Neuroimmune interactions in the airways: Implications for asthma, allergy, and other inflammatory airway diseases

Recent evidence suggests that several bioactive polypeptides, among them substance P, neurokinin A, and calcitonin gene-related peptide, are contained in tracheobronchial C-fibers. These peptides can be released from the lung by irritant chemicals or local inflammatory mediators like histamine or bradykinin. Substance P mimicks the increase in vascular permeability caused by vagal nerve stimulation and neurokinin A mimicks noncholinergic bronchoconstriction by vagal nerve stimulation. Calcitonin gene-related peptide displays vasodilator activity. Experiments carried out with sensitized guinea pigs showed a contribution of tracheobronchial C-fibers to the anaphylactic response. Additionally, capsaicin, which in high concentration selectively blocks sensory C-fibers, was found to be effective in treatment of hyperreactive rhinopathy (vasomotor rhinitis). It is concluded that peptide mediators released from tracheobronchial C-fibers may contribute to the pathophysiology of various allergic or inflammatory airway diseases.     

Capsaicin induced release of multiple tachykinins (substance P, neurokinin A and eledoisin-like material) from guinea-pig spinal cord and ureter

The release of tachykinins from isolated slice preparations of the guinea-pig spinal cord and ureter was studied in vitro. Capsaicin (10 microM) caused release of substance P, neurokinin A and an eledoisin-like component from both the spinal cord and ureter. The release of tachykinins induced by capsaicin or potassium (60 mM) was calcium dependent. No detectable release of neurokinin B or neuropeptide K, an N-terminally extended form of neurokinin A, was induced by capsaicin. No detectable release of tachykinins could be demonstrated after exposure to agents which are known to activate C-fibre afferents, such as histamine, bradykinin, serotonin, prostaglandins E1, E2 or acetylcholine. Protein extravasation in the ureter, as determined by the Evans Blue extravasation technique was used as a functional correlate to the tachykinin release. Protein extravasation was induced in vivo by local intraluminal injections of capsaicin at several hundred-fold lower concentrations than those required to induce a detectable release of tachykinins in vitro. The difference may, however, partly depend on the experimental conditions and the detection limit of the tachykinin assay used. The protein extravasation response to capsaicin was absent after systemic capsaicin pretreatment, which causes a marked depletion of tachykinins in the ureter. In conclusion, capsaicin evokes release of several tachykinins from both central and peripheral endings of primary afferent neurons. The peptides released from sensory nerves in the periphery may induce effects such as protein extravasation and smooth muscle contraction.     

Neuropeptide Y- and alpha-adrenergic receptors in pig spleen: localization, binding characteristics, cyclic AMP effects and functional responses in control and denervated animals

The localization of neuropeptide Y binding sites in the pig spleen, as revealed by [125I]Bolton-Hunter-labelled porcine neuropeptide Y and alpha 1-adrenergic receptor binding sites, as revealed by [125I](2-beta/4-hydroxy-phenyl/-ethylaminomethyl)-tetralone as radioligand, was compared with the distribution of neuropeptide Y and noradrenaline nerves, the latter revealed by tyrosine hydroxylase and dopamine-beta-hydroxylase, using immunohistochemistry. A large degree of codistribution was obtained between [125I]neuropeptide Y and alpha 1-binding sites in the capsule, trabeculae, blood vessels and the red pulp of the spleen. Neuropeptide Y and tyrosine hydroxylase as well as dopamine-beta-hydroxylase-positive nerves were identical in the spleen and had a similar gross distribution pattern as the [125I]neuropeptide Y and alpha 1 binding sites. In functional studies using the isolated blood-perfused spleen from pentobarbital-anaesthetized pigs, neuropeptide Y, noradrenaline and the alpha 1-selective agonist phenylephrine contracted the capsule and induced vasoconstriction in the spleen in vivo. However, the selective alpha 2-adrenoceptor agonists clonidine and azepexole had no effects on blood flow or perfusion pressure, suggesting that postjunctional alpha-receptors were of the alpha 1 type. Neuropeptide Y inhibited the forskolin-evoked, cyclic adenosine monophosphate formation in vitro. The [125I]neuropeptide Y binding, with an equilibrium-dissociation constant of 503 +/- 73 pM and a maximal number of specific binding sites of 23 +/- 3 fmol/mg protein, the neuropeptide Y-induced perfusion-pressure increase in vivo and the inhibition of forskolin-evoked cyclic adenosine monophosphate formation in vitro were dependent on the amidation of the C-terminal portion of the peptide molecule. Furthermore, the effects of neuropeptide Y were not changed by alpha- and beta-adrenoceptor blockade using prazosin and propranolol. Two weeks after postganglionic denervation the neuropeptide Y and the noradrenaline contents of the pig spleen were reduced by 97% and 99%, respectively. These changes were associated with a selective supersensitivity for the noradrenaline-induced perfusion-pressure increase in vivo compared with the effect of neuropeptide Y. However, a similar potentiation of the noradrenaline effect was induced by the monoamine-uptake blocker desipramine in the absence of denervation, and there was no change in the functional response to phenylephrine after denervation.(ABSTRACT TRUNCATED AT 400 WORDS)     

