Release Of Tachykinins Research Articles

Carcinoid Syndrome: A Review.

Carcinoid syndrome (CS) is a paraneoplastic syndrome caused by the release of serotonin and other substances from well-differentiated neuroendocrine tumors (NETs). The hallmark symptoms of carcinoid syndrome are flushing and diarrhea; atypical signs and symptoms can include wheezing, abdominal pain, valvular heart disease, telangiectasias, pellagra, and the complications of mesenteric fibrosis, including ureteral obstruction, bowel obstruction, and bowel ischemia. These symptoms are mediated by the release of serotonin (5-HT), histamine, kallikrein, prostaglandins, and tachykinins. The diagnosis of CS requires these symptoms and corresponding elevations in lab tests. Treatment options include surgery and medical management with somatostatin analogs.

N/OFQ-NOP System and Airways.

Asthma is a heterogeneous chronic inflammatory disease of the airways. The most prevalent form is atopic asthma, which is initiated by the exposure to (inhaled) allergens. Intermittent attacks of breathlessness, airways hyperresponsiveness, wheezing, coughing, and resultant allergen-specific immune responses characterize the disease. Nociceptin/OFQ-NOP receptor system is able to combine anti-hyperresponsiveness and immunomodulatory actions. In particular, N/OFQ is able to inhibit airways microvascular leakage and bronchoconstriction through a presynaptic and non-opioid mechanism of action that blocks tachykinin release. Moreover, it also acts on allergenic sensitization because it is able to modulate the immune response that triggers the development of airway hyperresponsiveness through an interaction on cell membranes of dendritic cells (DCs) that are generally responsible to start and sustain allergic T helper 2 (TH2)-cell responses to inhaled allergens in asthma. In asthmatic patients, sputum showed elevated N/OFQ levels that are related to increased eosinophil counts. The addition of exogenous N/OFQ in sputum obtained from patients with severe asthma attenuated eosinophils migration and release of inflammatory mediators. These observations confirmed that elevated endogenous N/OFQ levels in asthmatic sputum were lower than the ones required to exert beneficial effects, suggesting that supplementation with exogenous N/OFQ may need. In conclusion, the innovative role of N/OFQ in counteracting airways inflammation/hyperresponsiveness opens new potential targets/strategies in asthma treatment.

NKA enhances bladder-afferent mechanosensitivity via urothelial and detrusor activation.

Tachykinins are expressed within bladder-innervating sensory afferents and have been shown to generate detrusor contraction and trigger micturition. The release of tachykinins from these sensory afferents may also activate tachykinin receptors on the urothelium or sensory afferents directly. Here, we investigated the direct and indirect influence of tachykinins on mechanosensation by recording sensory signaling from the bladder during distension, urothelial transmitter release ex vivo, and direct responses to neurokinin A (NKA) on isolated mouse urothelial cells and bladder-innervating DRG neurons. Bath application of NKA induced concentration-dependent increases in bladder-afferent firing and intravesical pressure that were attenuated by nifedipine and by the NK2 receptor antagonist GR159897 (100 nM). Intravesical NKA significantly decreased bladder compliance but had no direct effect on mechanosensitivity to bladder distension (30 µl/min). GR159897 alone enhanced bladder compliance but had no effect on mechanosensation. Intravesical NKA enhanced both the amplitude and frequency of bladder micromotions during distension, which induced significant transient increases in afferent firing, and were abolished by GR159897. NKA increased intracellular calcium levels in primary urothelial cells but not bladder-innervating DRG neurons. Urothelial ATP release during bladder distention was unchanged in the presence of NKA, whereas acetylcholine levels were reduced. NKA-mediated activation of urothelial cells and enhancement of bladder micromotions are novel mechanisms for NK2 receptor-mediated modulation of bladder mechanosensation. These results suggest that NKA influences bladder afferent activity indirectly via changes in detrusor contraction and urothelial mediator release. Direct actions on sensory nerves are unlikely to contribute to the effects of NKA.

Smoke-induced nausea; mediated by the release of the lung tachykinin, endokinin, into the circulation?

Smoke-induced nausea; mediated by the release of the lung tachykinin, endokinin, into the circulation?

