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Jeremy P. T. Ward - One of the best experts on this subject based on the ideXlab platform.
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Ion currents in smooth muscle cells from human small Bronchioles: presence of an inward rectifier K+ current and three types of large conductance K+ channel.
Experimental physiology, 1999Co-Authors: V. A. Snetkov, Jeremy P. T. WardAbstract:Bronchoconstriction of small Bronchioles plays a major role in the increase in airway resistance following agonist challenge. There is evidence that the airway smooth muscle (ASM) of small Bronchioles differs functionally from that in larger airways. Little is known however about the electrophysiology of small Bronchioles. Ion currents were therefore studied in airway smooth muscle cells freshly dissociated from human intralobular Bronchioles, with a diameter between 0.3 and 1.0 mm. As previously reported for human large airways, the major outward current in these cells was due to activity of large conductance K+ (BK) channels, with a relatively minor component due to a voltage-gated delayed rectifier current (IDR), which was only observed in 30 % of cells. Three distinct types of iberiotoxin- and TEA-sensitive large conductance K+ channel contributed to large conductance K+ current (IBK). These included a highly voltage- and Ca2+-sensitive 200 pS channel previously reported in human large airways, and two smaller channels of 150 and 100 pS previously seen only in human fetal or cultured ASM. In contrast to large airways, ASM cells from Bronchioles also demonstrated a voltage-gated inward rectifier current (IIR). IIR was activated by hyperpolarisation below the K+ equilibrium potential and could be blocked by submillimolar concentrations of Cs+ or Ba2+, and partially by physiological concentrations of Na+. Corresponding single channels with a conductance of 17 pS could also be recorded in the cell-attached configuration. A small voltage-independent current was also observed which was resistant to classic K+ and Cl- channel blockers but which could be abolished by replacement of Na+ with the impermeant cation N-methyl-D-glucamine (NMDG+). Corresponding non-selective single channels of 20 pS could be seen in inside-out mode. These results demonstrate that ASM from small Bronchioles differs in terms of ion currents and channels from ASM derived from large airways, with possible implications for function.
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Effects of Protein Tyrosine Kinase Inhibitors on Contractility of Isolated Bronchioles of the Rat
American journal of respiratory cell and molecular biology, 1997Co-Authors: Lorna C. Chopra, Charles H. C. Twort, D Hucks, Jeremy P. T. WardAbstract:The role of protein tyrosine kinases (PTK) in modulating contractility has not been investigated in airway smooth muscle (ASM). We have examined the effects of the PTK inhibitors ST638, genistein, and tyrphostin A47 on contractions induced by carbachol, serotonin, ionomycin, and 75 mM KCl in isolated Bronchioles of the rat with internal diameters of 614 +/- 16 microm (small, n = 143), and 1,433 +/- 39 microm (large, n = 57). ST638 caused a dose-dependent decrease in the maximum response to carbachol, and shifted the carbachol concentration-response curve to the right. This effect was greater in small Bronchioles. Tyrphostin A47 (100 microM) and genistein (74 microM) had a similar effect to ST638. ST638 caused a concentration-dependent relaxation (EC50 approximately 7.2 microM) in Bronchioles precontracted with 0.5 microM carbachol, and was maximally effective at 50 microM when tone was reduced by 82.5 +/- 3.8% in small Bronchioles, and 57.2 +/- 2.8% in large Bronchioles. ST638 also reduced the maximal response to serotonin, and caused a large shift to the right of the serotonin concentration-response curve. Pretreatment with ST638 (50 microM) reduced the response to 75 mM KCl in both small and large Bronchioles in the presence of atropine (small: by 88.9 +/- 5.6%, n = 11; large: by 90.1 +/- 4.4%, n = 11). Tyrphostin A47 (100 microM) had a similar effect (91%). ST638 (50 microM) and tyrphostin A47 (100 microM) substantially relaxed small Bronchioles contracted with 1.5 microM ionomycin (ST638: by 86.7 +/- 1.8%, n = 6; tyrphostin: by 89.3 +/- 1.7%, n = 5). We have therefore demonstrated that PTK inhibitors can suppress contraction induced by a number of different mechanisms in ASM. These results suggest that PTK signaling pathways are not only important for proliferation of ASM, but also fon contractile function.
