Many factors influence the inflammatory responses in rat trachea, including inflammatory mediators released from nerve fibers, histamine released by mast cells and endotoxin from the cell walls of bacteria. The inflammatory responses include plasma extravasation, subepithelial edema, and hypersecretion of secretory cells. But the mechanism of inflammation mediated by these factors was not completely understood. In the present study, a high dose of histamine was administered intravenously to induce the inflammation in rat airway. India ink was also injected as a tracer to label the leaky blood vessels in different time points. To investigate the serous cell secretion and subepithelial edema formation, the treacheal tissue was processed for histological study. Electron microcopy was carried out to investigate the ultrastructure of serous cells. To investigate the mechanism of histamine effect, the muscarinic receptor antagonist atropine (1 mg/ml/kg) or histamine H1 receptor antagonist mepyramine (10 mg/ml/kg) was injected 15 min before histamine injection. Five minutes after histamine, plasma leakage and serous cell secretion were extensive. The area density of India ink-labeled leaky vessels was 17.24 % ¡Ó 2.03 %. Saline, the vehicle of histamine, produced only a little extravasation. Mepyramine inhibited the histamine-induced plasma extravasation and serous cell degranulation significantly but atropine had no effect. The results suggest that histamine-induced serous cell degranulation is mainly through histamine H1 receptors but not through cholinergic muscarinic receptors in rat trachea.

¡iAbstract¡j Neurogenic inflammation is an acute inflammatory tissue response, that is mediated by sensory axon reflex. Accompanied with neurogenic inflammation, plasma extravasation, occurs in the eyes, esophagus, bladder, joints, the tip of tongue, and the respiratory tract of the mammal. Recently, many studies have investigated the neurogenic inflammation by electrical stimulation of nerves and intravascular injection of irritants. Upon stimulation, the sensory nerve endings in mucosa can release neuropeptides such as substance P, that causes formation of the venular endothelial gaps, plasma extravasation and tissue edema in various organs. Substance P also cause smooth muscle contraction and mucus secretion in the respiratory tract. Neurogenic plasma extravasation has been studied extensively in the trachea, and bronchi, but rarely in the esophagus. It is known that a plexus of substance P-immunoreactive axons exists in the mucosal and submucosal layers. They play an important role in releasing substance P to act on the receptors of the venular endothelium through diffusion. Based on plasma extravasation and other studies related to the respiratory tract, the purpose of the present study was to investigate neurogenic inflammatory response in the esophagus of the digestive tract. In this study, capsaicin (90 µg/ml/kg) and substance P (3 µg/ml/kg) were used as the irritant and inflammatory mediator, respectively to reduce neurogenic inflammation in the esophagus. India ink was used to label the affected venules. The magnitude of the neurogenic inflammation was expressed as area density of India ink-labeled leaky venules. Histopathological changes in the esophageal tissue were studied under the light microscope. The result of this study indicated that capsaicin at the dose of (90 µg/ml/kg) and substance P at the dose of (3 µg/ml/kg) caused similar magnitude of inflammation in the esophagus. India ink-labeled venules distributed like a network in the mucosal tissue and in connective tissue of the submucosal layer. The upper, middle and lower parts of esophagus exhibited the same degree of inflammatory response, that was similar to that in the lower respiratory tract as the previous studies reported. These results suggest that nerve branches from the vagal trunk send sensory axons to innervate both the esophagus and airways.

Störungen im Bereich der Mikrozirkulation gelten als ursächlich für die Entstehung des Multiorganversagens bei Sepsis, wobei der Darm eine zentrale Rolle einnimmt. Aktivierte Leukozyten setzen u.a. Sauerstoffradikale frei, die entscheidend zur Zerstörung der endothelialen Integrität beitragen. Die Antagonisierung schädigender Mediatoren stellt ein Prinzip der adjunktiven Sepsis-Therapie dar, wobei die antioxidativ wirkenden Substanzen N-Acetylcystein (NAC) und Tirilazad Mesylat (TM) in mehreren Studien positive Effekte gezeigt haben. In einer tierexperimentellen Untersuchung an Ratten wurde der Effekt der kombinierten Gabe von NAC und TM auf die mesenteriale Mikrozirkulation, auf die Freisetzung von TNF-alpha, IL-1beta, IL-6, IL-10 und auf die Leukozytenzahl unter einer kontinuierlichen Lipopolysaccharidbelastung (LPS) von 10 mg/kg KG untersucht. Die Beurteilung der mesenterialen Mikrozirkulation erfolgte mittels Intravitalmikroskopie. Hierbei wurde das Ausmaß der Leukozytenadhärenz am Endothel der mesenterialen Venolen als Maß für die Leukozytenaktivierung und die Plasmaextravasation als Parameter für die Endotheldysfunktion bestimmt. Dabei konnte während zwei Stunden Endotoxinämie die Zunahme der Plasmaextravasation an mesenterialen Venolen durch die kombinierte Gabe von NAC und TM nicht signifikant beeinflusst werden (p>0,05). Eine tendenziell erhöhte Plasmaextravasation unterstützt die Hypothese, dass leukozytenunabhängige Mechanismen für die Plasmaextravasation existieren. Während zwei Stunden Endotoxinämie kam es zu einer signifikanten Reduktion der Anzahl der fest adhärenten Leukozyten in der NAC/TM-Gruppe im Vergleich zur LPS-Gruppe (p=0,001). Durch die kombinierte Gabe von NAC und TM konnte die endotoxininduzierte Freisetzung von TNF-alpha, IL-1beta, IL-6, IL-10 und die endotoxinbedingte Leukopenie nicht signifikant beeinflusst werden. / Disturbances of the microcirculation are causal for the pathophysiology of multiorgan failure related to sepsis in which the gut plays a central part. Activated leukocytes release i.e. oxygen radicals which decisively contribute to the destruction of the endothelial integration. To antagonize the damaging mediators is a principle of the adjunctive sepsis therapy in which the antioxidant agents N-acetylcysteine (NAC) and tirilazad mesylate (TM) showed positive effects in several studies. The effect of the combined administering of NAC and TM under continuous lipopolysaccharide (LPS) exposure of 10 mg/kg BW on the mesenteric microcirculation, on the release of TNF-alpha, IL-1beta, IL-6, IL-10 and on the number of leukocytes was examined in an animal study on rats. The appraisal of the microcirculation was done by intravital microscopy. The degree of leukocyte adherence on the endothelium of mesenteric venules was determined for the degree of leukocyte activation, and the plasma extravasation was the parameter for the endothelial dysfunction. The increase of plasma extravasation on mesenteric venules during 2 hours of endotoxemia could not be affected significantly by the combined administering of NAC and TM. The tendency of increased plasma extravasation supports the hypothesis of the existence of a leukocyte independent mechanism of plasma extravasation. During 2 hours of endotoxemia the NAC/TM group showed a significant decrease in the number of firmly adherent leukocytes in comparison to the LPS group. There was no significant effect on the endotoxin induced release of TNF-alpha, IL-1beta, IL-6, IL-10 and the endotoxin induced leukopenia by the combined administration of NAC and TM.