Airway wall remodeling: friend or foe?

Airway wall remodeling is well documented for asthmatic airways and is believed to result from chronic and/or short-term exposure to inflammatory stimuli. Airway wall remodeling can contribute to airway narrowing as well as to the airway hyperresponsiveness, which is a characteristic abnormality in asthma. However, the potential for airway narrowing could be much worse if it were not for some of the protective effects of remodeling that may help to limit airway narrowing in asthmatic patients. This minireview discusses the evidence for airway wall remodeling and its effects, friend and/or foe, on airway narrowing in asthmatic patients.

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Decreased airway narrowing and smooth muscle contraction in hyperresponsive pigs

Journal of Applied Physiology ◽

10.1152/japplphysiol.00150.2002 ◽

2002 ◽

Vol 93 (4) ◽

pp. 1296-1300 ◽

Cited By ~ 12

Author(s):

Debra J. Turner ◽

Peter B. Noble ◽

Matthew P. Lucas ◽

Howard W. Mitchell

Keyword(s):

Smooth Muscle ◽

Airway Hyperresponsiveness ◽

Porcine Model ◽

Smooth Muscle Contraction ◽

Airway Wall ◽

Muscle Contractility ◽

Smooth Muscle Contractility ◽

Airway Narrowing

Increased smooth muscle contractility or reduced smooth muscle mechanical loads could account for the excessive airway narrowing and hyperresponsiveness seen in asthma. These mechanisms were investigated by using an allergen-induced porcine model of airway hyperresponsiveness. Airway narrowing to electric field stimulation was measured in isolated bronchial segments, over a range of transmural pressures (0–20 cmH2O). Contractile responses to ACh were measured in bronchial segments and in isolated tracheal smooth muscle strips isolated from control and test (ovalbumin sensitized and challenged) pigs. Test airways narrowed less than controls ( P < 0.0001). Test pigs showed reduced contractility to ACh, both in isolated bronchi ( P < 0.01) and smooth muscle strips ( P < 0.01). Thus isolated airways from pigs exhibiting airway hyperresponsiveness in vivo are hyporesponsive in vitro. The decreased narrowing in bronchi from hyperresponsive pigs may be related to decreased smooth muscle contractility. These data suggest that mechanisms external to the airway wall may be important to the hyperresponsive nature of sensitized lungs.

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Structural basis for exaggerated airway narrowingThis article is one of a selection of papers published in the Special Issue on Recent Advances in Asthma Research.

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y07-051 ◽

2007 ◽

Vol 85 (7) ◽

pp. 653-658 ◽

Cited By ~ 23

Author(s):

Peter D. Paré ◽

Brent E. McParland ◽

Chun Y. Seow

Keyword(s):

Airway Hyperresponsiveness ◽

Structural Changes ◽

Airway Remodeling ◽

Structural Basis ◽

Airway Wall ◽

Special Issue ◽

Airway Narrowing ◽

Quantitative Changes ◽

Or Organization ◽

Selection Of

Airway hyperresponsiveness, particularly the ability of airways to narrow excessively in response to stimuli that normally cause little airway narrowing in nonasthmatic subjects, is a characteristic feature of asthma and the basis of its symptoms. Although airway hyperresponsiveness may be partly the result of alterations in the contractile phenotype of the airway smooth muscle, there is evidence that it may also be caused by structural changes in the airway wall, collectively termed airway remodeling. Airway remodeling is defined as changes in composition, quantity, and (or) organization of cellular and molecular constituents of the airway wall. Airway wall remodeling that occurs in asthma can result in functional alterations because of quantitative changes in airway wall compartments, and (or) because of changes in the biochemical composition or material properties of the various constituents of the airway wall. This brief review summarizes the quantitative changes in the dimensions and organization of the airway wall compartments that have been described and explains how structural alterations may lead to the exaggerated airway narrowing.

