Asthma mediators: current views.
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Asthma↗
Biomedical subjects
D Spina
Publications and source records attributed to D Spina.
The potential of PDE4 inhibitors in asthma or COPD.
At least 11 families of distinct phosphodiesterase (PDE) isoenzymes are known to regulate the function of many cells secondary to altering the intracellular levels of second messengers including cyclic 3'5-monophosphate (cyclic AMP) and cyclic 3'5 guanosine monophosphate (cyclic GMP). While there is a wide distribution of these enzymes throughout the body, it is of interest that inflammatory cells thought to participate in the pathogenesis of inflammatory diseases including asthma and chronic obstructive pulmonary disease (COPD), preferentially express PDE4. This finding has stimulated the search for highly selective inhibitors of these enzymes. Unfortunately, PDE4 inhibitors tend to be associated with a number of unwanted side effects including headache and emesis. However, attempts have been made through rational drug design to synthesize compounds that demonstrate improved side effect profile. Such drugs offer an exciting opportunity to selectively downregulate inflammatory cell function as a novel therapeutic approach in the treatment of airway disease.
3',5'-Cyclic-AMP Phosphodiesterases↗
The role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in the guinea-pig.
The racemic mixture propranolol (RS-(+/-)-, and the S-(-)- and R-(+)-) isomers of propranolol have been shown to induce bronchial hyperresponsiveness in the guinea-pig unrelated to beta-adrenoreceptor occupancy, that is attenuated by vagal section and mediated via the generation of 5-lipoxygenase metabolites of arachidonic acid. We have investigated the role of sensory nerves in propranolol-induced bronchial hyperresponsiveness in guinea-pigs. Airways responsiveness to acetylcholine, bradykinin and bombesin was determined before and 10 min after intravenous infusion with RS-(+/-)-, S-(-)- and R-(+)-propranolol (1 mg/kg) in vehicle and capsaicin-treated guinea-pigs. Propranolol (1 mg/kg, iv) significantly augmented the bronchoconstrictor response to acetylcholine, bradykinin and bombesin (P<0.001), an effect that was observed for RS-(+/-)-, S-(-)- and R-(+)-propranolol. In capsaicin-treated animals, the increased airways responsiveness to acetylcholine following intravenous infusion of S-(-)-propranolol was significantly inhibited. Capsaicin treatment tended to reduce the increase in airways responsiveness to bradykinin following infusion with R-(+)-propranolol, but was only significant for the highest dose used. Similarly, capsaicin treatment had no effect on the ability of RS-(+/-)-, S-(-)- and R-(+)-propranolol to enhance the bronchoconstrictor response to bombesin. Our results suggest that propranolol-induced bronchial hyperresponsiveness to certain spasmogens is in part mediated by the action of capsaicin-sensitive nerves.
Acetylcholine↗
Antigen-induced bronchial hyperresponsiveness in the rabbit is not dependent on M(2)-receptor dysfunction.
We have assessed the effect of sensitization to allergen on airway smooth muscle responsiveness and acetylcholine (ACh) release from cholinergic nerves in tracheal preparations from rabbits immunized at birth to Alternaria tenuis and littermate control rabbits injected with saline. ACh release induced by EFS was significantly greater in tracheal preparations obtained from immunized rabbits compared with littermate controls. The ability of the muscarinic-receptor agonist, oxotremorine, to inhibit ACh release to EFS (4 Hz) was not altered by immunization. The contractile response evoked by electrical field stimulation (EFS), ACh and 5-hydroxytryptamine (5-HT) was not significantly altered in tracheal preparations from antigen immunized rabbits compared with littermate controls. Antigen challenge of immunized rabbits did not affect the release of ACh from isolated trachea following EFS, or the ability of oxotremorine to inhibit ACh release. Furthermore, antigen challenge of immunized rabbits failed to alter the contractile response to EFS or ACh, but reduced the contractile potency of 5-HT. These results demonstrate increased ACh release in tracheal preparations following immunization which had no functional consequence on airway smooth muscle responsiveness. Moreover, the increased release in ACh was not associated with an alteration in M(2)-receptor function. Thus, antigen-induced bronchial hyperresponsiveness in the rabbit does not appear to depend upon M(2)-receptor dysfunction.