Gender-related differential effect of tachykinin NK2receptor-mediated visceral hyperalgesia in guinea pig colon

The tachykinin NK2 receptor antagonist ibodutant is under Phase III clinical investigation to treat female patients with irritable bowel syndrome. The aim of this study was to investigate the NK2 receptor-related gender specificity in a model of colitis. Colitis was induced by rectal instillation of 2,4,6-trinitrobenzenesulfonic acid (TNBS, 0.5mL, 30mg·mL(-1) in 30% ethanol) in female and male guinea pigs. Electromyographic recording of the responses to colorectal distension (CRD) was made 3days later. Ibodutant (0.33 , 0.65, 1.9 and 6.5mg·kg(-1) ) was given s.c., 30min before CRD. Release of neurokinin A and substance P from isolated mucosal and smooth muscle tissues following treatment with KCl (80mM) or capsaicin (10μM) was measured by EIA. Plasma pharmacokinetics of ibodutant following a single s.c. administration (0.73 or 2.1mg·kg(-1) ) were measured over 24h. Ibodutant did not affect abdominal contractions in control animals. After TNBS-induced colitis, ibodutant prevented the increased visceral hypersensitivity to CRD in females, at lower doses than in males. Ibodutant pharmacokinetics did not differ between females and males. Tachykinins release was greater in smooth muscle than in mucosal samples. Capsaicin-stimulated release of tachykinins from inflamed mucosal samples from females was significantly lower than in males. Ibodutant prevented abdominal nociception in a model of visceral hypersensitivity in guinea pigs with a greater efficacy in females than in males. Our results highlight a gender-related difference in colonic visceral hypersensitivity and mucosal nerve activation.

Autonomic and sensory nerve modulation of peristalsis in the upper urinary tract.

The primary function of the upper urinary tract is to propel urine and various water-soluble toxic compounds from the kidneys to the bladder for storage and evacuation to maintain body ionic balance and contribute to the regulation of blood volume and pressure. The mechanism by which the upper urinary tract propels urine has long been considered to be myogenic in origin as peristaltic contractions in vivo and in vitro (pyeloureteric peristalsis) propagate in a manner little affected by drugs that block nerve conduction or the sympathetic and parasympathetic transmission. However, it is now well established that the release of intrinsic prostaglandins and neuropeptides from primary sensory nerves (PSNs) helps to maintain pyeloureteric peristalsis. Electrical field stimulation of PSNs evokes species-specific positive inotropic and chronotropic effects that have been attributed to release of excitatory tachykinins superimposed on negative inotropic and chronotropic effects associated with the release of calcitonin gene related peptide (CGRP), a rise in cellular cyclic-adenosine monophosphate (cAMP) and a protein kinase A-dependent activation of glibenclamide-sensitive ATP-dependent K+ (KATP) channels. This review summarises the existing evidence of the nervous control of the upper urinary tract and recent evidence suggesting that the autonomic innervation may indirectly modulate pyeloureteric peristalsis via the activation of PSN nicotinic receptors and via the modulation of KV7 channels located on interstitial cells within the renal pelvis wall.

Activation of angiotensin II type 1 receptors and contractile activity in human sigmoid colon in vitro.

To analyse the effects of angiotensin II (Ang II) on the contractility of human sigmoid colon, and to characterize the subtype(s) of receptor(s) involved and the related action mechanism. The contractility of sigmoid colon circular muscle strips was recorded isometrically. RT-PCR and immunohistochemistry were used to reveal the eventual existence of a local renin-angiotensin system (RAS) and the distribution of Ang II receptors. Transcripts encoding for the Ang II type 1 (AT1 ) and the Ang II type 2 (AT2 ) receptor subtypes and for the angiotensin-converting enzyme in the whole-thickness muscular wall were observed. Ang II caused a concentration-dependent contractile response, which is antagonized by losartan, AT1 receptor antagonist, but not by PD123319, AT2 receptor antagonist. The joint application of losartan and PD123319 did not produce any additive effect. The contractile response to Ang II was partially reduced by tetrodotoxin, Na(+) voltage-gated neural channel blocker, and to some extent by SR48968, tachykinin NK2 receptor antagonist. However, hexamethonium, nicotinic receptor antagonist, atropine, cholinergic muscarinic receptor antagonist and SR140333, tachykinin NK1 receptor antagonist, were ineffective. Immunohistochemical analysis showed that AT1 receptors were expressed on the smooth muscle layers and myenteric plexus. Ang II positively modulates the spontaneous contractile activity of human sigmoid colon via activation of post-junctional and pre-junctional AT1 receptors, the latter located on the enteric nerves that modulate the release of tachykinins. The presence of the components of RAS in the human colon suggests that Ang II can be also locally generated to control colonic motility.