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Differences in sensitivity to the specific protein kinase C inhibitor Ro31-8220 between small and large Bronchioles of the rat.
British journal of pharmacology, 1994Co-Authors: Lorna C. Chopra, Charles H. C. Twort, Jeremy P. T. WardAbstract:1. The involvement of protein kinase C (PKC) in constriction of small Bronchioles has never been investigated. In this study we have examined the effects of the specific PKC inhibitors Ro31-8220 and Ro31-7549 and the non-specific inhibitor H7 on carbachol-, 5-hydroxytryptamine (5-HT)- and 4 beta-phorbol dibutyrate (4 beta-PDBu)-induced contractions in large and small Bronchioles. 2. The study was performed on isolated Bronchioles of the rat with internal diameters of 574 microns +/- 11 (small, n = 128), and 1475 microns +/- 32 (large, n = 93), using a Mulvaney-Halpen small vessel myograph. 3. In these preparations 4 beta-PDBu had no effect if added on its own. However, after precontracting with 30 mM K+, 0.5 microM 4 beta-PDBu caused a contractile response of 110.4 +/- 7.0% TK (TK = maximum response to 75 mM K+ in small and 69.3 +/- 6.5% TK in large Bronchioles. Ro31-8220, Ro31-7549 and H7 all showed concentration-dependent inhibition of this response. 4. In small Bronchioles 10 microM Ro31-8220 shifted both the carbachol and 5-HT concentration-response curves to the right, and reduced the maximum response. In contrast, 10 microM Ro31-8220 had no significant effect on the EC50 to carbachol of larger Bronchioles, although the maximum response was reduced, and had no significant effect on the 5-HT concentration-response curve. 200 microM H7 shifted the carbachol concentration--response curve to the right as well as reducing the maximal response in both small and large Bronchioles. 5 Large Bronchioles exhibited a greater rate of decay of carbachol-induced contraction than did small Bronchioles. Pretreatment with Ro31-8220 accelerated the rate of decay.6 Pretreatment with 10 JM Ro3l-8220 caused a small reduction in the response to 75 mM K+ in both small and large Bronchioles (small: to 87.8 +/- 3.0% TK; large: to 94.1 +/- 0.8% TK). H7 at 200 JM caused a much larger reduction in both preparations (small: to 75.1 +/- 3.0% TK); large: to 82.7 +/- 0.6% TK).7 Small Bronchioles were more sensitive than larger Bronchioles to agonists and phorbol ester. The protein kinase inhibitor Ro31-8220 could reduce agonist-induced constriction in small and large Bronchioles,as well as reducing or abolishing phorbol ester-induced contractions. Small Bronchioles were more sensitive than large Bronchioles to Ro31-8220. These results suggest that there is a significant PKC involvement in constriction of Bronchioles to carbachol and 5-HT, and that the proportion of the contractile response that can be attributed to PKC is greater in smaller than larger Bronchioles.
Laurel J. Gershwin - One of the best experts on this subject based on the ideXlab platform.
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Smooth muscle development during postnatal growth of distal Bronchioles in infant rhesus monkeys
Journal of applied physiology (Bethesda Md. : 1985), 2004Co-Authors: Mai-uyen T. Tran, Alison J. Weir, Michelle V. Fanucchi, April E. Murphy, Laura S. Van Winkle, Michael J. Evans, Suzette Smiley-jewell, Lisa A. Miller, Edward S. Schelegle, Laurel J. GershwinAbstract:Development of smooth muscle in conducting airways begins early in fetal life. Whereas the pattern and regulation of smooth muscle differentiation are well-defined, the impact of airway growth on the process is not. To evaluate the transformations in organization during postnatal growth, smooth muscle bundle organization (size, abundance, and orientation) was mapped in five generations of distal airways of infant rhesus monkeys (5 days and 1, 2, 3, and 6 mo old). On the basis of direct measurement of the bronchiole proximal to the terminal bronchiole, length increased by 2-fold, diameter by 1.35-fold, and surface area by 2.8-fold between 5 days and 6 mo of age. Smooth muscle bundle size was greater in proximal Bronchioles than in respiratory Bronchioles and did not change with age. However, relative bundle size decreased in proportion to airway size as the airways grew. Relative bundle abundance was constant regardless of airway generation or age. The distribution of smooth muscle bundle orientation changed with age in each airway generation, and there were significant changes in the terminal and respiratory Bronchioles. We conclude that smooth muscle undergoes marked organizational changes as airways grow during postnatal development.