Acetylcholine↗
P53 accumulation is a prognostic factor in intestinal-type gastric carcinoma but not in the diffuse type.
BACKGROUND: The prognostic value of p53 nuclear accumulation in gastric cancer is still unclear, as shown by the discordant results still reported in the literature. In this study, we evaluated the correlation between p53 accumulation and long-term survival of patients resected for intestinal and diffuse-type gastric cancer. METHODS: Eighty-three patients with carcinoma of the intestinal type and 53 patients with carcinoma of the diffuse type were included in the study. Immunohistochemical staining of the paraffin sections was performed by using monoclonal antibody DO1; cases were considered positive when nuclear immunostaining was observed in 10% or more of the tumor cells. Prognostic significance of different variables was investigated by univariate and multivariate analysis. RESULTS: p53 positivity was found in 51.8% of intestinal-type and 50.9% of diffuse-type cases. No significant correlation between the rate of p53 overexpression and age, sex, tumor location, tumor size, depth of invasion, lymph node involvement, distant metastases, and surgical radicality was found in the two groups of patients. A statistically significant difference in survival rate was observed between p53-negative and p53-positive cases in the intestinal type (P < .05), confirmed by multivariate analysis (P < .005; relative risk = 3.09). On the contrary, no correlation with survival was found in diffuse-type cases according to p53 overexpression. CONCLUSIONS: These results suggest that the immunohistochemical detection of p53 accumulation is a useful indicator of poor prognosis in the intestinal but not in the diffuse type of gastric cancer, and are indicative of distinct molecular pathways and pattern of progression in the two histotypes.
Adult↗
Airway nerves and protein phosphatases.
Much attention has focused on the important role played by phosphatases in the control of gene transcription, cell differentiation and memory regulation. It is also clear that phosphatases may regulate a number of biochemical pathways which can modulate cellular function. Of particular interest is the role of phosphatases in the control of neuronal function. Alterations in neuronal function may contributed to the heightened airways responsiveness observed in asthma to a number of physiological stimuli including distilled water, sulfur dioxide, metabisulfite, hypertonic saline, exercise, allergens, viruses and cold air. An understanding of the mechanisms which regulate the function of sensory nerves could have important clinical implications. In this review we will highlight a number of studies that have investigated the role of phosphatases in the regulation of airway nerve function.
Bronchi↗
Oncocytic (Hürthle cell) tumors of the thyroid: distinct growth patterns comparedẁith clinicopathological features.
Neoplastic growth results from cell production that exceeds cell loss. We registered mitotic and apoptotic indices (MI and AI) in 97 immunohistochemically verified oncocytic (Hürthle cell) tumors of the thyroid (OT; 50 adenomas [OA], 20 atypical adenomas [aOA], and 27 carcinomas [OC]) and compared these kinetic data with histological diagnoses and other parameters. MI, although very low in all, was significantly higher in carcinomas than in adenomas. Conversely, AI did not differ as much among the 3 groups. This indicates that the magnitude of cell deletion did not play a prominent role in determining the disparate growth of the 3 types of oncocytic tumors. Cluster analysis with MI and AI per case as variables revealed the existence of 3 groups of neoplasms with highly distinct growth characteristics: (1) near-steady state (n = 78, all diagnostic categories represented); (2) progressive (n = 9, mostly carcinomas); and (3) regressive (n = 10, mostly adenomas). MI distinguished between histologically benign and malignant with the greatest discriminant power of the variables tested. Proliferative indices should thus be included in the differential diagnostic evaluation of oncocytic thyroid tumors. Our study also suggests that invasiveness and growth are 2 diverging properties of carcinomas.
