Airway Neurogenic Inflammation Research Articles

This Month in the Journal

This Month in the Journal

The Role and Localization of Nitric Oxide Synthasein Neurogenic Inflammation of the Rat Airways

BACKGROUND: There have been many debates about the effects of nitric oxide on the neurogenic inflammation. The role of nitric oxide in the neurogenic inflammation of airways will be required a better understanding of the localization and types of nitirc oxide synthase(NOS) activity in the neurogenic inflammation of airways. METHOD: To investigate the role of nitric oxide in airway neurogenic inflammation, 1) the effects of neurokinin receptor antagonist (FK224) and nitric oxide synthase inhibitor, N(omega)-nitro-L-arginine (L-NNA) on plasma extravastion were evaluated in four groups of Sprague-Dawley rats ; sham operation group(sham NANC group), electrical vagal stimulation group(NANC2 group), intravenous pretreatment groups with FK224 (1mg/kg ; FK224 group), and L-NNA(1mg/kg ; L-NNA group) 15 minutes before vagal NANC stimulation 2) NOS activity in trachea with neurogenic inflammation was localized by immunohistochemical stain. Immunohistochemical stain was performed by antibodies specific for inflammatory cells (iNOS), brain (bNOS), and endothelium (eNOS) on trachea obtained from sham NANC, NANC2, and FK224 groups. RESULTS: The results are that plasma extravsation in neurogenic inflammation of rat airways was inhibited by FK224, but enhanced by L-NNA pretreatment (P<0.05). There was significantly increased infiltration of inflammatory cells in subepithelium of neurogenic inflammatory trachea, but the reduction of subepithelial infiltration of inflammatory cells was observed after pretreatment with FK224 (P<0.05). Immunostaining with anti-iNOS antibody showed strong reactivity only in infiltrated inflammatory cells in neurogenic rat trachea, and these iNOS reactivity was reduced by pretreatment with FK224. bNOS immunoreactivity was significantly increased only in the nerves both of neurogenic inflammatory and FK224 pretreated trachea compared with sham NANC trachea(p<0.05). eNOS immunoreactivity was not significant change in endothelium in neurogenic inflammation of rat trachea. CONCLUSION: These results suggest that nitric oxide released from iNOS in infiltrated inflammatory cells has main role in neurogenic inflammation of rat trachea. The presence of bNOS immunoreactivity in the nerves indicates that nitric oxide may be released from the nerves in rat trachea with neurogenic inflammation.

Effects of FK224, a NK1 and NK2 Receptor Antagonist, on Plasma Extravasation of Neurogenic Inflammation in Rat Airways

BACKGROUND: Asthma is an inflammatory disease because there are many inflammatory changes in the asthmatic airways. Axon reflex mechanisms may be involved in the pathogenesis of asthma. Sensory neuropeptides are involved in this inflammation, which is defined as neurogenic inflammation. Substance p, neurokinin A, and neurokinin B may be main neuropeptides of neurogenic inflammation in airways. These tachykinins act on neurokinin recptors. Three types of neurokinin receptors, such as NK1, NK2, and NK3, are currently recognized, at which substance p,neurokinin A, and neurokinin B may be the most relvant natural agonist of neurogenic inflammation in airways. The receptor subtypes present in several tissues have been characterized on the basis of differential sensitivity to substance p, neurokinin A, and neurokinin B. Plasma extravasation and vasodilation are induced by substance p more potently than by neurokinin A, indicating NK1 receptors on endothelial cells mediate the response. But airway contraction is induced by neurokinin A more potently than by substance P, indicating the NK2 receptors in airway smooth muscles. These receptors are used to evaulate the pathogenesis of brochial asthma. FK224 was identified from the fermentation products of Streptomyces violaceoniger. FK224 is a dual antagonist of both NK1 and NK2 recptors. PURPOSE: For a study of pathogenesis of bronchial asthma, the effect of FK224 on plasma extravasation induced by vagal NANC electrical stimulation was evaluated in rat airway. METHOD: Male Sprague-Dawley rats weighing 180~450gm were anesthetized by i.p. injection of urethane. Plasma extravasation was induced by electrical stimulation of cervical vagus NANC nerves with 5Hz, 1mA, and 5V for 2 minutes(NANC2 group) and for sham operation without nerve stimulation(control group). To evaluate the effect of FK224 on plasma extravasation in neurogenic inflammation, FK224(lmg/kg, Fujisawa Pharmaceutical Co., dissolved in dimethylsul- phoxide; DMSO, Sigma Co.) was injected 1 min before nerve stimulation(FK224 group). To assess plasma exudation, Evans blue dye(20mg/kg,dissolved in saline) was used as a plasma marker and was injected before nerve stimulation. After removal of intravascular dye, the evans blue dye in the tissue was extracted in formamide(37degreesC, 24h) and quantified spectrophotometrically by measuring dye absorbance at 629nm wavelength. Tissue dye content was expressed as ng of dye per mg of wet weight tissue. The amount of plasma extravasation was measured on the part of airways in each groups. RESULTS: 1) Vagus nerve(NANC) stimulation significantly increased plasma leakage in trachea, main bronchus, and peripheral bronchus compared with control group, 14.1 +/-1.6 to 49.7+/-2.5, 17.5 +2.0 to 38.7 +/-2.8, and 12.7+/-2.2 to 19.1 +/-1.6ng of dye per mg of tissue(mean +/- SE), respectively(p< 0.05). But there was not significantly changed in lung parenchyma(p >0.05) 2) FK224 had significant inhibitory effect upon vagal nerve stimulation-induced airway plasma leakage in any airway tissues of rat,such as trachea, main bronchus, and peripheral bronchus compared with vagus nerve stimulation group, 49%, 58%, and 70%, respectively(p<0.05). Inhibitory effect of FK224 on airway plasma leakage in neurogenic inflammation was revealed the more significant in peripheral bronchus, but no significant in lung parenchyma. CONCLUSION: These results suggest that FK224 is a selective NK receptor antagonist which effectively inhibits airway plasma leakage induced by the endogenous neurotransmitters relased by neurogenic inflammation in rat airway. Tachykinin receptor antagonists may be useful in the treatment of brochial asthma.