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Smooth muscle development during postnatal growth of distal Bronchioles in infant rhesus monkeys. Commentary
Journal of Applied Physiology, 2004Co-Authors: Mai-uyen T. Tran, Alison J. Weir, Michelle V. Fanucchi, April E. Murphy, Laura S. Van Winkle, Michael J. Evans, Suzette Smiley-jewell, Lisa A. Miller, Edward S. Schelegle, Laurel J. GershwinAbstract:Development of smooth muscle in conducting airways begins early in fetal life. Whereas the pattern and regulation of smooth muscle differentiation are well-defined, the impact of airway growth on the process is not. To evaluate the transformations in organization during postnatal growth, smooth muscle bundle organization (size, abundance, and orientation) was mapped in five generations of distal airways of infant rhesus monkeys (5 days and 1, 2, 3, and 6 mo old). On the basis of direct measurement of the bronchiole proximal to the terminal bronchiole, length increased by 2-fold, diameter by 1.35-fold, and surface area by 2.8-fold between 5 days and 6 mo of age. Smooth muscle bundle size was greater in proximal Bronchioles than in respiratory Bronchioles and did not change with age. However, relative bundle size decreased in proportion to airway size as the airways grew. Relative bundle abundance was constant regardless of airway generation or age. The distribution of smooth muscle bundle orientation changed with age in each airway generation, and there were significant changes in the terminal and respiratory Bronchioles. We conclude that smooth muscle undergoes marked organizational changes as airways grow during postnatal development.
Ulf Simonsen - One of the best experts on this subject based on the ideXlab platform.
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activation of endothelial and epithelial kca2 3 calcium activated potassium channels by ns309 relaxes human small pulmonary arteries and Bronchioles
British Journal of Pharmacology, 2012Co-Authors: Christel Kroigaard, Thomas Dalsgaard, Gorm Nielsen, Britt Elmedal Laursen, Hans K. Pilegaard, Ralf Köhler, Ulf SimonsenAbstract:BACKGROUND AND PURPOSE Small (KCa2) and intermediate (KCa3.1) conductance calcium-activated potassium channels (KCa) may contribute to both epithelium- and endothelium-dependent relaxations, but this has not been established in human pulmonary arteries and Bronchioles. Therefore, we investigated the expression of KCa2.3 and KCa3.1 channels, and hypothesized that activation of these channels would produce relaxation of human Bronchioles and pulmonary arteries. EXPERIMENTAL APPROACH Channel expression and functional studies were conducted in human isolated small pulmonary arteries and Bronchioles. KCa2 and KCa3.1 currents were examined in human small airways epithelial (HSAEpi) cells by whole-cell patch clamp techniques. RESULTS While KCa2.3 expression was similar, KCa3.1 protein was more highly expressed in pulmonary arteries than Bronchioles. Immunoreactive KCa2.3 and KCa3.1 proteins were found in both endothelium and epithelium. KCa currents were present in HSAEpi cells and sensitive to the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34. In pulmonary arteries contracted by U46619 and in Bronchioles contracted by histamine, the KCa2.3/ KCa3.1 activator, NS309, induced concentration-dependent relaxations. NS309 was equally potent in relaxing pulmonary arteries, but less potent in Bronchioles, than salbutamol. NS309 relaxations were blocked by the KCa2 channel blocker apamin, while the KCa3.1 channel blocker, charybdotoxin failed to reduce relaxation to NS309 (0.01–1 µM). CONCLUSIONS AND IMPLICATIONS KCa2.3 and KCa3.1 channels are expressed in the endothelium of human pulmonary arteries and epithelium of Bronchioles. KCa2.3 channels contributed to endo- and epithelium-dependent relaxations suggesting that these channels are potential targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease.