The neuropeptide tachykinin is essential for pheromone detection in a gustatory neural circuit.

Gustatory pheromones play an essential role in shaping the behavior of many organisms. However, little is known about the processing of taste pheromones in higher order brain centers. Here, we describe a male-specific gustatory circuit in Drosophila that underlies the detection of the anti-aphrodisiac pheromone (3R,11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol (CH503). Using behavioral analysis, genetic manipulation, and live calcium imaging, we show that Gr68a-expressing neurons on the forelegs of male flies exhibit a sexually dimorphic physiological response to the pheromone and relay information to the central brain via peptidergic neurons. The release of tachykinin from 8 to 10 cells within the subesophageal zone is required for the pheromone-triggered courtship suppression. Taken together, this work describes a neuropeptide-modulated central brain circuit that underlies the programmed behavioral response to a gustatory sex pheromone. These results will allow further examination of the molecular basis by which innate behaviors are modulated by gustatory cues and physiological state.

Both exogenous 5-HT and endogenous 5-HT, released by fluoxetine, enhance distension evoked propulsion in guinea-pig ileum in vitro.

The roles of 5-HT3 and 5-HT4 receptors in the modulation of intestinal propulsion by luminal application of 5-HT and augmentation of endogenous 5-HT effects were studied in segments of guinea-pig ileum in vitro. Persistent propulsive contractions evoked by saline distension were examined using a modified Trendelenburg method. When 5-HT (30 nM), fluoxetine (selective serotonin reuptake inhibitor; 1 nM), 2-methyl-5-HT (5-HT3 receptor agonist; 1 mM), or RS 67506 (5-HT4 receptor agonist, 1 μM) was infused into the lumen, the pressure needed to initiate persistent propulsive activity fell significantly. A specific 5-HT4 receptor antagonist, SB 207266 (10 nM in lumen), abolished the effects of 5-HT, fluoxetine, and RS 67506, but not those of 2-methyl-5-HT. Granisetron (5-HT3 receptor antagonist; 1 μM in lumen) abolished the effect of 5-HT, fluoxetine, RS 67506, and 2-methyl-5-HT. The NK3 receptor antagonist SR 142801 (100 nM in lumen) blocked the effects of 5-HT, fluoxetine, and 2-methyl-5-HT. SB 207266, granisetron, and SR 142801 had no effect by themselves. Higher concentrations of fluoxetine (100 and 300 nM) and RS 67506 (3 and 10 μM) had no effect on the distension threshold for propulsive contractions. These results indicate that luminal application of exogenous 5-HT, or increased release of endogenous mucosal 5-HT above basal levels, acts to lower the threshold for propulsive contractions in the guinea-pig ileum via activation of 5-HT3 and 5-HT4 receptors and the release of tachykinins. The results further indicate that basal release of 5-HT is insufficient to alter the threshold for propulsive motor activity.

Neuromodulation of Olfactory Sensitivity in the Peripheral Olfactory Organs of the American Cockroach, Periplaneta americana

Olfactory sensitivity exhibits daily fluctuations. Several studies have suggested that the olfactory system in insects is modulated by both biogenic amines and neuropeptides. However, molecular and neural mechanisms underlying olfactory modulation in the periphery remain unclear since neuronal circuits regulating olfactory sensitivity have not been identified. Here, we investigated the structure and function of these signaling pathways in the peripheral olfactory system of the American cockroach, Periplaneta americana, utilizing in situ hybridization, qRT-PCR, and electrophysiological approaches. We showed that tachykinin was co-localized with the octopamine receptor in antennal neurons located near the antennal nerves. In addition, the tachykinin receptor was found to be expressed in most of the olfactory receptor neurons in antennae. Functionally, the effects of direct injection of tachykinin peptides, dsRNAs of tachykinin, tachykinin receptors, and octopamine receptors provided further support for the view that both octopamine and tachykinin modulate olfactory sensitivity. Taken together, these findings demonstrated that octopamine and tachykinin in antennal neurons are olfactory regulators in the periphery. We propose here the hypothesis that octopamine released from neurons in the brain regulates the release of tachykinin from the octopamine receptor neurons in antennae, which in turn modulates the olfactory sensitivity of olfactory receptor neurons, which house tachykinin receptors.

