scholarly journals Role of TRPP2 in mouse airway smooth muscle tension and respiration

2019 ◽  
Vol 317 (4) ◽  
pp. L466-L474 ◽  
Author(s):  
Dacheng Sang ◽  
Suwen Bai ◽  
Sheng Yin ◽  
Sen Jiang ◽  
Li Ye ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Transient Receptor Potential ◽  
Muscle Tension ◽  
Pulmonary Arteries ◽  
Conditional Knockout ◽  
Wild Type ◽  
High Potassium ◽  
Cross Sectional ◽  
Significant Difference

The transient receptor potential polycystin-2 (TRPP2) is encoded by the Pkd2 gene, and mutation of this gene can cause autosomal dominant polycystic kidney disease (ADPKD). Some patients with ADPKD experience extrarenal manifestations, including radiologic and clinical bronchiectasis. We hypothesized that TRPP2 may regulate airway smooth muscle (ASM) tension. Thus, we used smooth muscle- Pkd2 conditional knockout ( Pkd2SM-CKO) mice to investigate whether TRPP2 regulated ASM tension and whether TRPP2 deficiency contributed to bronchiectasis associated with ADPKD. Compared with wild-type mice, Pkd2SM-CKO mice breathed more shallowly and faster, and their cross-sectional area ratio of bronchi to accompanying pulmonary arteries was higher, suggesting that TRPP2 may regulate ASM tension and contribute to the occurrence of bronchiectasis in ADPKD. In a bioassay examining isolated tracheal ring tension, no significant difference was found for high-potassium-induced depolarization of the ASM between the two groups, indicating that TRPP2 does not regulate depolarization-induced ASM contraction. By contrast, carbachol-induced contraction of the ASM derived from Pkd2SM-CKO mice was significantly reduced compared with that in wild-type mice. In addition, relaxation of the carbachol-precontracted ASM by isoprenaline, a β-adrenergic receptor agonist that acts through the cAMP/adenylyl cyclase pathway, was also significantly attenuated in Pkd2SM-CKO mice compared with that in wild-type mice. Thus, TRPP2 deficiency suppressed both contraction and relaxation of the ASM. These results provide a potential target for regulating ASM tension and for developing therapeutic alternatives for some ADPKD complications of the respiratory system or for independent respiratory disease, especially bronchiectasis.

scholarly journals Methacholine causes reflex bronchoconstriction

1999 ◽  
Vol 86 (1) ◽  
pp. 294-297 ◽  
Author(s):  
Elizabeth M. Wagner ◽  
David B. Jacoby
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Bronchial Artery ◽  
Muscle Tension ◽  
Reflex Response ◽  
Resistance Change ◽  
Bilateral Vagotomy ◽  
Airways Resistance ◽  
Lower Airways

To determine whether methacholine causes vagally mediated reflex constriction of airway smooth muscle, we administered methacholine to sheep either via the bronchial artery or as an aerosol via tracheostomy into the lower airways. We then measured the contraction of an isolated, in situ segment of trachealis smooth muscle and determined the effect of vagotomy on the trachealis response. Administering methacholine to the subcarinal airways via the bronchial artery (0.5–10.0 μg/ml) caused dose-dependent bronchoconstriction and contraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased an average of 186% over baseline. Aerosolized methacholine (5–7 breaths of 100 mg/ml) increased trachealis tension by 58% and airways resistance by 183%. As the bronchial circulation in the sheep does not supply the trachea, we postulated that the trachealis contraction was caused by a reflex response to methacholine in the lower airways. Bilateral vagotomy essentially eliminated the trachealis response and the airways resistance change after lower airways challenge (either via the bronchial artery or via aerosol) with methacholine. We conclude that 1) methacholine causes a substantial reflex contraction of airway smooth muscle and 2) the assumption may not be valid that a response to methacholine in humans or experimental animals represents solely the direct effect on smooth muscle.

scholarly journals MiR-365-3p is Involved in IL17-Mediated Asthma in Mouse Model

2020 ◽  
Author(s):  
Weijia Wang ◽  
Ying Li ◽  
Xiaoyan Qu ◽  
Dong Shang ◽  
Qiaohong Qin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Target Gene ◽  
Alveolar Epithelial Cells ◽  
Mouse Lung ◽  
Collagen Deposition ◽  
Wild Type ◽  
Sterile Saline ◽  
The Relationship

