental mice model. All those immune cell-induced cellular inflammatory pathways have been so far characterized in the COPD disease state.

4.4 TRPM8

Expression of TRP channels has been confirmed in vagal afferent neurons. Cold and menthol, a TRPM8 ligand, both have been reported as TRPM8 activators [69]. So-called thermoreceptor sensory function of TRPM8 channels operating at non-physiological low temperature zone has not proved to be of beyond doubt. Cold air is known to cause airway constriction, mucus secretion, cough and plasma protein infiltration which is characteristic to processes associated with inflammatory airway diseases [70, 71]. COPD being one of the well-characterized inflammatory airway diseases certainly draws attention with a possible linkage between TRPM8 pathology and the disease presentation. Presence of a functional variant of TRPM8 protein in human epithelial cell has recently been reported that promotes ER calcium release and subsequent increase in inflammatory cytokine transcription [72, 73].

Consistent with this notion of the presence of oxidant and TRM8-mediated mechanisms in COPD has been further supported by the fact that menthol cigarette smokers in COPD patients had shown severe airway inflammation compared to non-menthol smokers with COPD individuals [74]. In the same study employing in vitro model, the degree of ROS production has been compared between non-menthol cigarette smoke extract (Non-M-CSE) and menthol cigarette smoke extract (M-CSE) groups. Initially similar degree of increased extracellular ROS production has been reported in both groups. However, M-CSE group eventually produced a robust cytoplasmic calcium elevation, MAP Kinase (MAPK) activation, NF-κB signaling and release of IL-8. N-acetyl-cysteine (NAC), a ROS scavenger, was able to block the ROS-induced responses in both CSE treatment groups.

Additionally EGTA (an extracellular Ca2+ chelator) and AMTB (a TRPM8 antagonist), or both were able to completely inhibit both CSE-induced responses. Those findings strongly indicate a functional role of TRPM8 channel in oxidant-induced airway inflammation and possibility of TRPM8 being a therapeutic target to treat COPD. When menthol has been introduced into the Non-M-CSE groups, the rise in cytoplasmic calcium and release of IL-8 had been significantly increased compared to the Non-M-CSE only group. The involvement of TRPM8 in oxidative stress-induced inflammatory responses in smokers has been supported by employing either TRPM8 knocked down cells or TRPM8 knock out animal models [75].

4.5 TRPA1

Involvement of TRPA1 channel has been proved beyond doubt as major signaling mechanisms in COPD disease pathology [76]. Cigarette smoke extract (CSE), acrolein and crotonaldehyde have been shown to produce contraction of bronchial rings in guinea pigs which has been shown to be prevented by pretreatment with HC-030031, a specific TRPA1 antagonist and not by capsazepine, a TRPV1 antagonist or reactive oxygen scavengers [77].

Covalent modification of the N-terminus cysteine residues of TRPA1 by prostaglandins is one of the well-studied mechanisms of the channel activation [78, 79]. Another important activation mechanism is the lipid peroxidation, a mediator of cigarette smoke-induced inflammation [80, 81]. TRPA1 agonist-induced tussive responses in preclinical guinea pig model were found to be inhibited by HC-030031 [82]. Considering COPD disease etiology, the involvement of TRPA1s role in neurogenic inflammation is not well established. Recent evidence also suggests the involvement of TRPA1 in the non-neurogenic inflammatory pathways in experimental mice model [55].

TRPA1-induced neurogenic inflammation is usually associated with COPD [77]. Studies on preclinical animal models have provided evidence that TRPA1 channels play a significant role in cigarette smoke-induced bronchial inflammation [77]. Cigarette smoke is a complex mixture of several irritants known for potentially activating TRPA1 channel. Acrolein and crotonaldehyde [77, 83,84,85,86], along with nicotine [87] present in cigarette smoke, have been identified as direct TRPA1 activators. Biomass smoke (BM), mainly produced by burning wood, has been recently identified as activator of TRPA1-induced chemosensation in cultured jugular ganglia isolated from guinea pig [88]. Primary cultures of human airway fibroblasts, smooth muscle cells and epithelial cells have been reported to release IL-8 upon cigarette smoke-induced TRPA1 stimulation [55].