Angiotensin II contractile effects in mouse colon: role for pre‐ and post‐junctional AT1A receptors

This study investigates whether a local renin-angiotensin system (RAS) exists in mouse colon and whether angiotensin II (Ang II) may play a role in the regulation of the contractile activity. Isometric recordings were performed in vitro on the longitudinal muscle of mouse proximal and distal colon. Transcripts encoding for RAS components were investigated by RT-PCR. Ang II caused, in both preparations, a concentration-dependent contractile effect, antagonized by losartan, AT(1) receptor antagonist, but not by PD123319, AT(2) receptor antagonist. The combination of losartan plus PD123319 caused no change on the Ang II-induced contraction than losartan alone. Tetrodotoxin, neural blocker, reduced the contractile response to Ang II in the proximal colon, whilst the response was abolished in the distal colon. In both preparations, atropine, muscarinic receptor antagonist, or SR140333, NK(1) receptor antagonist, reduced the Ang II responses. Ondansetron, 5-HT(3) receptor antagonist, SR48968, NK(2) receptor antagonist, or hexamethonium, nicotinic receptor antagonist, were ineffective. The joint application of atropine and SR140333 produced no additive effect. Atropine reduced NK(1) -induced contraction. Transcripts encoding RAS components were detected in the colon samples. However, just AT(1A) mRNA was expressed in both preparations, and AT(2) mRNA was expressed only in the distal colon. In the murine colon, local RAS may play a significant role in the control of contractile activity. Ang II positively modulates the spontaneous contractile activity via activation of post-junctional and pre-junctional AT(1A) receptors, the latter located on the enteric neurones, modulating the release of tachykinins and acetylcholine.

Morpho-functional alterations of colonic neuromuscular compartment in experimental Parkinson’s disease

Parkinson’s disease (PD) is a degenerative neurological disorder, which is often associated with gastrointestinal symptoms. Among these disturbances, constipation has received considerable attention owing to its potential value as early marker of disease onset [1, 2]. Our study aims at evaluating motor dysfunctions and neurochemical coding of colonic neuromuscular compartment in a rat model of PD. Experimental PD was induced in rats by unilateral injection of 6-idroxydopamine (6-OHDA) into two sites of the right medial forebrain bundle. Functional and morphological studies were carried out 28 and 56 days after treatment. Colonic circular muscle contractions were revorded in organ baths after electrical stimulation or in the presence of exogenous substance P (SP). Colonic samples were examined by immunohistochemistry for the following parameters: density of myenteric HuC/D+ neurons and GFAP+ glial cells; distribution pattern and quantitative expression of SP, tyrosine hidroxylase (TH) and choline acethyltransferase (ChAT). Contractions elicited by electrically evoked tachykinin release as well as by exogenous SP were enhanced at both day 28 and 56, as compared to controls. Myenteric ganglia of PD animals displayed a significant increase in HuC/D+ neuron density, but no alteration in GFAP+ expression. SP+ myenteric neurons progressively increased over time, while the expression of TH and ChAT were significantly reduced at both time points. Experimental PD, elicited by nigrostriatal dopaminergic degeneration, is associated with functional and histopathological/neurochemical changes of the colonic neuromuscular compartment. The enhanced tachykinenergic motor control, associated with an upregulation of neuronal SP expression, together with reduced expression of TH and ChAT, may account for the colonic motor dysfunctions often associated to PD.

Modulation of TRPV1-dependent contractility of normal and diabetic bladder smooth muscle by analgesic toxins from sea anemone Heteractis crispa