Adenoma↗
Cell growth and death in malignant lymphomas. A quantitative analysis.
OBJECTIVE: To review the value of biopathologic factors in single lymphomatous patients across the boundaries of histologic classification. STUDY DESIGN: In a series of previous studies, based on a large collection of biopsy samples, the value of the above biopathologic characteristics in individual lymphomatous patients was quantitatively evaluated. RESULTS: The relationships between apoptotic index and growth fraction, in light of the expression of oncogenes, which regulate cell birth and death, were of particular value in determining the growth pattern of different lymphoma cases across the boundaries of histologic classification. CONCLUSION: The study of mechanisms that regulate cell proliferation and death might have therapeutic implications as the proper therapeutic approach should be based on detailed knowledge of the kinetic and molecular characteristics of each tumor.
Apoptosis↗
Modulation of Sensory Nerve Function in the Airways.
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Journal Article↗
The effect duration of selective phosphodiesterase inhibitors in the guinea pig.
The beta-adrenoceptor agonists, isoprenaline, salbutamol and salmeterol, the non-selective phosphodiesterase (PDE) isoenzyme inhibitors, theophylline, trequinsin; the PDE3 isoenzyme inhibitor, milrinone; the PDE3/4 isoenzyme inhibitor, benzafentrine; and the PDE4 isoenzyme inhibitors, denbufylline, nitraquazone, RP 73401, Ro-20-1724, rolipram and tibenelast all induced concentration-dependent reversal of prostaglandin F2alpha-induced contraction of guinea-pig superfused trachea in vitro. The relaxant response of the non-selective PDE isoenzyme inhibitor trequinsin was slow in onset and demonstrated very slow recovery, similar to that observed with the long-acting beta2-adrenoceptor agonist, salmeterol and the PDE4 inhibitor, RP 73401. The relaxant agonists also significantly reversed bombesin-induced bronchospasm in anaesthetised guinea-pigs and there was a highly significant correlation between the ability of drugs to reverse PGF2alpha-induced contraction of guinea-pig isolated trachea in vitro and bombesin-induced bronchoconstriction in vivo. Furthermore, both salmeterol and trequinsin demonstrated long lasting bronchodilator responses consistent with the in vitro data. These results show that PDE isoenzyme inhibitors demonstrate different pharmacodynamic profiles that is not determined by PDE4 inhibitory potency and indicate that other factors may be important in this regard.
Adrenergic beta-Agonists↗
A comparison of sensory nerve function in human, guinea-pig, rabbit and marmoset airways.
We have investigated the role of sensory nerves in regulating airway smooth muscle function in the guinea-pig, marmoset, rabbit and man. Tissue levels of the sensory neuropeptides CGRP and substance P in the airways of the guinea-pig were significantly greater compared with the rabbit and marmoset. The relative order of tissue content was guinea-pig >>> rabbit = marmoset. Marmoset bronchial and tracheal preparations responded weakly to exogenously administered substance P and neurokinin A but contracted to methacholine and demonstrated atropine-sensitive cholinergic responses. In marmoset, rabbit and human airway preparations, capsaicin mediated weak contractile responses to exogenously administered capsaicin. However, high concentrations of capsaicin elicited a relaxation response that was epithelium-independent, cyclo-oxygenase-insensitive, not involving nitric oxide and not dependent on the activation of capsaicin-sensitive afferents. These results suggest that rabbit and marmoset airways respond functionally in a similar way to human airway preparations and maybe more relevant than guinea-pig airways with regard to understanding the role of sensory neuropeptides in airways.
Animals↗
Modulation of sensory nerve function in the airways.