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Short-Term Observation on the Change of Lower Airway Inflammation and Airway Hyperresponsiveness in Non Asthmatic Patients With Allergic Rhinitis

CHEST Journal ◽

10.1016/j.chest.2016.02.010 ◽

2016 ◽

Vol 149 (4) ◽

pp. A8

Author(s):

Baojuan Liu ◽

Yanqing Xie ◽

KeFang Lai ◽

Wei Luo

Keyword(s):

Allergic Rhinitis ◽

Airway Inflammation ◽

Airway Hyperresponsiveness ◽

Lower Airway ◽

Short Term ◽

Asthmatic Patients

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Abstract T5: Molecular Mechanisms Involved In The Vascular Protective Effects Of Mas1 And Et B R Interaction

Hypertension ◽

10.1161/hyp.78.suppl_1.t5 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Jithin Kuriakose ◽

Augusto C Montezano ◽

Rheure Lopes ◽

Angie YY Sin ◽

Delyth Graham ◽

...

Keyword(s):

High Throughput Screening ◽

Molecular Mechanisms ◽

Protective Effects ◽

Vascular Protection ◽

Functional Responses ◽

Short Term ◽

Akt Phosphorylation ◽

Short Term Exposure ◽

New Strategy

We demonstrated that Mas1 and ET B R physically interact in endothelial cells inducing Ang-(1-7) vascular protection. Using high throughput screening of >20,000 druggable compounds, we identified a number of molecules that enhance Mas1:ET B R interactions. Of these, 2 potently enhanced interaction between the receptors. These enhancers (Enh), termed Enh3 and Enh4 were used to assess Mas1:ET B R interaction and cellular functional responses in vascular smooth muscle cells (VSMCs) from normotensive WKY and hypertensive SHRSP rats. Cells were exposed to Enh 3 and Enh4 (10 -5 M) for short (5,15 and 30min) and long timepoints (5hours). Expression of signaling molecules was assessed by immunoblotting and Ca 2+ influx was evaluated using fluorescence microscopy. In WKY VSMCs, Enh 3 short term stimulation reduced basal ERK1/2 phosphorylation (26.8±5.9% vs veh, p<0.01), an effect absent in SHRSP VSMCs, while Enh 4 had no effect. Short term exposure to Enh 4, but not Enh3, reduced basal MLC20 phosphorylation (54.9±7.5% vs veh, p<0.001) in WKY but not in SHRSP VSMCs. In SHRSP VSMCs, Enh 3, but not Enh4, reduced basal AKT phosphorylation (63.5±8.9% vs veh, p<0.001). Long term stimulation with Enh 3 reduced expression of AKT (38.0±2.0% vs veh, p<0.001), PCNA (60.0±7.0% vs veh, p<0.001), and VCAM-1 (35.0±8.0% vs veh, p<0.001) in WKY VSMCs. Similarly, AKT (35.0±12.0% vs veh, p<0.05) expression was reduced by Enh 3, with no effect on other markers in SHRSP VSMCs. Enh 4 long-term stimulation reduced AKT expression (30.0±10.0% vs veh, p<0.05) in WKY VSMCs, without effect on SHRSP VSMCs. ET-1 induced Ca 2+ influx in WKY and SHRSP VSMCs was unaffected by Enh3 and Enh4. In conclusion, enhancing Mas1:ET B R interaction attenuates mitogenic and pro-inflammatory signaling pathways in WKY and SHRSP VSMCs. Enhancing interaction between these receptors does not increase Ca 2+ signaling, important in VSMC contraction. Our data suggest that Enh3 and Enh4 may have VSMC protective effects and that they do not amplify injurious signaling induced by ET-1/ETBR. These findings identify a potential new strategy in vasoprotection.

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Homeokinesis and short-term variability of human airway caliber

Journal of Applied Physiology ◽

10.1152/jappl.2001.91.3.1131 ◽

2001 ◽

Vol 91 (3) ◽

pp. 1131-1141 ◽

Cited By ~ 86

Author(s):

Cheng-Li Que ◽

C. M. Kenyon ◽

R. Olivenstein ◽

Peter T. Macklem ◽

Geoffrey N. Maksym

Keyword(s):