AimsTRPV1-expressing, capsaicin (CAP)-sensitive afferent fibers innervating bladder in addition to sensory function also exhibit “efferent” features consisting in TRPV1-dependent release of tachykinins (TAC) affecting detrusor smooth muscle (DSM) contractions. Our aim was to investigate the effects of two novel polypeptide inhibitors of TRPV1 from the venom of tropical sea anemone Heteractis crispa, APHC1 and APHC3, on the contractions of DSM from bladders of normal and diabetic rats. Main methodsExperiments were conducted on urothelium-devoid DSM strips from normal rats and rats 8weeks after streptozotocin-induced diabetes by means of contraction force measurements. Key findingsPre-exposure of DSM strips to APHC1 or APHC3 (200nM) specifically inhibited CAP-induced, TRPV1-dependent contractions. Both peptides also transiently enhanced basal tone and spontaneous contractions of DSM strips followed by delayed suppression of electric field stimulation (EFS)-evoked nonadrenergic–noncholinergic (NANC) contractions. The decrease of the amplitude of EFS-evoked NANC contractions by АРНС1 or АРНС3 reached 38.5±3.4% and 25.1±1.6%, respectively, in normal DSM strips and 46.3±3.3% and 43.9±1.8%, respectively, in diabetic ones. APHC-peptide-induced transient enhancement of basal tone could be mimicked by serine protease inhibitor, 4-(2-aminoethyl)bezenesulfonyl fluoride (300μM). SignificanceOur results demonstrate that АРНС1 and АРНС3 may be considered as effective inhibitors of bladder contractility especially during diabetic cystopathy. Modality of action of APHC-polypeptides via the mechanisms involving decreased TRPV1-dependent release of TAC from bladder afferents and suppression of TAC degradation due to their activity as endogenous proteases inhibitors is proposed.

Tachykinins Stimulate a Subset of Mouse Taste Cells

The tachykinins substance P (SP) and neurokinin A (NKA) are present in nociceptive sensory fibers expressing transient receptor potential cation channel, subfamily V, member 1 (TRPV1). These fibers are found extensively in and around the taste buds of several species. Tachykinins are released from nociceptive fibers by irritants such as capsaicin, the active compound found in chili peppers commonly associated with the sensation of spiciness. Using real-time Ca2+-imaging on isolated taste cells, it was observed that SP induces Ca2+ -responses in a subset of taste cells at concentrations in the low nanomolar range. These responses were reversibly inhibited by blocking the SP receptor NK-1R. NKA also induced Ca2+-responses in a subset of taste cells, but only at concentrations in the high nanomolar range. These responses were only partially inhibited by blocking the NKA receptor NK-2R, and were also inhibited by blocking NK-1R indicating that NKA is only active in taste cells at concentrations that activate both receptors. In addition, it was determined that tachykinin signaling in taste cells requires Ca2+-release from endoplasmic reticulum stores. RT-PCR analysis further confirmed that mouse taste buds express NK-1R and NK-2R. Using Ca2+-imaging and single cell RT-PCR, it was determined that the majority of tachykinin-responsive taste cells were Type I (Glial-like) and umami-responsive Type II (Receptor) cells. Importantly, stimulating NK-1R had an additive effect on Ca2+ responses evoked by umami stimuli in Type II (Receptor) cells. This data indicates that tachykinin release from nociceptive sensory fibers in and around taste buds may enhance umami and other taste modalities, providing a possible mechanism for the increased palatability of spicy foods.

Th17 Cytokines Are Critical for Respiratory Syncytial Virus-Associated Airway Hyperreponsiveness through Regulation by Complement C3a and Tachykinins

Respiratory syncytial virus (RSV) infection is associated with serious lung disease in infants and immunocompromised individuals and is linked to development of asthma. In mice, acute RSV infection causes airway hyperresponsiveness (AHR), inflammation, and mucus hypersecretion. Infected cells induce complement activation, producing the anaphylatoxin C3a. In this paper, we show RSV-infected wild-type mice produce Th17 cytokines, a response not previously associated with viral infections. Mice deficient in the C3aR fail to develop AHR following acute RSV infection, and production of Th17 cytokines was significantly attenuated. Tachykinin production also has been implicated in RSV pathophysiology, and tachykinin receptor-null mice were similarly protected from developing AHR. These animals were also deficient in production of Th17 cytokines. Tachykinin release was absent in mice deficient in C3aR, whereas C3a levels were unchanged in tachykinin receptor-null animals. Thus, our data reveal a crucial sequence following acute RSV infection where initial C3a production causes tachykinin release, followed by activation of the IL-17A pathway. Deficiency of either receptor affords protection from AHR, identifying two potential therapeutic targets.