Several clinical studies document a greater discrimination between asthmatic and healthy subjects in bronchial responsiveness to a range of stimuli such as cold air, distilled water and sodium metabisulphite, than to conventional bronchoconstrictor agonists including histamine and methacholine. One of the mechanisms thought to account for the bronchoconstriction induced by these agents is via reflex activation of the cholinergic pathway. An increase in sensory nerve (afferent) activity in asthma might account for the increased responsiveness to these agents. If so, a number of strategies are available to inhibit the function of afferent nerves which could lead to a suppression of bronchial hyperresponsiveness, including (1) inhibition of afferent activity, (2) inhibition of neuropeptide release and (3) antagonism of tachykinin receptors. As there are numerous reviews dealing with the latter, in this review Domenico Spina, Saloni Shah and Selena Harrison focus on the first two strategies.
Anti-Asthmatic Agents↗
The role of phosphodiesterase enzymes in allergy and asthma.
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Animals↗
Nociceptin inhibits non-adrenergic non-cholinergic contraction in guinea-pig airway.
1. Electrical field stimulation (EFS) of guinea-pig isolated main bronchi induced a non-adrenergic non-cholinergic (NANC) contractile response. Nociceptin (0.01-1 microm) significantly inhibited the contractile response to EFS (P<0.01), but not to capsaicin (P>0.05). 2. The mu-, delta- and kappa-opioid receptor antagonists, naloxone (0.3 microM), naltrindole (3 microM) and norbinaltorphimine (1 microm), respectively, did not significantly affect the inhibitory effect of nociceptin (0.03 microM; P>0.05). 3. The novel nociceptin antagonist, [Phe1psi(CH2-NH)Gly2]nociceptin(1-13)NH2 (0.03-1 microM); the sigma ligands, carbetapentane (30 microM), 3-phenylpiperidine (30-100 microM) and (+)-cyclazocine (10-100 microM) significantly reversed the inhibitory effect of nociceptin (0.03 microM, P<0.05). In contrast, rimcazole, did not significantly reverse the inhibitory effect of nociceptin (0.03 microM) at any concentration tested (P>0.05). 4. EFS of guinea-pig bronchial preparations significantly increased SP-LI release above basal SP-LI (P<0.05). In the presence of nociceptin (1 microM), EFS induced a significant increase in SP-LI release above basal SP-LI release (P<0.05). Nociceptin caused a 59+11% (n=5) inhibition of EFS-induced release of SP-LI. 5. Nociceptin reduces the release of sensory neuropeptides induced by EFS, but not capsaicin, from guinea-pig airways. These experiments provide further evidence for a role for nociceptin in regulating the release of sensory neuropeptides in response to EFS.
Animals↗
Stimulation of airway sensory nerves by cyclosporin A and FK506 in guinea-pig isolated bronchus.
We have investigated the contractile property of cyclosporin A and FK506 in guinea-pig isolated bronchus. Cyclosporin A (10 microM) failed to significantly attenuate the excitatory non-adrenergic non-cholinergic (eNANC) and cholinergic contractile response (per cent methacholine Emax) induced by electrical field stimulation (EFS). In contrast, eNANC responses were significantly attenuated by both the neurokinin (NK)-1 and (NK)-2 receptor antagonists, N-acetyl-L-tryptophan 3,5-bis (trifluoromethyl)-benzyl and SR48968, respectively. Cyclosporin A and FK506 caused a concentration-dependent contraction in guinea-pig isolated bronchus, which was significantly attenuated by NK-1 and NK-2 receptor antagonists. The capsaicin receptor antagonist, capsazepine (10 microM) significantly reduced the contractile response to cyclosporin A and capsaicin, but not to FK506. The N-type calcium channel blocker, omega-Conotoxin (omegaCTX: 10 nM), significantly reduced the contractile response to FK506 and the eNANC response following EFS. In contrast, omega-CTX failed to significantly reduce the contractile potency to capsaicin or cyclosporin A. In bronchial preparations desensitized by repeated application of capsaicin (1 microM), the contractile responses to both cyclosporin A (100 microM) and FK506 (100 microM), were significantly reduced. In contrast, the contractile responses to substance P and neurokinin A (10 microM) were not altered. Furthermore, repeated application of cyclosporin A (100 microM) significantly inhibited the contractile response to capsaicin (1 microM). The findings from this study would indicate that cyclosporin A and FK506 mediate contraction of guinea-pig isolated bronchus secondary to the release of neuropeptides from airway sensory nerves. However, the release of sensory neuropeptides appears to be mediated via different mechanisms for cyclosporin A and FK506, the former by stimulation of the vanilloid receptor and the latter via opening of N-type calcium channels.