4.6 TRPV1

Neuronal TRPV1 channels are mostly expressed in C- and Aδ- fibers of primary sensory neurons. This channel has been widely described as nociceptors. TRPV1 channels are major intra and intercellular communication channels of the respiratory tract covering nose, alveoli, smooth muscle and blood vessel [13, 89].

Present TRPV1 research in relation to COPD is revolving in the areas of TRPV1’s role in sensory nerves and, especially, in tussive response associated with COPD [90, 91]. Involvement of neuronal TRPV1 responses in COPD pathology in human is still questionable while the role of non-neuronal TRPV1-response is becoming more evident in recent years [92].

Heat, protons, voltage, endogenous chemicals (including lipoxygenase products) and exogenous chemicals (including capsaicin and resiniferatoxin) are the known activators of TRPV1 [57]. Protein kinase A (PKA), protein kinase C (PKC) and other kinase-induced direct phosphorylation also activate TRPV1 channel [93, 94]. Phospholipase C (PLC) also has been shown as a TRPV1 mediator [95]. TRPV1-induced release of TNF-α and downstream proinflammatory response in sensory neurons has been reported [96]. Elevated levels of endogenous TRPV1 activators such as arachidonic acid metabolites involved in PKA, PKC and PLC pathways have been found in the lungs of COPD patients.

Low pH, a known TRPV1 activator, has been found in the exhaled breath condensate of COPD sufferers [97]. Hypersensitive tussive response upon capsaicin inhalation has been noted in COPD patients, an indicator of TRPV1 signaling mechanisms [98]. In experimental rat model, hypersensitivity of capsaicin-induced airway inflammation responses in pulmonary myelinated primary afferents was reported [99]. A systematic meta-analysis also suggests a strong correlation of TRPV1 in COPD disease pathology [100].

Apoptosis caused by inhaled airborne particulate material has been found to be completely inhibited by capsazepine in human airway epithelial cells and in TRPV1−/− mice [101]. Parallel studies also reported TRPV1 agonist-induced ER stress and loss of cell viability in BEAS-2B and A549 airway epithelial cell lines [102]. TRPV1 stimulation also caused release of IL-6, a proinflammatory cytokine from airway bronchial epithelial cells [103]. These evidences strongly support the role of non-neurogenic TRPV1 responses in COPD. Back in 1984, it has been reported that capsaicin treatment-induced ablation of TRPV1 in neonatal rats were resistant to cigarette smoke (CS)-induced increase in vascular permeability in the airways. In recent years, TRPV1 homozygous KO (TRPV1−/−) mice were found to be resistant to LPS-induced inflammation and bronchial hyperactivity, and that pretreatment with TRPV1 agonist SA13353 failed to produce both neutrophil influx and increase in cytokines TNFα and CXCL1 [104].

Tiotropium, a widely prescribed drug for COPD treatment as bronchodilator opened up the initial idea about possible linkage of TRPV1 in COPD disease pathology [105]. Tiotropium was found to inhibit capsaicin, a potent TRPV1 agonist-induced cough (Tussive stimulation) and single C-fiber firing in the guinea pig model [105] and in other preclinical studies [106].

Both TRPV1 and TRPV4 mRNA have been found to be upregulated in patients with COPD and were shown to be involved in CS-induced elevated ATP release in the COPD airways [107].

4.7 TRPV4

Known functions of TRPV4 channels include epithelial cell volume control, epithelial and endothelial permeability, bronchial smooth muscle contraction and participation in autoregulation of mucociliary transport. Those functions of TRPV4 appear important for the regulation of COPD pathogenesis, and thus TRPV4 emerges as a candidate gene for COPD. TRPV4 is widely expressed in heart, lung, kidney, CNS and skin [108]. In the lungs the highest levels of TRPV4 expression have been found in the epithelial linings of the trachea, bronchi and lower airways and the alveolar septal walls [109, 110].

TRPV1 and TRPV4 both channels are thermo- and osmo-sensitive [111]. TRPV1 has been emerging as a hyperosmotic sensor and TRPV4 as hypoosmotic [112] and mechanical sensor [113]. TRPV4 also senses and responds to chemical stimuli including, 4α-phorbol 12, 13-didecanoate (4α PDD) [111], GSK1016790A [110] and 5′, 6′-epoxyeicosatrienoic acid (EET) [114]. TRPV4 is important in controlling epithelial and endothelial barrier function, especially in response to increased vascular pressure and stretch. TRPV4 channel activation has been implicated in cellular ATP release mechanisms and subsequent downstream purinergic signaling pathways. It is important to note that increased levels of ATP have been found in bronchoalveolar lavage fluid (BALF) from COPD patients [115]. Recently association of small nuclear polymorphisms (SNPs) in TRPV4 in relation to COPD disease pathology has been confirmed [25].