Role of tachykinin receptors in the modulation of colonic peristaltic activity in mice

Tachykinins are important mediators of neuroneuronal and neuromuscular transmission in the gastrointestinal tract, however their contribution to colonic peristalsis in mice remains unclear. Therefore, our aim was to characterise the functional role of tachykinins in mediating peristalsis by evaluating the effect of selective tachykinin NK 1, NK 2 and NK 3 receptor agonists and antagonists on in vitro colonic peristaltic activity in mice. Using a modified Trendelenburg set-up, gradual distension of proximal and distal colonic segments evoked rhythmic, aborally migrating contractions. Peristaltic activity was assessed by quantifying the amplitude and interval of the corresponding pressure waves. Stimulation of NK 1 receptors showed regional differences as both the pressure amplitude and interval were enhanced in the distal colon without affecting peristalsis proximally. Blockade of NK 1 receptors reduced the peristaltic pressure amplitude in the proximal and distal colon while the interval was not significantly altered. NK 2 receptor stimulation resulted in a modest enhancement of the amplitude in proximal and distal segments and a slightly prolonged interval distally. Blockade of NK 2 receptors reduced the peristaltic pressure amplitude and interval in the distal colon. NK 3 receptor stimulation significantly augmented the amplitude in both segments and prolonged the interval distally. However, NK 3 receptor blockade had no effect on peristaltic activity. In conclusion, tachykinins contribute to colonic peristalsis in mice by acting mainly on NK 1 and NK 2 receptors and their effects show a proximal-to-distal gradient. NK 3 receptors might play a role in conditions of excess tachykinin release but appear not to be involved under the conditions of the present study.

Tongue angioedema in vivo: Antagonist response of anti-inflammatory drugs

Introduction. The toxicity of Dieffenbachia picta, an ornamental plant, arises from its ability to cause painful edema of oral mucous membranes, buccal ulcerations, and tongue hypertrophy after chewing on the stem or contact with the sap. Objectives. We compared the anti-inflammatory effect of eugenol (2-methoxy-4-(2-propenyl)phenol) to different drugs, and investigated the role of oxalate crystals in the development of the inflammation reaction. Methods. Tongue edema in live mice were measured with a digital tachymeter, 2 h after topical application (0.1 mL) or tissue injection (0.05 mL) of D. picta sap. The mice were treated by intraperitoneal or topical application of drugs, 15 min after edema induction. Vascular permeability was quantified based on abdominal skin plasma extravasation of Evans blue dye in response to intradermal administration of D. picta sap. The proteolytic assay was carried out as previously described (Kunitz M. Crystalline soybean trypsin inhibitor. General properties. J Gen Physiol 1947; 30:291–310.). Results. Arachidonate cascade antagonists and eugenol showed anti-edematogenic effects. High doses of eugenol (50 μg/kg) and sodium cromoglycate (100 mg/kg), but not a combination of the two, inhibited plasma extravasations. The sap without crystals, its methanol extract, or the ethanol-washed crystals in saline-reconstituted solution did not reproduce the tongue edema seen with the original sap. Topical application of 10% sodium bicarbonate completely abolished the tongue edema. Conclusions. The inflammatory response induced by D. picta may be due to mechanical tissue damage resulting from the physical presence of calcium oxalate crystals. We were, however, unable to exclude the possibility of an insoluble toxicity present within the sap as an etiological agent. We realized that emergency treatment should also aim to inhibit antidromic vasodilation and axon reflex flare, reducing mastocyte degranulation and release of tachykinins from nerve endings. We speculate that eugenol showed better antiedematogenic results because it seems to function not only as a classic non-steroidal anti-inflammatory drug, but also as a local anesthetic, blocking neurotransmission in the damaged tissue.

The Nose as a Target of Air Pollution, Physiological Aspects and Clinical Relevance of Nasal Trpa1 (Transient Receptor Potential A1) Receptors

Worldwide more than several hundred million humans are exposed to severe air pollution, and a significant part of them also smoke. The effect of air pollution on human health has been recognized for many years. The nose, as the first portal of entry to the respiratory system is constantly exposed to a large volumes of air, which is composed of a mixture of gases, particulate matter and infectious agent, and any material other than physiological amount of oxygen, nitrogen, carbon dioxide and water is considered as pollutant. Being exposed to critical amount of air pollutants, nasal cavity shares sophisticated system of protective and defensive mechanisms regarding the lower airways and lungs, however the highest risk of direct exposure to relevant air pollutants is just within the nose. Air pollution is considered to be responsible for some of the pathological processes affecting airways prone to allergic reactions in predisposed subjects, onset of nasal sensorineural hyperresponsiveness, nonspecific inflammation, sinonasal cancer and definitely, the risk is not limited just to the nasal mucosa, but can proceed toward the lower airways. The broad spectrum of irritants probably shares very similar molecular background of action. They are capable to activate the cation channenl tranisient receptor potential A1-TRPA1 by covalent modification of the channel protein, because many of them are highly reactive and nonstable molecules with possibilities for various chemical reactions. Activation of this channel is responsible for nociceptive reactions mediated by stimulation of afferent trigeminal nerves, retrograde release of tachykinins, activation of parasympathetic afferent drive leading to increase of mucus output and decrease of nasal patency, with subsequent alteration of nasal functions. Based on the recently described neuro-immune bidirectional relationships, air pollutants may be responsible for recruitment of immune cells with infiltration of the nasal mucosa possibly leading to the inflammatory processes and allergies. Our paper is discussing the nose as the target for air pollution, and focuses on the relevance of TRPA1 channel on trigeminal afferents in pollution mediated responses.

