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In mammals, the neurogenic inflammatory response can be induced by stimulation or activation on the peripheral sensory C-fibers to release neuropeptides from the peripheral terminals, at the same time their afferent functions are enhanced. There are several neuropeptides stored and released from peripheral terminals of the afferent fibers, such as substance P (SP), neurokinin A, and calcitonin gene related peptide (CGRP). SP is one of the major inflammatory mediators of neurogenic inflammation that can act on neurokinin-1 receptors on smooth muscles and endothelial cells of blood vessels, causing vasodilatation, endothelial gap formation, and local plasma leakage. There are many studies and reports indicate that animals pretreated with a short period non-lethal hyperthermia can induce heat shock response and activate the expression of a group of inducible proteins called heat shock proteins (HSPs), and this stress response reduces the injury by same or other following stresses. In this study, the hyperthermia treatment (HT) was implemented by 42¢J hot water bath and the core body temperature of anesthetized rat was elevated and maintained around 42.0¡Ó0.5¢J for 15 min, and the normothermia control treatment (NT) was implemented by 37¢J warm water bath with the same period. 24 hours after NT or HT, the neurogenic plasma leakage was induced by intravascular injection with capsaicin (90 £gg/kg), SP (3 £gg/kg), or electrical stimulation on the right thoracic vagus nerve. The blood pressures of each animal were continually recorded during the neurogenic inflammation induction or sham operation. The amount of neurogenic inflammation of airway was evaluated by the area density leaky blood vessels. The leaking vessels were labeled with India ink and quantitative analysis by morphometric method. Plasma leakage was also measured by interstitial Evans blue concentration. The results indicated that HT could reduce plasma leakage and hypotension of the neurogenic inflammation that induced by capsaicin, SP or electrical stimulation on vagus nerve. Animals pretreated with aminoguanidine (a selective inhibitor of iNOS) had no significant effect on the neurogenic inflammation by following systemic SP infusion, but that could eliminate the anti-neurogenic inflammatory effect of HT. Animal applied with diphenhydramine (an antagonist of histamine H1 receptor) could attenuate the neurogenic inflammation by following systemic SP infusion, and HT could attenuate the neurogenic inflammation that with or without H1 receptor antagonist. This result indicates that NO synthesis and the activity of iNOS have few effects on neurogenic inflammation of airway, but it plays a critical factor on the initiation of heat shock response. The neurogenic inflammation induced by SP not only direct act on blood vessels but have other indirect effect by the histamine H1 receptor to enhance inflammation. Neonatal rats received high dose capsaicin treatment would induce irreversible sensory C-fiber denervation. The adult rats that were neonatally treated with capsaicin showed a more serious inflammatory response to systemic SP infusion as compared with animals neonatally treated with vehicle. HT still had the anti-inflammatory effects on the neurogenic inflammation that induced by SP. The results indicated that animals with sensory C-fiber denervation might conserve their neurogenic inflammatory responses and were hypersensitive to SP. In conclusion, the HT could attenuate the neurogenic inflammation that induced by different drugs or methods, and the anti-inflammatory effects were correlated with the increase in HSP72 expression. In the neurogenic inflammation induced by SP, the activation of histamine H1 receptors may enhance inflammation, but the activity of endogenous iNOS was less effective.

¡iAbstract¡j Neurogenic inflammation can be initiated by activation of sensory nerves to release neuropeptides, including tachykinins and calcitonin gene-related peptide. Capsaicin stimulation induces the release of substance P, the most important tachykinin and other neurotransmitters from sensory nerves to cause an increase of plasma leakage via the binding of substance P to NK1 receptors on endothelial cells. It has been proven that hyperthermic pretreatment decreases microvascular protein leakage and attenuates hypotension in anaphylactic shock in rats. Heat shock proteins¡]HSPs¡^are families of phylogenetically conserved molecules that have a protective role in all living cells under stress . Heat shock proteins are induced by whole-body hyperthermia and persist for 6 days. To establish the relationship between heat shock and neurogenic inflammation, the present study investigated whether whole-body hyperthermia pretreatment, at 42 ¢J for 15 min in rats 1 day earlier, could suppress inflammatory response in the lower airways and esophagus evoked by capsaicin (90 µg/ml/kg) or substance P (3 µg/ml/kg ). The magnitude of neurogenic inflammation in the trachea and bronchi was expressed by the area density of India ink-labeled leaky blood vessels in the airway mucosa. One day after heat shock pretreatment, capsaicin-evoked inflammation was reduced by one half to two thirds, and reduced substance P-evoked inflammation by one third. Six days after exposure to heat shock, neurogenic inflammation was not inhibited. HSPs appeared overexpressed in trachea and esophagus tissue in the rats one day after hyperthermia, but was less expressed 6 days after hyperthermia. It is suggested that exposure of the rats to whole-body hyperthermia caused an increased production of HSPs that might influence the affinity of the binding of substance P to NK1 receptors on venule endothelial cells, and reduce the amount of neurogenic plasma leakage.