Abstract BACKGROUND The IL-17 superfamily, which mediates cross-talk between the adaptive and innate immune systems, has been associated with severity of asthma. The role of miRNAs in the disease has been paid much attention. To explore the roles of IL-17 in asthma and the relationship between IL-17 and miRNAs, we used a model of severe asthma driven by chronic respiratory exposure to house dust mite (HDM) exposure in wild type and IL-17KO mice, followed with miRNA profiling assays and analysis.METHODS Male and female C57BL/6 mice (6-8 weeks old) and IL-17KO mice (C57BL/6 background) were exposed to purified HDM extract intranasally for 5 days/week for 5 consecutive weeks. Sterile saline was used as the control. The parameters including airway responsiveness, inflammatory cells in bronchoalveolar lavage fluid (BALF), airway smooth muscle bundle, collagen deposition, and cytokine levels in BALF were examined. The miRNA profile of mouse lung tissue was analyzed by microarray assays. The dysregulation of miRNA related to IL-17 and asthma was validated by qRT-PCR. The in vitro cell culture experiment was performed to confirm the relationship between IL-17 and selected miRNA. The regulation of miRNA on predicted target gene was validated by administration of miRNA mimics. RESULTS The expression of IL-17A significantly increased in wild type (WT) mice with HDM exposure compared to the control mice. IL-17 deficiency did not reduce airway hyper responsiveness (AHR) induced by HDM exposure. In comparison to HDM-exposed WT mice, BALF neutrophils in IL-17KO mice were significantly decreased. In WT mice, HDM exposure led to increased expression of IL-4 and KC, which was significantly decreased in IL-17KO mice. Furthermore, under HDM exposure, significantly less airway smooth muscle mass and collagen deposition was found in IL-17KO mice compared to WT mice. In the dysregulated miRNAs, the decreased expression of miR-365-3p in HDM-exposed WT mice was validated, and its expression recovered in IL-17KO mice. Furthermore, miR-365-3p was decreased in mouse alveolar epithelial cells by IL-17 treatment. The transfection of miR-365-3p mimics decreased the expression of predicted target gene ARRB2.

Relevance of classification by size to topographical differences in bronchial smooth muscle response

1993 ◽  
Vol 75 (5) ◽  
pp. 2013-2021 ◽  
Author(s):  
P. Chitano ◽  
S. B. Sigurdsson ◽  
A. J. Halayko ◽  
N. L. Stephens
Keyword(s):  
Smooth Muscle ◽  
Electrical Field Stimulation ◽  
Cross Sectional Area ◽  
Sectional Area ◽  
Cross Sectional ◽  
Muscle Response ◽  
Bronchial Responsiveness ◽  
Sixth Generation ◽  
Significant Difference ◽  
And Control

To investigate heterogeneity of airway smooth muscle response, we studied strips of large and small branches from third- to sixth-generation bronchi obtained from ragweed antigen-sensitized and control dogs. The response to electrical field stimulation and carbamylcholine chloride was greater in strips from larger branches of the same generation when expressed as "tissue stress" (force per unit cross-sectional area of the whole tissue), whereas no difference emerged with use of the more appropriate "smooth muscle stress" (force per unit cross-sectional area of the muscle tissue). The response to histamine was significantly higher in small branches than in large ones, and histamine sensitivity [mean effective concentration (EC50)] was 7.79 x 10(-6) [geometric standard error of the mean (GSEM) 1.20] and 1.49 x 10(-5) M (GSEM 1.14), respectively (P < 0.01). Strips from control and sensitized animals at each site and strips from different generations did not show any significant difference. When we clustered our preparations according to dimensions, the response to histamine was significantly higher in small bronchi than in large ones and histamine EC50 was 8.95 x 10(-6) (GSEM 1.17) and 1.57 x 10(-5) M (GSEM 1.18), respectively (P < 0.05). We conclude that evaluation of muscle response in different tissues requires appropriate normalization. Furthermore, classification into generations is inadequate to study bronchial responsiveness, inasmuch as major differences originate from airway size.

Maturation of respiratory reflex responses in the piglet

1991 ◽  
Vol 70 (2) ◽  
pp. 608-616 ◽  
Author(s):  
B. Haxhiu-Poskurica ◽  
W. A. Carlo ◽  
M. J. Miller ◽  
J. M. DiFiore ◽  
M. A. Haxhiu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Phrenic Nerve ◽  
Muscle Tone ◽  
Muscle Tension ◽  
Age Groups ◽  
Force Transducer ◽  
Reflex Responses ◽  
C Fiber ◽  
Lung Deflation