Alteration in airway microvascular leakage induced by sensorineural stimulation in rats exposed to inhaled formaldehyde

Inhaled formaldehyde can rapidly produce microvascular leakage in the airway through stimulation of tachykinin NK1 receptors by tachykinins released from sensory nerves. Tachykinin NK1 receptors are known to be internalized in the cytoplasm after being stimulated, thus leading to transient attenuation of their action. We investigated time changes in airway microvascular leakage during formaldehyde inhalation for 45 min, and whether pre-inhalation of formaldehyde (5 ppm, 30 min) decreases the responses induced by subsequent inhaled formaldehyde (5 ppm, 15 min), intravenous capsaicin (75 μg/kg) and intravenous substance P (10 μg/kg) in rat airway. Evans blue dye content extravasated into the tissues was measured as an index of plasma leakage. Formaldehyde rapidly produced dye leakage in the airway, a response that ended within 15 min after the start of formaldehyde inhalation. Pre-inhalation of formaldehyde markedly decreased the responses induced by formaldehyde and capsaicin, but not substance P. However, dye leakage induced by formaldehyde was significantly enhanced by formaldehyde inhalation 20 h earlier. Our results suggest that tachyphylaxis in neurogenic airway microvascular leakage seen after formaldehyde inhalation may be due to impairment of tachykinin release from sensory nerves or decreases in tachykinins within sensory nerves. However, desensitization of tachykinin NK1 receptors was unlikely to be important in the tachyphylactic response.

Proteinase-activated receptors-1 and 2 induce electrogenic Cl−secretion in the mouse cecum by distinct mechanisms

Proteinase-activated receptors (PAR(1)-PAR(4)) belong to a family of G protein-coupled receptors that are cleaved by proteases. Previous in vitro studies on the mouse large intestine have indicated that PAR(1) and PAR(2) were involved in regulating epithelial ion transport, but that their roles were different between the proximal and distal colon. This present study was done to elucidate the roles of PAR(1) and PAR(2) in regulating anion secretion in the cecum, another segment of the large intestine. A mucosa-submucosal sheet of the mouse cecum was mounted in Ussing chambers, and the short-circuit current (I(sc)) was measured. The addition of a PAR(1)-activating peptide (SFFLRN-NH(2)) to the serosal surface increased I(sc). This increase in I(sc) induced by SFFLRN-NH(2) was partially suppressed by serosal bumetanide and substantially suppressed by mucosal 5-nitro-2-(3-phenylpropylamino)benzoic acid (NPPB) and by the removal of Cl(-) from the bathing solution. The I(sc) increase was also substantially suppressed by serosal tetrodotoxin (TTX) and neurokinin-1 receptor antagonist L-703,606 and was partially inhibited by serosal atropine and hexamethonium. The addition of a PAR(2)-activating peptide (SLIGRL-NH(2)) to the serosal surface also induced an increase in I(sc); this increase was partially suppressed by bumetanide and substantially suppressed by NPPB and by the removal of Cl(-), but not by TTX. The expression of mRNA for PAR(1) and PAR(2) was confirmed in the mucosa as determined by RT-PCR. In conclusion, PAR(1) and PAR(2) both induced Cl(-) secretion in the mouse cecum. This secretion mediated by PAR(1) probably occurred by activation of the receptor on the submucosal secretomotor neurons, resulting mainly in the release of tachykinins and activation of the neurokinin-1 receptor, and partly in the release of ACh and activation of the muscarinic and nicotinic receptors. On the other hand, PAR(2)-mediated Cl(-) secretion probably occurred by activating the receptor on the epithelial cells. A variety of proteases would induce fluid secretion mediated by PAR(1) and PAR(2) in the cecum and thereby support bacterial fermentation and participate in mucosal inflammation.