Sustained gastroesophageal reflux (GER) causes airway inflammation and can be considered as a potential trigger of asthma. There are complex neural innervations and reflex mechanisms between trachea and esophagus, and close proximity between them also provide a chance that trachea and esophagus could heavily interact with each other. The studies of the interactions between trachea and esophagus began early, but how gastric contents in the esophagus cause airway inflammation are still not completely understood. In this study, we will observe the extent of airway inflammatory response of the Long Evans rats induced by intraesophageal infusion of different inflammatory agents. We simulated the condition of inflammatory substances in the esophagus by intraesophageal infusion of either capsaicin or 6-hydroxydopamine (6-OHDA). At the different time point after infusion of inflammatory substances, rats were sacrificed for the analysis of the amount of the plasma leakage in the lower airways and esophagus. The amount of plasma leakage was expressed by the area density of India ink-labeled leaky blood vessels in tissue whole mounts. From the previous studies, we realize that neural reflexes played an important role in GER-induced airway inflammation. In this research, we further studied whether vagus nerves were involved in this neural reflex pathway by the pretreatment of bilateral vagotomy. Free radicals generated by the oxidation of 6-OHDA and capsaicin damage the airway epithelium, and lead to the liberation of cellular contents and cytokines that will augment the inflammatory response. Free radicals also activate NF-£eB pathway and will further enhance the inflammatory response. We evaluate the extent of these free radicals involved in GER-induced airway inflammation, by pretreatment with a hydroxyl radical scavenger -dimethylthiourea (DMTU). Our results showed that plasma leakage in the airway increased time-dependently from 5 to 15 min after the infusion of 5 £gg/ml/kg of capsaicin. This response peaked at 15 min, and gradually diminished after 30 min of capsaicin application. Plasma leakage in the airways caused by the application of 10 mg/ml/kg of 6-OHDA also increased time-dependently and peaked at 30 min. We also demonstrated that the vagus nerve played an important role in GER-induced airway inflammation. Because bilateral vagotomy significantly alleviated the airway inflammatory response caused by the application of capsaicin. Free radicals also involved in this process, because pretreatment with (2.25 g/kg, i.v.) DMTU significantly lowered the amount of plasma leakage caused by capsaicin and 6-OHDA.

Thesis (Ph. D.)--Virginia Commonwealth University, 2009. / Prepared for: Dept. of Microbiology and Immunology . Bibliography: leaves 118-133 . Also available online via the Internet.