Animals↗
Epithelium smooth muscle regulation and interactions.
In the 1980s, studies in the vascular field revealed that the endothelium was not simply a metabolic and physical barrier, but liberated substances that could modulate the function of underlying vascular smooth muscle. Investigators in the respiratory field also found that the airway epithelium was more than a physical barrier to airborne insults. The epithelium is composed of at least eight different cell types that have a range of functions, including ciliary motility and mucous secretion, and contain enzymes for liberating arachidonic acid metabolites and peptides. The epithelium also contains degradative enzymes for a number of peptides and biological amines. It was also recognized that the epithelium released substances that, like their vascular counterparts, could regulate the function of a number of cell types, including nerves and airway smooth muscle. These studies document the importance the epithelium plays in the regulation of human airway smooth muscle.
Animals↗
Effect of chronic theophylline treatment on the methacholine dose-response curve in allergic asthmatic subjects.
Theophylline is a bronchodilator and immunomodulator drug which has recently been demonstrated to attenuate the recruitment and activation of inflammatory cells into lungs of asthmatics. This study investigated the effect of chronic treatment with theophylline for its ability to alter airway responsiveness, as indicated by changes in airway sensitivity and reactivity to inhaled methacholine. The subjects studied were mild asthmatics who relied on beta-agonist medication only and who were randomized into two groups, one receiving theophylline (median dose 250 mg twice daily; range 250-375 mg twice daily) and the other placebo. A number of parameters was measured before and after treatment, including baseline forced expiratory volume in one second (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20; sensitivity), dose-response slope (reactivity) and percentage eosinophils, eosinophil cationic protein and T-cell markers in peripheral blood (by flow cytometry). After 2 months of treatment with theophylline there was a significant lowering of airway reactivity (slope) to methacholine and improvement in methacholine sensitivity (PC20). However, such changes were not associated with any significant change in the number or activation status of eosinophils and lymphocytes in peripheral blood. In conclusion, chronic treatment with theophylline reduces the reactivity of the airways to methacholine, which might be beneficial in the treatment of persistent asthma. The cellular mechanisms of this improvement remain to be clarified.
Adult↗
The effect of L-arginine on guinea-pig and rabbit airway smooth muscle function in vitro.
We have investigated the effects of L-arginine, D-arginine and L-lysine on airway smooth muscle responsiveness to spasmogens in vitro. Both L-arginine and D-arginine (100 mM) significantly reduced the contractile potency and maximal contractile response to histamine but not to methacholine or potassium chloride in guinea-pig epithelium-denuded isolated trachea. Similarly, the contractile response to histamine was significantly reduced by L-arginine (100 mM) in rabbit epithelium-denuded isolated bronchus. The amino acid L-lysine (100 mM) failed to significantly alter the contractile potency of histamine in guinea-pig isolated trachea (P > 0.05). In guinea-pig isolated trachea precontracted with histamine, both L-arginine and D-arginine produced a concentration-dependent relaxation which was not significantly altered by epithelium removal or by the presence of the nitric oxide synthase inhibitor, NG-nitro L-arginine methyl ester (L-NAME; 50 microM). Thus, at very high concentrations, arginine exhibit a non-competitive antagonism of histamine-induced contraction of isolated airway preparations that was independent of the generation of nitric oxide and was not dependent on charge. These observations confirm previous studies of cutaneous permeability responses and of contractile responses of guinea-pig isolated ileal smooth muscle. Taken together, the data suggest that high concentrations of arginine can exert an anti-histamine effect.
Animals↗