6 results on '"Orfanos, S."'
Search Results
2. Effects of indomethacin on PMA-induced pulmonary endothelial enzyme dysfunction in vivo
- Author
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Chen, X., primary, Orfanos, S. E., additional, and Catravas, J. D., additional
- Published
- 1992
- Full Text
- View/download PDF
3. Epinephrine evokes shortening of human airway smooth muscle cells following β 2 adrenergic receptor desensitization.
- Author
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Deeney BT, Cao G, Orfanos S, Lee J, Kan M, Himes BE, Parikh V, Koziol-White CJ, An SS, and Panettieri RA Jr
- Subjects
- Adrenergic beta-Agonists, Bronchi, Bronchodilator Agents pharmacology, Epinephrine pharmacology, Humans, Muscle, Smooth, Receptors, Adrenergic, alpha-1, Myocytes, Smooth Muscle, Receptors, Adrenergic, beta-2
- Abstract
Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α
1 -adrenergic receptors (α1 ARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α1 ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating β2 -adrenergic receptors (β2 ARs). Conventionally, the selective β2 AR agonism of EPI was thought to be, in part, due to a predominance of β2 ARs and/or a sparse, or lack of α1 AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α1 AR subtype B) and identify a spontaneous "switch-like" activation of α1 ARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of β2 ARs and/or under experimental conditions that induce β2 AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α1 AR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining α1 AR inhibition for the management of stress/exercise-induced asthma and/or β2 -agonist insensitivity in patients with difficult-to-control, disease subtypes.- Published
- 2022
- Full Text
- View/download PDF
4. Budesonide enhances agonist-induced bronchodilation in human small airways by increasing cAMP production in airway smooth muscle.
- Author
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Koziol-White C, Johnstone TB, Corpuz ML, Cao G, Orfanos S, Parikh V, Deeney B, Tliba O, Ostrom RS, Dainty I, and Panettieri RA Jr
- Subjects
- Bronchi drug effects, Carbachol pharmacology, Cell Membrane drug effects, Cell Membrane metabolism, Cholera Toxin pharmacology, Colforsin pharmacology, Dinoprostone pharmacology, Fluticasone pharmacology, Formoterol Fumarate pharmacology, Humans, Muscle, Smooth drug effects, Myosin Light Chains metabolism, Phosphorylation drug effects, Prednisone pharmacology, Receptors, Glucocorticoid metabolism, Bronchi physiology, Bronchodilator Agents pharmacology, Budesonide pharmacology, Cyclic AMP biosynthesis, Muscle, Smooth physiology
- Abstract
The nongenomic mechanisms by which glucocorticoids modulate β
2 agonist-induced-bronchodilation remain elusive. Our studies aimed to elucidate mechanisms mediating the beneficial effects of glucocorticoids on agonist-induced bronchodilation. Utilizing human precision-cut lung slices (hPCLS), we measured bronchodilation to formoterol, prostaglandin E2 (PGE2 ), cholera toxin (CTX), or forskolin in the presence and absence of budesonide. Using cultured human airway smooth muscle (HASM), intracellular cAMP was measured in live cells following exposure to formoterol, PGE2 , or forskolin in the presence or absence of budesonide. We showed that simultaneous budesonide administration amplified formoterol-induced bronchodilation and attenuated agonist-induced phosphorylation of myosin light chain, a necessary signaling event mediating force generation. In parallel studies, cAMP levels were augmented by simultaneous exposure of HASM cells to formoterol and budesonide. Budesonide, fluticasone, and prednisone alone rapidly increased cAMP levels, but steroids alone had little effect on bronchodilation in hPCLS. Bronchodilation induced by PGE2 , CTX, or forskolin was also augmented by simultaneous exposure to budesonide in hPCLS. Furthermore, HASM cells expressed membrane-bound glucocorticoid receptors that failed to translocate with glucocorticoid stimulation and that potentially mediated the rapid effects of steroids on β2 agonist-induced bronchodilation. Knockdown of glucocorticoid receptor-α had little effect on budesonide-induced and steroid-dependent augmentation of formoterol-induced cAMP generation in HASM. Collectively, these studies suggest that glucocorticoids amplify cAMP-dependent bronchodilation by directly increasing cAMP levels. These studies identify a molecular mechanism by which the combination of glucocorticoids and β2 agonists may augment bronchodilation in diseases such as asthma or chronic obstructive pulmonary disease.- Published
