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Afhandling--Copenhagen. / "Also published as a supplement to volume 16, 1969 of Danish Medical Bulletin." Summary in Danish. Bibliography: p. 139-150.

Afhandling--Copenhagen. / "Also published as a supplement to volume 16, 1969 of Danish Medical Bulletin." Summary in Danish. Bibliography: p. 139-150.

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.

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BACKGROUND:Neurogenic detrusor overactivity (NDO) leads to impaired health-related quality of life (HRQoL), productivity, and greater healthcare resource burden. The humanistic and economic burden may be more apparent in NDO patients with urinary incontinence (UI). The objective of this study was to compare the HRQoL, productivity, and health resource use (HRU) between continent and incontinent NDO patients.METHODS:A retrospective database analysis was conducted using the Adelphi Overactive Bladder (OAB)/UI Disease Specific Programme, a multi-national, cross-sectional survey reported from both patients' and physicians' perspectives. The population for this analysis included NDO patients with or without UI. General and disease-specific HRQoL were assessed using the EuroQoL-5D (EQ-5D), Incontinence Quality of Life questionnaire (I-QOL), and the Overactive Bladder Questionnaire (OAB-q). Productivity and daily activity impairment were measured using the Work Productivity and Activity Impairment (WPAI) questionnaire. HRU indicators included OAB-related surgery, OAB-related hospitalizations, incontinence pad usage, switching anticholinergics used for OAB due to inadequate response or adverse effects, and OAB-related physician visits. Bivariate analyses, multivariate ordinary least squares (OLS) regression analyses and published minimal clinically important differences (MCID) were used to assess relationships between incontinent status and the aforementioned outcome measures.RESULTS:A total of 324 NDO patients with or without urinary incontinence were included, averaging 54years of age (SD 16), of whom 43.8 percent were male. Bivariate analyses detected no significant relationship between incontinent status and HRU variables. Regression analyses revealed that incontinent patients had clinically and statistically lower disease-specific HRQoL and greater impairment in daily activities as compared to continent patients. On average, incontinent patients scored 10 points lower on the I-QOL total score, 9 points lower on the OAB-q HRQoL score, 15 points higher on OAB-q symptom severity, and experienced 8.2 percent higher activity impairment due to their bladder condition (all p <0.001).CONCLUSIONS:Incontinent NDO patients experience significantly lower HRQoL and activity impairment as compared to continent NDO patients.