Supine Position ◽

Normal Subjects ◽

Forced Oscillations ◽

Short Term ◽

Frequency Distributions ◽

Airway Narrowing ◽

Asthmatic Patients ◽

Airway Caliber ◽

Normal Frequency ◽

Log Normal

We hypothesized that short-term variation in airway caliber could be quantified by frequency distributions of respiratory impedance (Zrs) measured at high frequency. We measured Zrs at 6 Hz by forced oscillations during quiet breathing for 15 min in 10 seated asthmatic patients and 6 normal subjects in upright and supine positions before and after methacholine (MCh). We plotted frequency distributions of Zrs and calculated means, skewness, kurtosis, and significance of differences between normal and log-normal frequency distributions. The data were close to, but usually significantly different from, a log-normal frequency distribution. Mean lnZrs in upright and supine positions was significantly less in normal subjects than in asthmatic patients, but not after MCh and MCh in the supine position. The lnZrs SD (a measure of variation), in the upright position and after MCh was significantly less in normal subjects than in asthmatic patients, but not in normal subjects in the supine position and after MCh in the supine position. We conclude that 1) the configuration of the normal tracheobronchial tree is continuously changing and that this change is exaggerated in asthma, 2) in normal lungs, control of airway caliber is homeokinetic, maintaining variation within acceptable limits, 3) normal airway smooth muscle (ASM) when activated and unloaded closely mimics asthmatic ASM, 4) in asthma, generalized airway narrowing results primarily from ASM activation, whereas ASM unloading by increasing shortening velocity allows faster caliber fluctuations, 5) activation moves ASM farther from thermodynamic equilibrium, and 6) asthma may be a low-entropy disease exhibiting not only generalized airway narrowing but also an increased appearance of statistically unlikely airway configurations.

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Seasonal differences in airway hyperresponsiveness in asthmatic patients: relationship with allergen exposure and sensitization to house dust mites

Clinical & Experimental Allergy ◽

10.1046/j.1365-2222.1997.d01-554.x ◽

1997 ◽

Vol 27 (6) ◽

pp. 627-633 ◽

Cited By ~ 26

Author(s):

S. VAN DER HEIDE ◽

J. G. R. DE MONCHY ◽

K. DE VRIES ◽

A. E. J. DUBOIS ◽

H. F. KAUFFMAN

Keyword(s):

House Dust ◽

Airway Hyperresponsiveness ◽

Allergen Exposure ◽

House Dust Mites ◽

Dust Mites ◽

Seasonal Differences ◽

Asthmatic Patients

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The Effect of Dimethyl Sulfoxide on In Vitro Platelet Function

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648027 ◽

1976 ◽

Vol 36 (01) ◽

pp. 221-229 ◽

Cited By ~ 16

Author(s):

Charles A. Schiffer ◽

Caroline L. Whitaker ◽

Morton Schmukler ◽

Joseph Aisner ◽

Steven L. Hilbert

Keyword(s):

Platelet Count ◽

Platelet Aggregation ◽

Dimethyl Sulfoxide ◽

Platelet Function ◽

Platelet Volume ◽

Short Term ◽

Platelet Factor ◽

Short Term Exposure ◽

Structural Abnormalities

SummaryAlthough dimethyl sulfoxide (DMSO) has been used extensively as a cryopreservative for platelets there are few studies dealing with the effect of DMSO on platelet function. Using techniques similar to those employed in platelet cryopreservation platelets were incubated with final concentrations of 2-10% DMSO at 25° C. After exposure to 5 and 10% DMSO platelets remained discoid and electron micrographs revealed no structural abnormalities. There was no significant change in platelet count. In terms of injury to platelet membranes, there was no increased availability of platelet factor-3 or leakage of nucleotides, 5 hydroxytryptamine (5HT) or glycosidases with final DMSO concentrations of 2.5, 5 and 10% DMSO. Thrombin stimulated nucleotide and 5HT release was reduced by 10% DMSO. Impairment of thrombin induced glycosidase release was noted at lower DMSO concentrations and was dose related. Similarly, aggregation to ADP was progressively impaired at DMSO concentrations from 1-5% and was dose related. After the platelets exposed to DMSO were washed, however, aggregation and release returned to control values. Platelet aggregation by epinephrine was also inhibited by DMSO and this could not be corrected by washing the platelets. DMSO-plasma solutions are hypertonic but only minimal increases in platelet volume (at 10% DMSO) could be detected. Shrinkage of platelets was seen with hypertonic solutions of sodium chloride or sucrose suggesting that the rapid transmembrane passage of DMSO prevented significant shifts of water. These studies demonstrate that there are minimal irreversible alterations in in vitro platelet function after short-term exposure to DMSO.

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