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Biomedical subjects

W Calhoun

Publications and source records attributed to W Calhoun.

18 recordsLinked to original sources
PubMed2000

Molecular mechanisms of increased nitric oxide (NO) in asthma: evidence for transcriptional and post-translational regulation of NO synthesis.

Evidence supporting increased nitric oxide (NO) in asthma is substantial, although the cellular and molecular mechanisms leading to increased NO are not known. Here, we provide a clear picture of the events regulating NO synthesis in the human asthmatic airway in vivo. We show that human airway epithelium has abundant expression of NO synthase II (NOSII) due to continuous transcriptional activation of the gene in vivo. Individuals with asthma have higher than normal NO concentrations and increased NOSII mRNA and protein due to transcriptional regulation through activation of Stat1. NOSII mRNA expression decreases in asthmatics receiving inhaled corticosteroid, treatment effective in reducing inflammation in asthmatic airways. In addition to transcriptional mechanisms, post-translational events contribute to increased NO synthesis. Specifically, high output production of NO is fueled by a previously unsuspected increase in the NOS substrate, l -arginine, in airway epithelial cells of asthmatic individuals. Finally, nitration of proteins in airway epithelium provide evidence of functional consequences of increased NO. In conclusion, these studies define multiple mechanisms that function coordinately to support high level NO synthesis in the asthmatic airway. These findings represent a crucial cornerstone for future therapeutic strategies aimed at regulating NO synthesis in asthma.

Adult↗
PubMed1997

Interferon gamma and interleukin 4 stimulate prolonged expression of inducible nitric oxide synthase in human airway epithelium through synthesis of soluble mediators.

Human respiratory epithelium expresses inducible nitric oxide synthase (iNOS) continuously in vivo, however mechanisms responsible for maintenance of expression are not known. We show that IFNgamma is sufficient for induction of iNOS in primary human airway epithelial cells (HAEC) in vitro, and IL-4 potentiates IFNgamma-induced iNOS expression in HAEC through stabilization of iNOS mRNA. IFNgamma/IL-4- induced iNOS expression in HAEC was delayed in onset and prolonged with expression up to 1 wk. Removal of overlying culture media resulted in loss of expression, while transfer of conditioned media induced iNOS mRNA in other HAEC. IFNgamma and IL-4 stimulation activated STAT1 and STAT6 in HAEC, but conditioned media transfer to HAEC produced even higher levels of STAT1 activation than achieved by direct addition of cytokines. Although cytokine induction of iNOS was dependent on new protein synthesis, conditioned media induction of iNOS in HAEC was not. Further, removal of overlying culture media from cells at different times after cytokine stimulation demonstrated that mediator synthesis and/or secretion important for induction and maintenance of iNOS occurs early after cytokine stimulation. In conclusion, a combination of IFNgamma/ IL-4, which occurs naturally in the lung epithelial lining fluid, leads to maintenance of iNOS expression in human airway epithelium through production of soluble mediators and stabilization of mRNA.

Adolescent↗
PubMed1997

Rhinovirus infection preferentially increases lower airway responsiveness in allergic subjects.

Rhinovirus (RV) infections are important triggers of acute asthma symptoms in susceptible persons. To determine whether the presence of allergy is a risk factor for enhanced lower airway effects during RV infection, we experimentally infected (RV16) 18 volunteers with allergic rhinitis and 13 normal control subjects and measured the effects on the response of the lower airways to histamine. All subjects were successfully infected, as indicated by increased upper respiratory symptoms and RV16 cultured from nasal secretions. The change in histamine PD20(deltaPD20) caused by RV infection was significantly different in allergic subjects from that in nonallergic control subjects (deltaPD20 = -0.40 versus -0.03 log units, p = 0.04). This relationship was strengthened after adjusting for initial PD20 and FEV1 (mean deltaPD20 = -0.43 versus 0.01 log units, p < 0.01). The virus-induced deltaPD20 was also influenced by baseline lung function: there was a positive correlation between initial FEV1 and deltaPD20, and a weak but significant negative correlation between baseline PD20 and deltaPD20. These findings indicate that host factors such as allergy, baseline FEV1, and baseline PD20 influence the changes in lower airway physiology caused by RV infection and raise the possibility that these factors contribute to the increased lower airway effects of RV infection in subjects with asthma.

Adult↗
PubMed1995

Synthesis and antiinflammatory activity of certain 5,6,7,8-tetrahydroquinolines and related compounds.

Modification of some 8-benzylidene-5,6,7,8-tetrahydroquinolines, which have good antiulcer activity, led to three distinct classes of compounds with good in vivo antiinflammatory activity. Initial efforts led to a series of alkenes derived from 5,6,7,8-tetrahydroquinolines substituted at the 8-position. A second approach concentrated on replacing the CH linkage of these 8-benzylidene-substituted compounds with other spacer groups and increasing the size of the cycloalkyl ring from a six- to seven-membered ring, which provided 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine analogues. Finally, the substituent was switched from the cycloalkyl ring to the 2-position of the pyridine ring. Variation of the 2-substituent was also examined. Optimal antiinflammatory activity after oral administration was found in both the rat carrageenan paw edema and rat developing adjuvant arthritis models with 2-substituted 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridines, and of particular interest was 27 (WY-28342).