Airway neurogenic inflammation and cough: Modulatory activity of DF 1012

Airway neurogenic inflammation and cough: Modulatory activity of DF 1012

Dexamethasone and oxytetracycline reverse the potentiation of neurogenic inflammation in airways of rats with Mycoplasma pulmonis infection.

Mycoplasma pulmonis infection in rats causes a chronic inflammatory airway disease. Along with extensive remodeling of the airway mucosa, lymphocytic infiltrates, angiogenesis, and mucosal thickening, there is an abnormal sensitivity of the blood vessels to mediators that evoke "neurogenic inflammation". As a result, substance P, a peptide released from sensory nerves, produces an unusually large amount of plasma leakage. These changes can be prevented or reduced by prophylactic treatment with antibiotics, but it is unknown whether the extensive remodeling of the airway mucosa and potentiation of neurogenic inflammation can be reversed once they are established. We addressed this issue in F344 rats that were infected with M. pulmonis at 8 wk of age. Six weeks later, the rats were treated daily with an antibiotic (oxytetracycline, 20 mg/kg intramuscularly), to reduce the number of infecting organisms, or with an antiinflammatory steroid (dexamethasone, 0.5 mg/kg intraperitoneally), to reduce the inflammatory and immunologic response to the infection. Sham-treated infected rats received daily injections of 0.9% NaCl. After 1, 2, or 4 wk of treatment the rats were anesthetized and then challenged with substance P (5 micrograms/kg intravenously). The sham-treated rats had pathologic changes in their airways typical of severe M. pulmonis infection, and had as much as a threefold increase in substance P-induced plasma leakage. By comparison, after 4 wk of treatment with oxytetracycline or dexamethasone, the chronic inflammation was nearly resolved and the response to substance P was in the normal range. Unexpectedly, dexamethasone, like oxytetracycline, reduced the number of infecting organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium channel opener, YM 934, inhibits neurogenic plasma leakage in guinea pig airways.

The effect of a potassium channel opener, YM 934, on neurogenic airway plasma leakage was examined in anesthetized guinea pigs. Airway plasma leakage was evoked by stimulation of both vagal nerves in the presence of atropine (1 mg/kg, intravenous) and propranolol (1 mg/kg, intravenous), and was measured by extravasation of Evans blue dye (30 mg/kg, intravenous) in trachea (Tr), main bronchi (MB), and central (cIPA) and peripheral intrapulmonary airways (pIPA). Vagal stimulation significantly increased the dye leakage in all portions of the airway. YM 934 (10, 30, and 100 micrograms/kg, intravenous) inhibited vagally-induced plasma leakage in Tr, MB, cIPA, and pIPA, and this inhibitory effect of YM 934 was reduced by the ATP-sensitive potassium channel blocker, glibenclamide (25 mg/kg, intravenous). By contrast, YM 934 (100 micrograms/kg, intravenous) had no inhibitory effect on exogenous substance P (0.5 and 1 micrograms/kg, intravenous)-induced plasma leakage in any parts of the airway. These results indicate that YM 934 inhibits airway neurogenic inflammation by modulating the release of neuropeptides from the sensory nerve endings, and that the inhibitory effect can be attributed to the potassium channel opening activity of this compound.

Neurogenic Inflammation in Airways and Its Modulation by Peptidasesa

Neurogenic Inflammation in Airways and Its Modulation by Peptidasesa

Elucidating airway neurogenic inflammation with CP-96,345

Elucidating airway neurogenic inflammation with CP-96,345