Neurogenic inflammatory responses can be induced by antidromic electrical stimulation or intravenous capsaicin injection. These responses were thought to be caused by neuropeptides released from the sensory axon of C-fiber nerve endings. The relation of tachykinins, reactive oxygen species (ROS) and reactive nitrogen species (RNS) on electrical stimulation of thoracic vagus nerve (TVNS) or capsaicin-evoked neurogenic inflammation in respiratory tract of atropine-treated rats was not clear. In the present studies, the role of ROS and RNS on neurogenic inflammation were investigated in TVNS and capsaicin injected rats. The experiments were divided into two parts. In the first part, TVNS was performed by thoracotomy, non-cholinergic regulation of neurogenic plasma extravasation in the trachea and bronchi were examined, and whether TVNS via NK receptor facilitates neurogenic inflammation by nuclear factor-kappaB (NF-£eB) activation and ROS production were expored. Our results in this part showed that TVNS evoked substance P release, hypotension, bronchoconstriction (as shown by increases in smooth muscle electromyographic activity and total pulmonary resistance), trachea plasma extravasation as well as increases in blood O2- and H2O2 ROS amount in a frequency-dependent manner. Histopathological examination demonstrated silver-stained leaky venules, India-ink labeled plasma extravasation, and accumulations of inflammatory cells in the right lower trachea after TVNS. L-732138 (NK1 receptor antagonist), SR-48968 (NK2 receptor antagonist), dimethylthiourea (H2O2 scavenger) or catechins (O2- and H2O2 scavenger) pretreatment reduced TVNS-enhanced hypotension, bronchoconstriction, and plasma extravasation. TVNS upregulated the expression of NF-£eB in nuclear protein and intercellular adhesion molecule-1 (ICAM-1) in total protein of the lower respiratory tract tissue in a frequency-dependent manner. The upregulation of NF-£eB and ICAM-1 was attenuated by NK receptor antagonist and antioxidants. In the second part, the contribution of nitric oxide (NO) to capsaicin-evoked airway responses was investigated in rats. The measurement of plasma NO level, airway dynamics, airway smooth muscle electromyogram, and plasma extravasation by India ink and Evans blue leakage technique was adapted. Our results in this part showed that capsaicin injection evoked hypotension, bronchoconstriction, trachea plasma extravasation as well as increases in plasma NO level in a dose-dependent manner. L-732138 or SR-48968 pretreatment reduced capsaicin-enhanced hypotension, bronchoconstriction, plasma extravasation, and plasma NO level. Inhibition of a non-selective NO synthase (NOS) inhibitor (NG-nitro-L-Arginine methyl ester, L-NAME), or a selective inducible NO synthase (iNOS) inhibitor (aminoguanidine), reduced capsaicin-induced increases in plasma NO level and protected against capsaicin-induced plasma extravasation, whereas L-arginine (a NO precursor), enhances capsaicin-evoked plasma NO level and plasma extravasation. L-Arginine pretreatment ameliorated capsaicin-induced bronchoconstriction, whereas L-NAME and aminoguanidine exaggerated capsaicin-induced bronchoconstriction. In summary, both TVNS and capsaicin injection may increase oxidative stress responses. TVNS enhances proinflammatory NF-£eB and ICAM-1 expression, increases the production of O2- and H2O2 activity in the respiratory tract of atropine-treated rats. Pretreatment with antioxidants and selective NK receptor antagonists attenuate TVNS evoked airway hyperactivity, proinflammatory response, and oxidative stress. Capsaicin injection stimulates the release of tachykinins, which act on NK1 and NK2 receptors located on the smooth muscles of airways and blood vessels. The interaction of NK receptors with tachykinin enhances furtherly the NO formation, bronchoconstriction, vasodilation, and plasma extravasation in the trachea. The released tachykinins also increase the production of NO via iNOS, and iNOS -evoked NO counteracts tachykinin-mediated bronchoconstriction, but exacerbates tachykinin-mediated plasma extravasation.

Thesis (M.S.)--University of Michigan, 2002. / Includes bibliographical references.