Animals↗
PubMed1994

Relationship of plasma epinephrine and circulating eosinophils to nocturnal asthma.

The mechanisms of nighttime airway obstruction are not fully established, but include circadian fluctuations in epinephrine and cortisol. To evaluate the relationship of circadian patterns in epinephrine and cortisol to nighttime airflow obstruction, 10 young adult asthma patients (ages 19 to 25 yr) were admitted to a hospital clinical research unit for a 3-day study during which plasma concentrations of epinephrine, cortisol, and histamine were determined along with white blood cell and eosinophil counts every 6 h (1600, 2200, 0400, and 1000 h). Six of the 10 patients experienced at least one episode of nocturnal asthma (defined by more than a 15% decrease in antemeridian (A.M.) to postmeridian (P.M.) FEV1 values). Plasma epinephrine levels (pg/ml) showed a circadian pattern, and the concentration at 2200 h was significantly (p = 0.039) different for the nocturnal and non-nocturnal asthma groups. Circulating eosinophil numbers were greater in subjects who had more frequent episodes of nocturnal asthma, and correlated with the frequency of nocturnal asthma (r = 0.732, p = 0.02, Spearman rank correlation) and average percent decrease in FEV1 (r = 0.667, p = 0.035). Plasma cortisol concentrations also showed circadian patterns, but no direct association with nocturnal asthma; plasma histamine concentrations showed no circadian patterns and no association with nocturnal asthma. Our findings indicate that changes in plasma epinephrine precede the development of nocturnal airway obstruction and contribute to the likelihood of nighttime airflow obstruction.

Adult↗
PubMed1993

Rapamycin, a potential disease-modifying antiarthritic drug.

Rapamycin (RAPA), a potent immunosuppressive agent that prevents organ graft rejection in animal models of transplantation, possesses a mechanism of action different than that of cyclosporin A and FK-506. In this study, the pharmacological activity of RAPA in a variety of immune and inflammatory models was assessed in order to define better its potential utility as an antiarthritic agent. RAPA inhibited T cell-mediated inflammation in mouse methylated bovine serum albumin-induced delayed-type hypersensitivity (ED40 = 4.7 mg/kg p.o.) and produced oral ED50 of 2.0 mg/kg against developing adjuvant arthritis in rats (3-day dosing schedule) and 9.5 mg/kg in established adjuvant arthritis in rats (daily dosing schedule). In both models of adjuvant arthritis, effects of RAPA were maintained even after cessation of drug dosing. In contrast, after discontinuation of cyclosporin A (5- and 10-mg/kg doses), disease activity returned. RAPA was also effective in another T cell-mediated model, experimental allergic encephalomyelitis (ED50 approximately 5 mg/kg p.o.). At higher doses, RAPA significantly inhibited carrageenan paw edema in rats, a model of acute inflammation (ED40, 56 mg/kg p.o.), without increasing serum corticosterone levels. In this model, doses approximately 10 to 20 times greater than active doses in T cell-mediated models were required. RAPA at 1 to 50 microM did not inhibit in vitro human synovial phospholipase A2 or 5-lipoxygenase and cyclo-oxygenase activity in the human blood leukocyte assay. The total profile of RAPA suggests that it may be effective in the treatment of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases.

Acute-Phase Reaction↗
PubMed1992

Interaction studies of tilomisole, aspirin, and naproxen in acute and chronic inflammation with assessment of gastrointestinal irritancy in the rat.

The effect of combination NSAID therapy of tilomisole with aspirin or naproxen was studied in rats with carrageenan-induced paw edema and established adjuvant arthritis. Inflamed paws were measured using mercury plethysmography and the arthritic paws were X-rayed to determine any bony/soft tissue changes. The gastrointestinal tract was also examined for bleeding and ulceration. Tilomisole had a less potent acute anti-inflammatory effect than aspirin or naproxen, but produced no significant gastrointestinal damage. A significant reduction in anti-inflammatory activity was observed with the tilomisole/aspirin combination in acute inflammation. Only additive interactions were observed with the naproxen inhibition. In the established arthritis assay, a significant synergistic anti-inflammatory response, i.e. both inhibition of paw edema and bone erosion, was also observed with the 80 and 93% tilomisole/naproxen combinations. The gastric ulcerogenic effect of the combination paralleled its increased activity. The synergism between tilomisole and naproxen in this chronic arthritic model may be due to enhanced cyclooxygenase inhibitory activity. These drug interaction studies suggest possible interactions in human clinical trials of rheumatoid arthritis.

Animals↗
PubMed1991

Role of corticosterone in modulation of eicosanoid biosynthesis and antiinflammatory activity by 5-lipoxygenase (5-LO) and cyclooxygenase (CO) inhibitors.