5 ROS and RNS: Potential Activators for the TRP Channels

Infiltrating neutrophils, eosinophils and macrophages into the lung alveolar space significantly increases the pulmonary oxidant burden by generating ROS including O2−., H2O2 and hypochlorite. The NO produced by the inflamed tissue occasionally reacts with ROS and results in more damaging reactive nitrogen species (RNS) including peroxynitrite (ONOO−) and nitrogen dioxide (NO2). RNS cause additional nitrative stress in airway diseases [116].

TRPV1 and TRPA1 both have been identified as a potential target for ROS/RNS-mediated cellular calcium signaling processes in both chronic and acute responses to oxidative stress into the lung. ROS-mediated activation of different TRP channels expressed in airway epithelial cells and in sensory nerves towards neurogenic inflammation is schematically shown in Fig. 10.2.

Fig. 10.2
figure 2

Schematic diagram showing the ROS-induced activation and signal transduction events of TRP channels expressed in sensory nerves and in airway epithelial cells. ROS-induced TRP channel activation following release of proinflammatory mediators leads to the neurogenic inflammation. PGE2 Prostaglandin E2, NGF nerve growth factor, and TNF-α tumor necrosis factor-α. (Taken from Ref. [152])

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RNS damages the membrane integrity by directly attacking the unsaturated fatty acids (e.g. oleic acid) of the cell membrane and generates highly reactive nitro-oleic acid [117]. Oxidative stress can directly activate TRPA1 channels by oxidizing cysteine residue of the cytoplasmic N Terminal [118]. TRPA1 channels are found to respond to both the electrophiles and the oxidizing agents entering in the airways. 3-Niro-tyrosine (3-NT), with high biological activity, is one of the several RNS generated by the reaction between RNS and NO and has potential to be used as a marker for NOO−-mediated cellular damages in vivo. Reactive lipid aldehydes are usually formed by an autocatalytic pathway in lipid peroxidation of the cell membrane.

6 Biomass Smoke and TRP Channel Activation

The correlation between COPD and biomass smoke (BS) exposure is now well established. At present there is around 3 billion COPD sufferer worldwide. Burning biomass fuel such as wood and coke is common in developing countries as a cheap alternative to the conventional source of energies including electricity and gas. Burning of these materials releases several air pollutants in large quantities that includes nitrogen oxides, sulphur oxides, hydrogen chloride, polyaromatic hydrocarbons, volatile organic compounds, methane, furans, dioxins and aerosol particulates of both organic and inorganic origin [119]. In COPD patients, inhaled BS has been identified as a major contributing factor towards developing inflammatory responses. The late responses of such inflammatory processes result in tissue proliferation in small airways and severe tissue damage in lung parenchyma. Additionally, the disease state contains recruitment of immune cells to the airway compartments [120].

7 Diesel Exhausts Particle and TRP Channel Activation

Diesel exhausts particle (DEP) is a very common component in the city environment generated by the automobiles. DEP inhalation has been widely implicated in developing COPD and chronic asthma worldwide. The role of DEP as a direct activator of lung-specific afferent sensory nerves in relation to initiation of respiratory symptoms has been studied. The study on the effect of organic extract of diesel exhaust (DEP-OE) on human and in vitro studies and in vivo electrophysiological studies has identified a list of compounds causing TRPA1 activation. DEPs contain high amount of polyaromatic hydrocarbons (PAHs) on their surface and exert toxic and carcinogenic effects. Phenanthrene, a common PAH found in DEP has been found to cause depolarization of vagus nerve [121]. DEP exposure in human primary airway epithelia has been reported to reduce ciliary beat frequency and results in increased oxidative damage, NF-κB pathway activation and increased secretion of proinflammatory cytokines. Some of the secreted immune-responsive biomolecules also act as mediators and sensitize airway sensory neurons [122,123,124,125,126,127,128,129,130]. Signal transduction pathways specifically responsible for such a DEP-evoked events are not fully understood.

