scholarly journals Allergen-induced tRNA halves repress focal adhesion of airway smooth muscle cells

2019 ◽  
Author(s):  
Megumi Shigematsu ◽  
Kamlesh Pawar ◽  
Takuya Kawamura ◽  
Sushrut D. Shah ◽  
Deepak A. Deshpande ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Focal Adhesion ◽  
Protein Modification ◽  
Biological Significance ◽  
Airway Smooth Muscle Cells ◽  
Functional Changes ◽  
Trna Half ◽  
Focal Adhesion Pathway ◽  
Trna Halves

AbstractIn the pathogenesis of asthma, inflammatory mediators cause structural and functional changes in resident airway cells including airway smooth muscle (ASM) cells. Here, we report that intranasal treatment of mice with house dust mite (HDM) highly upregulated the expression of tRNA half molecules in asthmatic lungs. The 5′-tRNA haves contain a 2′,3′-cyclic phosphate (cP) and thus belong to cP-containing RNAs (cP-RNAs). Capturing the whole cP-RNA transcriptome using cP-RNA-seq revealed the global upregulation of not only tRNA halves but also the cP-RNAs derived from mRNAs and rRNAs. Our investigation of the biological significance of the major upregulated 5′-tRNA half species in human primary ASM cells revealed that the 5′-tRNA halves repress autophosphorylation at Tyr416 of Src protein kinase, a key regulator of the cellular focal adhesion pathway, leading to reduction of ASM cellular focal adhesion. These results assign a novel role as a protein modification modulator to tRNA half molecules and unveil a tRNA-engaged pathway in the molecular pathogenesis of asthma.

Chronic oscillatory strain induces MLCK associated rapid recovery from acute stretch in airway smooth muscle cells

2011 ◽  
Vol 111 (4) ◽  
pp. 955-963 ◽  
Author(s):  
Sarah C. Connolly ◽  
Paul G. Smith ◽  
Nigel J. Fairbank ◽  
Carolyn A. Lall ◽  
Darren J. Cole ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Strain Gradient ◽  
Cultured Cells ◽  
Enhanced Recovery ◽  
Single Cells ◽  
Cyclic Stretch ◽  
Airway Smooth Muscle Cells ◽  
Shortening Velocity ◽  
Functional Changes

A deep inspiration (DI) temporarily relaxes agonist-constricted airways in normal subjects, but in asthma airways are refractory and may rapidly renarrow, possibly due to changes in the structure and function of airway smooth muscle (ASM). Chronic largely uniaxial cyclic strain of ASM cells in culture causes several structural and functional changes in ASM similar to that in asthma, including increases in contractility, MLCK content, shortening velocity, and shortening capacity. However, changes in recovery from acute stretch similar to a DI have not been measured. We have therefore measured the response and recovery to large stretches of cells modified by chronic stretching and investigated the role of MLCK. Chronic, 10% uniaxial cyclic stretch, with or without a strain gradient, was administered for up to 11 days to cultured cells grown on Silastic membranes. Single cells were then removed from the membrane and subjected to 1 Hz oscillatory stretches up to 10% of the in situ cell length. These oscillations reduced stiffness by 66% in all groups ( P < 0.05). Chronically strained cells recovered stiffness three times more rapidly than unstrained cells, while the strain gradient had no effect. The stiffness recovery in unstrained cells was completely inhibited by the MLCK inhibitor ML-7, but recovery in strained cells exhibiting increased MLCK was slightly inhibited. These data suggest that chronic strain leads to enhanced recovery from acute stretch, which may be attributable to the strain-induced increases in MLCK. This may also explain in part the more rapid renarrowing of activated airways following DI in asthma.

Transgenic smooth muscle expression of the human CysLT1 receptor induces enhanced responsiveness of murine airways to leukotriene D4

2004 ◽  
Vol 286 (5) ◽  
pp. L992-L1001 ◽  
Author(s):  
Guochang Yang ◽  
Angela Haczku ◽  
Hang Chen ◽  
Viviane Martin ◽  
Helen Galczenski ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Transgenic Mice ◽  
Airway Smooth Muscle ◽  
Ex Vivo ◽  
Allergic Sensitization ◽  
Tracheal Ring ◽  
Airway Smooth Muscle Cells ◽  
Leukotriene D4 ◽  
Functional Changes

Cysteinyl leukotrienes (CysLTs) exert potent proinflammatory actions and contribute to many of the symptoms of asthma. Using a model of allergic sensitization and airway challenge with Aspergillus fumigatus ( Af), we have found that Th2-type inflammation and airway hyperresponsiveness (AHR) to methacholine (MCh) were associated with increased LTD4 responsiveness in mice. To explore the importance of increased CysLT signaling in airway smooth muscle function, we generated transgenic mice that overexpress the human CysLT1 receptor (hCysLT1R) via the α-actin promoter. These receptors were expressed abundantly and induced intracellular calcium mobilization in airway smooth muscle cells from transgenic mice. Force generation in tracheal ring preparations ex vivo and airway reactivity in vivo in response to LTD4 were greatly amplified in hCysLT1R-overexpressing mice, indicating that the enhanced signaling induces coordinated functional changes of the intact airway smooth muscle. The increase of AHR imposed by overexpression of the hCysLT1R was greater in transgenic BALB/c mice than in transgenic B6 × SJL mice. In addition, sensitization- and challenge-induced increases in airway responsiveness were significantly greater in transgenic mice than that of nontransgenic mice compared with their respective nonsensitized controls. The amplified AHR in sensitized transgenic mice was not due to an enhanced airway inflammation and was not associated with similar enhancement in MCh responsiveness. These results indicate that a selective hCysLT1R-induced contractile mechanism synergizes with allergic AHR. We speculate that hCysLT1R signaling contributes to a hypercontractile state of the airway smooth muscle.

A human airway smooth muscle cell line that retains physiological responsiveness

1989 ◽  
Vol 256 (2) ◽  
pp. C329-C335 ◽  
Author(s):  
R. A. Panettieri ◽  
R. K. Murray ◽  
L. R. DePalo ◽  
P. A. Yadvish ◽  
M. I. Kotlikoff
Keyword(s):  
Smooth Muscle ◽  
Cell Line ◽  
Airway Smooth Muscle ◽  
Cytosolic Calcium ◽  
Airway Smooth Muscle Cell ◽  
Airway Smooth Muscle Cells ◽  
Functional Coupling ◽  
Functional Responses ◽  
Human Airway Smooth Muscle ◽  
Human Airway

We report the development of a nontransformed line of human airway smooth muscle cells retaining smooth muscle-specific contractile protein expression and physiological responsiveness to agonists implicated in inflammatory airway diseases. Specific responses to histamine, leukotrienes, bradykinin, platelet-activating factor, substance P, and thromboxane analogues are demonstrated as well as functional coupling to beta-adrenergic receptors. The cell line was characterized using indirect immunofluorescence, as well as electrophoretic separation and immunoblot analysis of smooth muscle-specific actin. Functional responses were assessed by measurements of cytosolic calcium and stimulation of adenosine 3',5'-cyclic monophosphate production. The cells retain their responsiveness over many population doublings and should be a useful model to examine specific receptor-effector mechanisms, as well as the effects of neurohumoral agents on the regulation of airway smooth muscle growth and differentiation.

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