The effectiveness of 5-lipoxygenase (LO) and dual LO/cyclooxygenase (CO) inhibitors when administered by the topical or oral routes was significantly decreased in corticosterone depleted (adrenalectomized, Adx) mice as compared to sham mice in the mouse arachidonic acid (AA) induced ear edema model. In contrast, rat carrageenan paw edema was inhibited similarly in sham and Adx animals by 5-LO and dual 5-LO/CO inhibitors. Supplementation of cortisol levels (100 micrograms/dl) in human whole blood for 2 hr increased the observed inhibition of LTB4 biosynthesis by A-64077, WY-50,295 tromethamine and naproxen while having no effect on thromboxane B2 (TXB2) biosynthesis. Thus, corticosteroids may have a permissive effect by modulating 5-LO inhibitor effects on mouse AA induced ear edema and human blood leukocytes.

Animals↗
PubMed1989

Preliminary studies on phospholipase A2-induced mouse paw edema as a model to evaluate antiinflammatory agents.

Phospholipase A2 (PLA2) is a key component of the inflammatory process because of its role in the generation of eicosanoids and platelet-activating factor (PAF). Manipulation of PLA2 activity offers a novel therapeutic approach for the development of antiinflammatory agents; however, there is a need for a suitable in vivo model. Injection of 1 microgram of snake venom PLA2 (A. piscivorus piscivorus, D-49) into the mouse hind footpad produced a significant three- to four-fold rise in paw edema within 10 min, compared to the saline control. Edema formation depended on enzyme concentration and appeared specific for PLA2 since edema was negated by enzyme pretreatment with p-bromophenacyl bromide, a nonspecific PLA2 inhibitor. Moreover, injection of a protein such as bovine serum albumin did not result in significant edema. Coinjection of phenidone (lipoxygenase inhibitor, 50 micrograms), indomethacin (cyclooxygenase inhibitor, 50 micrograms), cyproheptadine (antihistamine/antiserotonin, 50 micrograms), aristolochic acid (putative PLA2 inhibitor, 100 micrograms), or kadsurenone (PAF antagonist, 50 micrograms) with PLA2 (1 microgram/paw) resulted in partial reduction (44.5, 34.2, 54.7, 64, and 50% inhibition, respectively) of edema formation. Oral administration of cyproheptadine (10 mg/kg), indomethacin (10 mg/kg), BW 755c (100 mg/kg), or dexamethasone (1 mg/kg) 1-3 h before challenge also decreased PLA2-induced edema (63.0, 30.1, 47.8, or 62.5% inhibition, respectively). The data suggest that mouse paw edema resulting from PLA2 injection is a multicomponent event, influenced by both autacoids and lipid mediators of inflammation.

Animals↗
PubMed1989

Effect of a 5-lipoxygenase (5-LO)/cyclooxygenase (CO) inhibitor, WY-47, 288, on cutaneous models of inflammation.

WY-47,288 (2-[(1-naphthalenyloxy)methyl]quinoline) demonstrated topical antiinflammatory activity in several animal models of skin inflammation. Application of WY-47,288 to mouse ear surfaces inhibited arachidonic acid (ED50 = 0.3 mg/ear) and tetradecanoylphorbol acetate (TPA)-induced inflammation (40% at 1 mg/ear). Administration of WY-47,288 (1 mg/ear) at 30 min and 5 h after TPA reduced ear edema and epidermal proliferation by 50%. WY-47,288 also inhibited oxazolone-induced contact hypersensitivity in mouse ears (ED50 = 0.4 mg/ear) and UVB-induced guinea pig skin erythema (ED50 approximately 0.25 mg/spot). These antiinflammatory effects may be due to inhibition of 5-lipoxygenase (5-LO) and cyclooxygenase (CO) since the synthesis of 5-LO and CO products by rat neutrophils and mouse macrophages was dose-dependently reduced by WY-47,288. By contrast, WY-47,288 demonstrated no appreciable inhibition of 12-LO (rabbit platelet), 15-LO (soybean) or phospholipase A2 (human platelet). Furthermore, no systemic adverse effects were observed after topical, parenteral or oral administration of WY-47,288, suggesting that WY-47,288 is a safe topical 5-LO/CO inhibitor for treating skin inflammation.

Animals↗
PubMed1989

Pharmacologic modulation of D-49 phospholipase A2-induced paw edema in the mouse.

Paw edema was produced in CD-1 mice by the injection of 0.3 micrograms of snake venom PLA2 (A.p. piscivorus D-49) into the hind paw. Edema peaked at 10 min, remained elevated until 60 min, and then declined slowly. The PLA2 inhibitors, luffariellolide and aristolochic acid, reduced the edema but only when coinjected with the PLA2. The histamine/serotonin antagonists were the most effective drug class against PLA2-induced paw edema. The PAF antagonists, CV-6202 (iv) and kadsurenone (coinjected) reduced the PLA2-induced edema, whereas high doses of the corticosteroids, dexamethasone and hydrocortisone, were also effective. NSAIDs only partially inhibited the paw edema. The LO/CO inhibitors yielded varying activities, with only BW755C and NDGA inhibiting the edema. These results suggest that PLA2 induces paw edema in the mouse via the action of several classes of inflammatory mediators.

Animals↗
PubMed1987

Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse.

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.

Animals↗