A gastrosquise (G) é o defeito congênito de fechamento da parede abdominal, que causa inflamação intestinal. Avaliou-se aqui a expressão protéica e gênica de marcadores neurogênicos e oxidativos no intestino de fetos de ratas tratadas ou não com dexametasona - DMT. Estes foram divididos em grupos: não manipulado (controle; C), falso operado (sham; S) e operado (G). A atividade da mieloperoxidase (MPO) aumentou no grupo G vs. C, não sendo afetada pela DMT. A expressão RNAm do receptor NK2, mas não NK1, VPAC e TRPV1, foi reduzida nos grupos G e S vs. C, sendo esta revertida pela DMT. A iNOS, mas não nNOS e eNOS, foi maior no grupo G. A DMT não inibiu a iNOS mas aumentou a eNOS. COX-2 aumentou na G e não foi afetada pela DMT. A expressão protéica da SOD-1 ou 3-NT não diferiu entre grupos G e controle. O grupo G tratado com DMT exibiu maior nitração protéica. A IL-6 aumentou no grupo G versus C. Conclui-se que a inflamação no intestino de fetos com G origina-se de uma possível combinação entre mecanismos oxidativos, geração de prostanóides e fatores neurovasculares. / Gastroschisis (G) is a congenital defect of the abdominal wall closure resulting in perivisceritis. The role of neurovascular and oxidative mechanisms in this condition was investigated by analyzing the gene and proteic expressions of these markers in the gut of foetus from female rats treated or not with dexamethasone (DMT). Increased MPO activity was found in G vs. control (C) but not sham (S) group. Reduced mRNA expression of NK2 receptor was found in G and S groups. Neither NK1 nor both VIP and TRPV1 receptors expression changed among groups. Increased expression of iNOS and COX-2, but not nNOS, eNOS and COX-1, was seen in G group. DMT reversed the expression of NK2R and increased that of NK1R without affecting iNOS and COX-2 expression. Increased levels of IL-6 but neither SOD-1 nor 3-NT was found in G group. In conclusion, the inflammatory process observed in the gut of foetus with G arises through a combination of neurogenic mechanisms that act in concert with reactive oxygen species and generation of prostanoids to produce gut dysfunction.

Vagal sensory afferent innervation corresponds to regulation of neurogenic inflammation in the airways. Capsaicin is mostly used for stimulation of sensory nerves that induce pain and inflammatory responses. It can specifically stimulate sensory afferent nerves, inducing neurogenic inflammation in the airways. According the past studies, we have found the right thoracic vagus nerve (RTVN) and right recurrent laryngeal nerve (RRLN); branches of right thoracic vagus trunk (RTVT) mediate different degree of neurogenic inflammation by intraenous injection of capsaicin (300 nmol/ml/kg). In order to investigate the innervation from the RTVN and RRLN of rat tracheobronchi and their involvement in plasma exudation, we injected 3 £gl of capsaicin (10 mg/ml) into RTVT and denervated the RRLN or RTVN and used India ink as tracer dye to label the leaky microvessels. Our observation indicated that injection of capsaicin into the RTVT coud induce obvious plasma exudation in trachea (area density of leaky blood vessels was about 22%), but plasma exudation was significantly decreased after denervation of RRLN. The left upper side of trachea was decreased by 77.6% and the right upper side decreased by 84.5%. This phenomenon was not caused by denervation of RTVN. The results suggest that vagal nerve innervation of upper trachea mostly came from the RLN. Otherwise, capsaicin injection into the RTVT also induced neurogenic inflammation in the larynx. Experimental denervation of both superior and recurrent laryngeal nerves resulted in a decrease of plasma extravasation by 84.98%. Denervation of either RTVN or RRLN also decreased the plasma extravasation in the larynx. The evidence suggest that sensory fibers in the superior laryngeal nerve, recurrent laryngeal nerve, and thoracic vagus nerve might come from the same population of vagal ganglion sensory neurons.

Diabetes mellitus is a chronic syndrome affecting carbohydrate, protein, and fat metabolism. It is characterized primarily by relative or absolute insufficiency of insulin secretion (type I diabetes or IDDM) or concomitant insensitivity / resistance to the metabolic action of insulin on target tissues (Type II diabetes or NIDDM), both resulting in hyperglycaemia. Diabetes mellitus is known to induce microvascular changes and alterations to neuronal functions. The neurovascular system comprising of unmyelinated primary afferent sensory neurones and the microvasculature innervated by these nerves play a major role in modulating inflammatory and tissue repair processes. Sensory nerve terminals respond to injury via the release of sensory neuropeptides which mediate inflammation and tissue repair. These processes are known to be altered in diabetes. This thesis is concerned with the role of diabetes in modulating microvascular blood flow directly and indirectly via modulating sensory nerve activity and the effect of these changes on repair processes in skin of 4 weeks streptozotocin (STZ)-induced diabetic rats. The following hypotheses were examined: 1. That factors implicated in long-term diabetic vascular damage play a role in altering skin microvascular function in early diabetes. 2. That preventing the deleterious effects of these factors could improve skin microvascular blood flow and skin repair processes in early diabetes. (For complete abstract open document)