Electrophiles activate TRPA1 channels and involve covalent modification of the cysteine residues on the N-terminus (Cytoplasmic domain) [131, 132]. This finding possibly provides clues why endogenously produced oxidative stress causes TRPA1 activation as an integral event in intracellular oxidative stress [118, 133]. Robinson et al. [121] have shown that H2O2 or DEP-OE depolarizes the vagus nerve in a TRPA1-dependent manner [134, 135], and this response was inhibited by the antioxidant N-acetyl cysteine (NAC).

8 Genetic Contributors of COPD

Finding key genetic contributor for the chronic diseases has been a challenge for the investigators and COPD is no exception. Earlier studies [136, 137] have shown evidence that genetic factors are linked to pulmonary function and COPD. Existence of familial aggregation of COPD strongly suggests this notion [136]. Till date, it is not very clear how genetic factors are associated for COPD development and progression. Environmental pollutants have been shown to produce adverse reactions to the bronchial epithelium and recruit inflammatory cells causing pulmonary disease pathology [138]. Association of COPD with polymorphisms of genes like α1-antitrypsin, TNFα and surfactant protein B genes has been suggested in case control studies [139,140,141]. A study on Indian population exposed to industrial pollutants has shown evidence that microsatellite (MSI) instability is weakly associated with smoker’s age and the extent of exposure to exogenous toxins, which are the known cause for developing COPD [142].

α1-antitrypsin deficiency has been previously positively correlated with COPD development in young adults [143]. Phosphorylated serine 19 residue in TRPV4 protein, a human genetic polymorphism, has been previously documented as COPD susceptibility locus. This specific polymorphism has been directly linked to matrix metalloproteinase (MMP1) activation associated with increased calcium influx and downstream signaling pathways [25, 144, 145].

9 Modulators of TRP Channel Expression and Function

Significant development took place in recent years in order to find both competitive and non-competitive inhibitors for the TRP channels in order to control disease states including asthma, COPD and several other airway diseases. The development of TRP antagonists happened slowly, but in recent years, there has been a wide interest in developing TRPV1 and TRPA1 antagonists because of their potential therapeutic role in targeting neuropathic pain. Ruthenium red (RR), a non-selective calcium channel blocker, blocks several TRP channels including TRPV1. Unfavorable cytotoxicity prevented this potent molecule to be considered as potential candidate for further drug development perspective. In recent years (±) camphor has been identified as week TRPA1 antagonist [146, 147]. SB-705498, a potent TRPV1 antagonist developed by GSK cleared its Phase 1 clinical trial in 2007. SB-705498 has shown promise for further clinical trials as it has been shown to be well tolerated in Phase 1 clinical trial with no serious adverse effects. Topical applications of SB-705498 have also been tested in two Phase 2 clinical trials in relation to chronic cough and non-allergic rhinitis [148].

Competitive TRP channel antagonists are therapeutically attractive because of their direct mode of action without upregulating or activating the receptors for the respective channels and usually do not associate with unwanted drug use-related side effects [149]. So far TRPA1 and TRPV1 both appear to be potential target of therapeutic intervention in order to treat respiratory airway diseases including COPD [150].

10 Conclusions and Future Directions

TRP channels have now gained wide interest because they have been documented as sensors for environmental stimuli that can sense and respond to exogenous stimuli. The multifunctional roles played by different TRP channels are important in terms of understanding how the cellular sensors work to respond to exogenous stimuli in normal and pathophysiological conditions and how these channels are linked to the mechanisms of disease progression.

A wide variety of exogenous and endogenous stimuli-induced activations of different TRP channels play a significant role in COPD development and progression. Targeting TRP channels has enormous potential in treating pulmonary diseases including COPD. TRP channels appear to be a family of endogenous defense system to combat noxious stimuli-induced cellular damages and play critical immunological roles in many lung diseases including COPD. Rise in cytoplasmic calcium through TRP channel and subsequent cellular signaling pathways that lead to hyperactivated proinflammatory and immunological responses including activation of different transcription factors, chromatin remodeling and altered gene expression have potential to shed lights on the mechanisms of the COPD for future drug development to combat the disease. Identification of specific TRP genes responsible for COPD will provide further knowledge about how a specific population of chronic COPD is predisposed to the disease and what genetic manipulation and pharmacological intervention could be done in order to prevent or slow down the disease progression.