Stimulation of chemo-, irritant, and pulmonary C-fiber receptors reflexly constricts airway smooth muscle and alters ventilation in mature animals. These reflex responses of airway smooth muscle have, however, not been clearly characterized during early development. In this study we compared the maturation of reflex pathways regulating airway smooth muscle tone and ventilation in anesthetized, paralyzed, and artificially ventilated 2- to 3- and 10-wk-old piglets. Tracheal smooth muscle tension was measured from an open tracheal segment by use of a force transducer, and phrenic nerve activity was measured from a proximal cut end of the phrenic nerve. Inhalation of 7% CO2 caused a transient increase in tracheal tension in both age groups, whereas hypoxia caused no airway smooth muscle response in either group. The phrenic responses to 7% CO2 and 12% O2 were comparable in both age groups. Lung deflation and capsaicin (20 micrograms/kg iv) administration did not alter tracheal tension in the younger piglets but caused tracheal tension to increase by 87 +/- 28 and 31 +/- 10%, respectively, in the older animals (both P less than 0.05). In contrast, phrenic response to both stimuli was comparable between ages: deflation increased phrenic activity while capsaicin induced neural apnea. Laryngeal stimulation did not increase tracheal tension but induced neural apnea in both age groups. These data demonstrate that between 2 and 10 wk of life, piglets exhibit developmental changes in the reflex responses of airway smooth muscle situated in the larger airways in response to irritant and C-fiber but not chemoreceptor stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Nicotine-induced respiratory effects of cigarette smoke in dogs

1985 ◽  
Vol 59 (1) ◽  
pp. 64-71 ◽  
Author(s):  
J. J. Hartiala ◽  
C. Mapp ◽  
R. A. Mitchell ◽  
W. M. Gold
Keyword(s):  
Smooth Muscle ◽  
Cigarette Smoke ◽  
Airway Smooth Muscle ◽  
Direct Effect ◽  
Muscle Tone ◽  
Muscle Tension ◽  
Respiratory Center ◽  
Parasympathetic Ganglia ◽  
Arterial Blood ◽  
Nicotine Receptors

We report that nicotine is responsible for both a blood-borne stimulation of the respiratory center and a direct effect on intrathoracic airway tone in dogs. We introduced cigarette smoke into the lungs of donor dogs and injected arterial blood obtained from them into the circulation of recipient dogs to show that a blood-borne material increased breathing and airway smooth muscle tone. Smoke from cigarettes containing 2.64 mg of nicotine was effective; that from cigarettes containing 0.42 mg of nicotine was not. Nicotine, in doses comparable to the amounts absorbed from smoke, also increased breathing and tracheal smooth muscle tension when injected into the vertebral circulation of recipient dogs. Finally, blockade of nicotine receptors in the central nervous system and in the airway parasympathetic ganglia inhibited the effects of inhaled cigarette smoke and intravenous nicotine on the respiratory center and on bronchomotor tone. We conclude that nicotine absorbed from cigarette smoke is the main cause of cigarette smoke-induced bronchoconstriction. It caused central respiratory stimulation, resulting in increased breathing and airway smooth muscle tension, and had a direct effect on airway parasympathetic ganglia as well.

Thromboxane A2 induces airway constriction through an M3 muscarinic acetylcholine receptor-dependent mechanism

2006 ◽  
Vol 290 (3) ◽  
pp. L526-L533 ◽  
Author(s):  
Irving C. Allen ◽  
John M. Hartney ◽  
Thomas M. Coffman ◽  
Raymond B. Penn ◽  
Jürgen Wess ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Acetylcholine Receptor ◽  
Airway Smooth Muscle ◽  
Muscle Tension ◽  
Muscarinic Acetylcholine Receptor ◽  
Airway Smooth Muscle Cells ◽  
Muscarinic Acetylcholine ◽  
Airway Constriction ◽  
Organ Systems ◽  
Lung Resistance

Thromboxane A2 (TXA2) is a potent lipid mediator released by platelets and inflammatory cells and is capable of inducing vasoconstriction and bronchoconstriction. In the airways, it has been postulated that TXA2 causes airway constriction by direct activation of thromboxane prostanoid (TP) receptors on airway smooth muscle cells. Here we demonstrate that although TXA2 can mediate a dramatic increase in airway smooth muscle constriction and lung resistance, this response is largely dependent on vagal innervation of the airways and is highly sensitive to muscarinic acetylcholine receptor (mAChR) antagonists. Further analyses employing pharmacological and genetic strategies demonstrate that TP-dependent changes in lung resistance and airway smooth muscle tension require expression of the M3 mAChR subtype. These results raise the possibility that some of the beneficial actions of anticholinergic agents used in the treatment of asthma and chronic obstructive pulmonary disease result from limiting physiological changes mediated through the TP receptor. Furthermore, these findings demonstrate a unique pathway for TP regulation of homeostatic mechanisms in the airway and suggest a paradigm for the role of TXA2 in other organ systems.