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Activation of endothelial and epithelial KCa2.3 calcium‐activated potassium channels by NS309 relaxes human small pulmonary arteries and Bronchioles
British journal of pharmacology, 2012Co-Authors: Christel Kroigaard, Thomas Dalsgaard, Gorm Nielsen, Britt Elmedal Laursen, Hans K. Pilegaard, Ralf Köhler, Ulf SimonsenAbstract:BACKGROUND AND PURPOSE Small (KCa2) and intermediate (KCa3.1) conductance calcium-activated potassium channels (KCa) may contribute to both epithelium- and endothelium-dependent relaxations, but this has not been established in human pulmonary arteries and Bronchioles. Therefore, we investigated the expression of KCa2.3 and KCa3.1 channels, and hypothesized that activation of these channels would produce relaxation of human Bronchioles and pulmonary arteries. EXPERIMENTAL APPROACH Channel expression and functional studies were conducted in human isolated small pulmonary arteries and Bronchioles. KCa2 and KCa3.1 currents were examined in human small airways epithelial (HSAEpi) cells by whole-cell patch clamp techniques. RESULTS While KCa2.3 expression was similar, KCa3.1 protein was more highly expressed in pulmonary arteries than Bronchioles. Immunoreactive KCa2.3 and KCa3.1 proteins were found in both endothelium and epithelium. KCa currents were present in HSAEpi cells and sensitive to the KCa2.3 blocker UCL1684 and the KCa3.1 blocker TRAM-34. In pulmonary arteries contracted by U46619 and in Bronchioles contracted by histamine, the KCa2.3/ KCa3.1 activator, NS309, induced concentration-dependent relaxations. NS309 was equally potent in relaxing pulmonary arteries, but less potent in Bronchioles, than salbutamol. NS309 relaxations were blocked by the KCa2 channel blocker apamin, while the KCa3.1 channel blocker, charybdotoxin failed to reduce relaxation to NS309 (0.01–1 µM). CONCLUSIONS AND IMPLICATIONS KCa2.3 and KCa3.1 channels are expressed in the endothelium of human pulmonary arteries and epithelium of Bronchioles. KCa2.3 channels contributed to endo- and epithelium-dependent relaxations suggesting that these channels are potential targets for treatment of pulmonary hypertension and chronic obstructive pulmonary disease.
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Mechanisms underlying epithelium-dependent relaxation in rat Bronchioles: analogy to EDHF-type relaxation in rat pulmonary arteries
American journal of physiology. Lung cellular and molecular physiology, 2010Co-Authors: Christel Kroigaard, Thomas Dalsgaard, Ulf SimonsenAbstract:This study investigated the mechanisms underlying epithelium-derived hyperpolarizing factor (EpDHF)-type relaxation in rat Bronchioles. Immunohistochemistry was performed, and rat Bronchioles and p...
Naoya Tanabe - One of the best experts on this subject based on the ideXlab platform.
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analysis of airway pathology in copd using a combination of computed tomography micro computed tomography and histology
European Respiratory Journal, 2018Co-Authors: Stijn E Verleden, Naoya Tanabe, Dragos M Vasilescu, Daisuke Kinose, Miranda Kirby, Harvey O Coxson, Bart M Vanaudenaerde, Yasutaka NakanoAbstract:The small conducting airways are the major site of obstruction in chronic obstructive pulmonary disease (COPD). This study examined small airway pathology using a novel combination of multidetector row computed tomography (MDCT), micro-computed tomography (microCT) and histology. Airway branches visible on specimen MDCT were counted and the dimensions of the third- to fifth-generation airways were computed, while the terminal Bronchioles (designated TB), preterminal Bronchioles (TB-1) and pre-preterminal Bronchioles (TB-2) were examined with microCT and histology in eight explanted lungs with end-stage COPD and seven unused donor lungs that served as controls. On MDCT, COPD lungs showed a decrease in the number of 2–2.5 mm diameter airways and the lumen area of fifth-generation airways, while on microCT there was a reduction in the number of terminal Bronchioles as well as a decrease in the luminal areas, wall volumes and alveolar attachments to the walls of TB, TB-1 and TB-2 Bronchioles. The combination of microCT and histology showed increased B-cell infiltration into the walls of TB-1 and TB-2 Bronchioles, and this change was correlated with a reduced number of alveolar attachments in COPD. Small airways disease extends from 2 mm diameter airways to the terminal Bronchioles in COPD. Destruction of alveolar attachments may be driven by a B-cell-mediated immune response in the preterminal Bronchioles.