Differential increases of neurokinin B- and enkephalin-like immunoreactivities and their mRNAs after chronic haloperidol treatment in the rat.

Changes in neurokinin B-like immunoreactivity (NKB-IR) and neurokinin B mRNA were investigated after daily injection of haloperidol for 10 days on adjacent sections by means of immunocytochemistry and in situ hybridization in the caudate putamen of the rat. In the dorsal striatum the number of NKB immunoreactive perikarya and the staining intensity of striatal efferents increased. The number of NKB mRNA-expressing cells (45%) and the grain density over single positive cells (37%) were significantly higher after the neuroleptic treatment. The levels for enkephalin mRNA were uniformly increased throughout the rostrocaudal extent of the caudate putamen (85%). A main difference to the enkephalin system was that the dorsal pallidum was nearly devoid of NKB-IR in untreated as well as in haloperidol-treated animals. The present data for the first time provide evidence for the regulation of the biosynthesis of NKB after pharmacological intervention.     

Differential release of calcitonin gene-related peptide and neuropeptide Y from the isolated heart by capsaicin, ischaemia, nicotine, bradykinin and ouabain

The influence of various drugs as well as total ischaemia on the outflow of calcitonin gene-related peptide (CGRP), which is present in sensory nerves, and neuropeptide Y (NPY), which is co-stored with noradrenaline (NA), from the isolated guinea-pig heart, was studied in vitro. Capsaicin exposure and total ischaemia for 5-30 min induced a Ca2+-dependent increase in the outflow, suggesting release, of CGRP- but not NPY-like immunoreactivity (LI) from the heart. When characterized by high performance liquid chromatography (HPLC), the CGRP-LI present in heart extracts and the released CGRP-LI by capsaicin eluted in a major peak corresponding to synthetic CGRP. Incubation with morphine, indomethacin or reserpine pretreatment did not influence the capsaicin-evoked release of CGRP-LI. Capsaicin pretreatment depleted the cardiac content of CGRP-LI but not NPY-LI. The increase in perfusate volume observed after 30 min ischaemia in controls was reduced after capsaicin pretreatment. Nicotine exposure induced release of CGRP- as well as NPY-LI in a concentration- and Ca2+-dependent manner. The increased outflow of NPY-LI was not influenced by capsaicin pretreatment. Among other agents tested, bradykinin and ouabain caused increased outflow of CGRP but not of NPY-LI. Noradrenaline, tyramine, histamine, vasopressin, alpha,beta methylene ATP, ATP or adenosine induced changes in cardiac contractility or flow but did not evoke any detectable release of CGRP- or NPY-LI. In conclusion, the release of multiple neuropeptides can be studied in combination with contractile recordings using the isolated perfused guinea-pig whole heart preparation. Activation of cardiac sensory nerves by capsaicin, nicotine, bradykinin and ouabain, as well as ischaemia, induced release of CGRP while nicotine also evoked NPY release.     