- 2020
- Full Text
- View/download PDF
5. Obesity increases airway smooth muscle responses to contractile agonists.
- Author
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Orfanos S, Jude J, Deeney BT, Cao G, Rastogi D, van Zee M, Pushkarsky I, Munoz HE, Damoiseaux R, Di Carlo D, and Panettieri RA Jr
- Subjects
- Adult, Asthma etiology, Asthma metabolism, Calcium metabolism, Cardiotonic Agents pharmacology, Case-Control Studies, Cells, Cultured, Female, Histamine Agonists pharmacology, Humans, Male, Muscle, Smooth drug effects, Myosin Light Chains metabolism, Prognosis, Respiratory System drug effects, Asthma physiopathology, Carbachol pharmacology, Histamine pharmacology, Muscle Contraction drug effects, Muscle, Smooth pathology, Obesity complications, Respiratory System pathology
- Abstract
The asthma-obesity syndrome represents a major public health concern that disproportionately contributes to asthma severity and induces insensitivity to therapy. To date, no study has shown an intrinsic difference between human airway smooth muscle (HASM) cells derived from nonobese subjects and those derived from obese subjects. The objective of this study was to address whether there is a greater response to agonist-induced calcium mobilization, phosphorylation of myosin light chain (MLC), and greater shortening in HASM cells derived from obese subjects. HASM cells derived from nonobese and obese subjects were age and sex matched. Phosphorylation of MLC was measured after having been stimulated by carbachol. Carbachol- or histamine-induced mobilization of calcium and cell shortening were assessed in HASM cells derived from nonobese and obese donors. Agonist-induced MLC phosphorylation, mobilization of calcium, and cell shortening were greater in obese compared with non-obese-derived HASM cells. The MLC response was comparable in HASM cells derived from obese nonasthma and nonobese fatal asthma subjects. HASM cells derived from obese female subjects were more responsive to carbachol than HASM cells derived from obese male subjects. Insulin pretreatment had little effect on these responses. Our results show an increase in agonist-induced calcium mobilization associated with an increase in MLC phosphorylation and an increase in ASM cell shortening in favor of agonist-induced hyperresponsiveness in HASM cells derived from obese subjects. Our studies suggest that obesity induces a retained phenotype of hyperresponsiveness in cultured human airway smooth muscle cells.
- Published
- 2018
- Full Text
- View/download PDF
6. Reduced lung endothelial angiotensin-converting enzyme activity in Watanabe hyperlipidemic rabbits in vivo.
- Author
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Orfanos SE, Parkerson JB, Chen X, Fisher EL, Glynos C, Papapetropoulos A, Gerrity RG, and Catravas JD
- Subjects
- 5'-Nucleotidase metabolism, Adenosine Monophosphate metabolism, Animals, Endothelium enzymology, Hyperlipidemias genetics, Kinetics, Male, Oligopeptides metabolism, Rabbits, Hyperlipidemias enzymology, Lung enzymology, Peptidyl-Dipeptidase A metabolism
- Abstract
We investigated pulmonary endothelial function in vivo in 12- to 18-mo-old male Watanabe heritable hyperlipidemic (WHHL; n = 7) and age- and sex-matched New Zealand White (n = 8) rabbits. The animals were anesthetized and artificially ventilated, and the chest was opened and put in total heart bypass. The single-pass transpulmonary utilizations of the angiotensin-converting enzyme (ACE) substrate [(3)H]benzoyl-Phe-Ala-Pro (BPAP) and the 5'-nucleotidase (NCT) substrate [(14)C]AMP were estimated, and the first-order reaction parameter A(max)/K(m), where A(max) is the product of enzyme mass and the catalytic rate constant and K(m) is the Michaelis-Menten constant, was calculated. BPAP transpulmonary utilization and A(max)/K(m) were reduced in WHHL (1.69 +/- 0.16 vs. 2.9 +/- 0.44 and 599 +/- 69 vs. 987 +/- 153 ml/min in WHHL and control rabbits, respectively; P < 0.05 for both). No differences were observed in the AMP parameters. BPAP K(m) and A(max) values were estimated separately under mixed-order reaction conditions. No differences in K(m) values were found (9.79 +/- 1 vs. 9.9 +/- 1.31microM), whereas WHHL rabbit A(max) was significantly decreased (5.29 +/- 0.88 vs. 7. 93 +/- 0.8 micromol/min in WHHL and control rabbits, respectively; P < 0.05). We conclude that the observed pulmonary endothelial ACE activity reduction in WHHL rabbits appears related to a decrease in enzyme mass rather than to alterations in enzyme affinity.
- Published
- 2000
- Full Text
- View/download PDF
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