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micro computed tomography comparison of preterminal Bronchioles in centrilobular and panlobular emphysema
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: Naoya Tanabe, John E Mcdonough, Dragos M Vasilescu, Daisuke Kinose, Masaru Suzuki, Joel D Cooper, Peter D Pare, James C HoggAbstract:Rationale: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal Bronchioles.Objectives: To examine the structure of preterminal Bronchioles located one generation proximal to terminal Bronchioles in centrilobular and panlobular emphysema.Methods: Preterminal Bronchioles were identified by backtracking from the terminal Bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs.Measurements and Main Results: The preterminal bronchiolar length, w...
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Micro–Computed Tomography Comparison of Preterminal Bronchioles in Centrilobular and Panlobular Emphysema
American journal of respiratory and critical care medicine, 2017Co-Authors: Naoya Tanabe, John E Mcdonough, Dragos M Vasilescu, Daisuke Kinose, Masaru Suzuki, Joel D Cooper, Peter D Pare, James C HoggAbstract:Rationale: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal Bronchioles.Objectives: To examine the structure of preterminal Bronchioles located one generation proximal to terminal Bronchioles in centrilobular and panlobular emphysema.Methods: Preterminal Bronchioles were identified by backtracking from the terminal Bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs.Measurements and Main Results: The preterminal bronchiolar length, w...
James C Hogg - One of the best experts on this subject based on the ideXlab platform.
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micro computed tomography comparison of preterminal Bronchioles in centrilobular and panlobular emphysema
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: Naoya Tanabe, John E Mcdonough, Dragos M Vasilescu, Daisuke Kinose, Masaru Suzuki, Joel D Cooper, Peter D Pare, James C HoggAbstract:Rationale: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal Bronchioles.Objectives: To examine the structure of preterminal Bronchioles located one generation proximal to terminal Bronchioles in centrilobular and panlobular emphysema.Methods: Preterminal Bronchioles were identified by backtracking from the terminal Bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs.Measurements and Main Results: The preterminal bronchiolar length, w...
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Micro–Computed Tomography Comparison of Preterminal Bronchioles in Centrilobular and Panlobular Emphysema
American journal of respiratory and critical care medicine, 2017Co-Authors: Naoya Tanabe, John E Mcdonough, Dragos M Vasilescu, Daisuke Kinose, Masaru Suzuki, Joel D Cooper, Peter D Pare, James C HoggAbstract:Rationale: Very little is known about airways that are too small to be visible on thoracic multidetector computed tomography but larger than the terminal Bronchioles.Objectives: To examine the structure of preterminal Bronchioles located one generation proximal to terminal Bronchioles in centrilobular and panlobular emphysema.Methods: Preterminal Bronchioles were identified by backtracking from the terminal Bronchioles, and their centerlines were established along the entire length of their lumens. Multiple cross-sectional images perpendicular to the centerline were reconstructed to evaluate the bronchiolar wall and lumen, and the alveolar attachments to the outer airway walls in relation to emphysematous destruction in 28 lung samples from six patients with centrilobular emphysema, 20 lung samples from seven patients with panlobular emphysema associated with alpha-1 antitrypsin deficiency, and 47 samples from seven control (donor) lungs.Measurements and Main Results: The preterminal bronchiolar length, w...