Low levels of frailty in HIV-positive older adults on antiretroviral therapy in northern Tanzania

Journal of NeuroVirology - There are over 3 million people in sub-Saharan Africa (SSA) aged 50 and over living with HIV. HIV and combined antiretroviral therapy (cART) exposure may accelerate the...     

Factor V G1691A (Leiden) and prothrombin G20210A single-nucleotide polymorphisms in type 2 diabetes mellitus

The association of the single nucleotide polymorphisms (SNPs) G1691A in coagulation factor V (FV)-Leiden and G20210A in prothrombin (PRT) genes with type 2 diabetes mellitus (T2DM) were analyzed in 112 T2DM patients (58 males, 54 females; mean age 55.24 +/- 13.5 years) and 249 healthy control subjects (118 males, 131 females; mean age 53.03 +/- 13.8 years). No association was found for FV-Leiden with T2DM, as the frequency of the G/G (82.1% vs. 85.5%), G/A (17.0% vs. 14.1%), and A/A (0.9% vs. 0.4%) genotypes was not different between patients and controls, respectively (P = 0.644). Similarly, lack of association of PRT G20210A with T2DM was seen among the population studied, and the frequency of the G/G (92.9% vs. 97.2%), G/A (6.3% vs. 2.8%), and A/A (0.9% vs. 0.0%) genotypes was similar among patients and controls, respectively (P = 0.094). Neither FV-Leiden nor PRT G20210A was associated with, and no evidence for interactions between these mutations was seen in, T2DM.     

A substance P antagonist inhibits vagally induced increase in vascular permeability and bronchial smooth muscle contraction in the guinea pig

Electrical stimulation of the cervical vagus nerve in anesthetized guinea pigs induced a rapid increase in respiratory insufflation pressure, suggesting increased airway resistance. After intravenous administration of a substance P (SP) antagonist, [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP, the insufflation pressure response to vagal stimulation was reduced by 78% while the cardiovascular effects were unchanged. Histamine receptor-blocking agents were used to inhibit the effects of histamine release induced by the SP-antagonist. [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP also reduced the increase in insufflation pressure caused by intravenous SP or capsaicin. The long-lasting noncholinergic contraction of the main and hilus bronchi induced by field stimulation in vitro, as well as the contractile effects of SP and capsaicin, were also blocked by the SP antagonist. The cholinergic contractions and the noncholinergic tracheal relaxation on field stimulation in vitro were, however, not blocked by the antagonist. Vagal stimulation in vivo also increased vascular permeability in the respiratory tract and esophagus, causing a subepithelial edema as indicated by Evans blue extravasation. Previous treatment with [D-Arg(1),D-Pro(2),D-Trp(7,9),Leu(11)]SP inhibited the permeability increase induced by both vagus nerve stimulation and exogenous SP. SP release from vagal sensory nerves was indirectly shown by reduction in the bronchial levels of SP after nerve stimulation in vivo. The data suggest that a major portion of the vagally or capsaicin-induced increase in smooth muscle tone is caused by SP release from sensory neurons. In addition, activation of vagal SP-containing sensory nerves induces local edema. Tracheobronchial afferent SP-containing C fibers may thus exert local control of smooth muscle tone and vascular permeability in normal and pathophysiological conditions.     

Effects of social anxiety and evaluative threat on cardiovascular responses to active performance situations

This study investigated the joint influence of trait social anxiety and evaluative threat on psychological and cardiovascular responses to active coping situations. Fifty-two normotensive female students characterized as either high or low in trait social anxiety performed a mental arithmetic task and a speech task requiring persuasive behavior in a context of high or low evaluative threat. Trait social anxiety exerted a substantial influence on cardiovascular reactivity. High socially anxious individuals overall exhibited greater heart rate reactivity. For systolic and diastolic blood pressure enhanced reactivity of socially anxious individuals was confined to low evaluative threat. At high levels of evaluative threat no group differences were observed due to somewhat attenuated reactivity in high compared to low socially anxious individuals. Cognitive appraisals and affective arousal were not found to mediate the effects of social anxiety on cardiovascular reactivity. Results were attributed to differences in effort expenditure rather than experienced anxiety.