Reduced peribronchial fibrosis in allergen-challenged MMP-9-deficient mice

2006 ◽  
Vol 291 (2) ◽  
pp. L265-L271 ◽  
Author(s):  
Dae Hyun Lim ◽  
Jae Youn Cho ◽  
Marina Miller ◽  
Kirsti McElwain ◽  
Shauna McElwain ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Remodeling ◽  
Muscle Thickness ◽  
Muscle Layer ◽  
Airway Responsiveness ◽  
Wild Type ◽  
Extracellular Proteases ◽  
Significant Difference ◽  
Deficient Mice ◽  
Modest Reduction

Matrix metalloproteinases (MMPs) are a family of extracellular proteases that are responsible for the degradation of the extracellular matrix during tissue remodeling. We have used a mouse model of allergen-induced airway remodeling to determine whether MMP-9 plays a role in airway remodeling. MMP-9-deficient and wild-type (WT) mice were repetitively challenged intranasally with ovalbumin (OVA) antigen to develop features of airway remodeling including peribronchial fibrosis and increased thickness of the peribronchial smooth muscle layer. OVA-challenged MMP-9-deficient mice had less peribronchial fibrosis and total lung collagen compared with OVA-challenged WT mice. There was no reduction in mucus expression, smooth muscle thickness, or airway responsiveness in OVA-challenged MMP-9-deficient compared with OVA-challenged WT mice. OVA-challenged MMP-9-deficient mice had reduced levels of bronchoalveolar lavage (BAL) regulated on activation, normal T cell expressed, and secreted (RANTES), as well as reduced numbers of BAL and peribronchial eosinophils compared with OVA-challenged WT mice. There were no significant difference in levels of BAL eotaxin, thymus- and activation-regulated chemokine (TARC), or macrophage-derived chemokine (MDC) in OVA-challenged WT compared with MMP-9-deficient mice. Overall, this study demonstrates that MMP-9 may play a role in mediating selected aspects of allergen-induced airway remodeling (i.e., modest reduction in levels of peribronchial fibrosis) but does not play a significant role in mucus expression, smooth muscle thickness, or airway responsiveness.

scholarly journals Specific detection of the endogenous transient receptor potential (TRP)-1 protein in liver and airway smooth muscle cells using immunoprecipitation and Western-blot analysis

2002 ◽  
Vol 364 (3) ◽  
pp. 641-648 ◽  
Author(s):  
Hwei Ling ONG ◽  
Jinglong CHEN ◽  
Tim CHATAWAY ◽  
Helen BRERETON ◽  
Lei ZHANG ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Guinea Pig ◽  
Western Blot ◽  
Airway Smooth Muscle ◽  
Blot Analysis ◽  
Western Blot Analysis ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Airway Smooth Muscle Cells ◽  
Transient Receptor

Although there are numerous reports of the presence of mRNA encoding the transient receptor potential (TRP)-1 protein in animal cells and of the detection of the heterologously expressed TRP-1 protein by Western-blot analysis, it has proved difficult to unequivocally detect endogenous TRP-1 proteins. A combination of immunoprecipitation and Western-blot techniques, employing a polyclonal antibody and a monoclonal antibody respectively, was developed. Using this technique, a band of approx. 80kDa was detected in extracts of H4-IIE rat liver hepatoma cell line and guinea-pig airway smooth muscle (ASM) cells transfected with human TRPC-1 cDNA. In extracts of untransfected H4-IIE cells, ASM cells, rat brain and guinea-pig brain, a band of approx. 92kDa was detected. Reverse transcriptase PCR experiments detected cDNA encoding both the α- and β-isoforms of TRP-1 in H4-IIE cells. Treatment of protein extracts with peptide N-glycosidase F indicated that the 92kDa band represents an N-glycosylated protein. Western blots conducted with a commercial polyclonal anti-(TRP-1) antibody (Alm) detected a band of 120kDa in extracts of H4-IIE cells and guinea-pig ASM cells. A combination of immunoprecipitation and Western-blotting techniques with the Alm antibody did not detect any bands at 92kDa or 120kDa in extracts of H4-IIE and ASM cells. It is concluded that (a) the 92-kDa band detected in untransfected H4-IIE and ASM cells corresponds to the N-glycosylated β-isoform of endogenous TRP-1, (b) the combined immunoprecipitation and Western-blot approach, employing two different antibodies, provides a reliable and specific procedure for detecting endogenous TRP-1 proteins, and (c) that caution is required in developing and utilizing anti-(TRP-1) antibodies.

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