Does airway smooth muscle express an inflammatory phenotype in asthma?

Mechanical tension and humoral stimuli can induce transitions in airway smooth muscle phenotype between a synthetic inflammatory state that promotes cytokine secretion and a differentiated state that promotes the expression of smooth muscle phenotype-specific proteins. When tissues are maintained under high tension, Akt activation and eotaxin secretion are suppressed, but expression of the differentiation marker protein, smooth muscle myosin heavy chain (SmMHC), is promoted. When tissues are maintained under low tension, Akt activation and eotaxin secretion are stimulated, and the differentiated phenotype is suppressed. We hypothesized that mechanical stimuli are differentially transduced to Akt-mediated signaling pathways that regulate phenotype expression by α-parvin and β-parvin integrin-linked kinase/PINCH/parvin (IPP) signaling complexes within integrin adhesomes. High tension or ACh triggered paxillin phosphorylation and the binding of phospho-paxillin to β-parvin IPP complexes. This inhibited Akt activation and promoted SmMHC expression. Low tension or IL-4 did not elicit paxillin phosphorylation and triggered the binding of unphosphorylated paxillin to α-parvin IPP complexes, which promoted Akt activation and eotaxin secretion and suppressed SmMHC expression. Expression of a nonphosphorylatable paxillin mutant or β-parvin depletion by siRNA promoted the inflammatory phenotype, whereas the depletion of α-parvin promoted the differentiated phenotype. Results demonstrate that phenotype expression is regulated by the differential interaction of phosphorylated and unphosphorylated paxillin with α-parvin and β-parvin IPP complexes and that these complexes have opposite effects on the activation of Akt. Our results describe a novel molecular mechanism for transduction of mechanical and humoral stimuli within integrin signaling complexes to regulate phenotype expression in airway smooth muscle.

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Allergen inhalation generates pro-inflammatory oxidised phosphatidylcholine associated with airway dysfunction

European Respiratory Journal ◽

10.1183/13993003.00839-2020 ◽

2020 ◽

pp. 2000839 ◽

Cited By ~ 1

Author(s):

Christopher D. Pascoe ◽

Aruni Jha ◽

Min Hyung Ryu ◽

Mirna Ragheb ◽

Jignesh Vaghasiya ◽

...

Keyword(s):

Oxidative Stress ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

High Performance ◽

Allergen Challenge ◽

Airway Narrowing ◽

Gm Csf ◽

Liquid Chromatography Tandem Mass ◽

Inflammatory Phenotype ◽

Novel Target

RationaleOxidised phosphatidylcholines (OxPC) are produced under conditions of elevated oxidative stress and can contribute to human disease pathobiology. However, their role in allergic asthma is unexplored.ObjectivesCharacterise the OxPC profile in the airways after allergen challenge of people with airway hyperresponsiveness (AHR) or mild-asthma. Determine the capacity of OxPC to contribute to pathobiology associated with asthma.MethodsUsing bronchoalveolar lavage (BAL) from two human cohorts, OxPC species were quantified using ultra high performance liquid chromatography tandem mass spectrometry. Murine thin cut lung slices (TCLS) were used to measure airway narrowing caused by OxPCs. Human airway smooth muscle (HASM) cells were exposed to OxPCs to assess concentration-associated changes in inflammatory phenotype and activation of signalling networks.Measurements and Main ResultsOxPC profiles were different in the airways of people with or without AHR and correlated with methacholine responsiveness. Exposure of mild-asthmatics to allergens produced unique OxPC signatures that were associated with the late asthma response severity. OxPCs dose-dependently induced 15% airway narrowing in murine TCLS. In HASM, OxPCs dose-dependently increased the biosynthesis of cyclooxygenase-2, IL-6, IL-8, GM-CSF, and the production of oxylipins via protein kinase C-dependent pathways.ConclusionsData from human cohorts and primary HASM culture we show that OxPCs are present in the airways, increase after allergen challenge, and correlate with metrics of a dysfunction. Furthermore, OxPCs may contribute to asthma pathobiology by promoting airway narrowing and inducing a pro-inflammatory phenotype and contraction of airway smooth muscle. OxPCs represent a potential novel target for treating oxidative stress-associated pathobiology in asthma.

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Monocyte-derived fibrocytes induce an inflammatory phenotype in airway smooth muscle cells

Clinical & Experimental Allergy ◽

10.1111/cea.12421 ◽

2014 ◽

Vol 44 (11) ◽

pp. 1347-1360 ◽

Cited By ~ 10

Author(s):

T.-Y. Lin ◽

N. Venkatesan ◽

M. Nishioka ◽

S. Kyoh ◽

L. Al-Alwan ◽

...

Keyword(s):

Smooth Muscle ◽

Smooth Muscle Cells ◽

Airway Smooth Muscle ◽

Muscle Cells ◽

Airway Smooth Muscle Cells ◽

Inflammatory Phenotype

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Elastase alters contractility and promotes an inflammatory synthetic phenotype in airway smooth muscle tissues

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00334.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. L626-L634 ◽

Cited By ~ 7

Author(s):

Angelia D. Lockett ◽

Yidi Wu ◽

Susan J. Gunst

Keyword(s):

Extracellular Matrix ◽

Smooth Muscle ◽

Airway Smooth Muscle ◽

Inflammatory Cells ◽

Contractile Force ◽

Airway Hyperreactivity ◽

Inflammatory Phenotype ◽

Increased Sensitivity

Neutrophil elastase is secreted by inflammatory cells during airway inflammation and can elicit airway hyperreactivity in vivo. Elastase can degrade multiple components of the extracellular matrix. We hypothesized that elastase might disrupt the connections between airway smooth muscle (ASM) cells and the extracellular matrix and that this might have direct effects on ASM tissue responsiveness and inflammation. The effect of elastase treatment on ASM contractility was assessed in vitro in isolated strips of canine tracheal smooth muscle by stimulation of tissues with cumulatively increasing concentrations of acetylcholine (ACh) and measurement of contractile force. Elastase treatment potentiated contractile responses to ACh at low concentrations but suppressed the maximal contractile force generated by the tissues without affecting the phosphorylation of myosin regulatory light chain (RLC). Elastase also promoted the secretion of eotaxin and the activation of Akt in ASM tissues and decreased expression of smooth muscle myosin heavy chain, consistent with promotion of a synthetic inflammatory phenotype. As the degradation of matrix proteins can alter integrin engagement, we evaluated the effect of elastase on the assembly and activation of integrin-associated adhesion junction complexes in ASM tissues. Elastase led to talin cleavage, reduced talin binding to vinculin, and suppressed activation of the adhesome proteins paxillin, focal adhesion kinase, and vinculin, indicating that elastase causes the disassembly of adhesion junction complexes and the inactivation of adhesome signaling proteins. We conclude that elastase promotes an inflammatory phenotype and increased sensitivity to ACh in ASM tissues by disrupting signaling pathways mediated by integrin-associated adhesion complexes.

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