Histamine stimulates proliferation of airway smooth muscle and induces c-fos expression

1990 ◽  
Vol 259 (6) ◽  
pp. L365-L371 ◽  
Author(s):  
R. A. Panettieri ◽  
P. A. Yadvish ◽  
A. M. Kelly ◽  
N. A. Rubinstein ◽  
M. I. Kotlikoff
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Protein Expression ◽  
Myosin Heavy Chain ◽  
Airway Smooth Muscle ◽  
Heavy Chain ◽  
Thymidine Incorporation ◽  
Dependent Manner ◽  
Altered Expression ◽  
Mrna Induction

Although chronic severe asthma is characterized by increased smooth muscle mass in the airways, the physiological stimuli that promote airway smooth muscle (ASM) proliferation (hyperplasia) or increase ASM protein expression (hypertrophy) are unknown. We examined the effects of histamine, an autocoid associated with airway hyperresponsiveness, on protein synthesis, myosin heavy chain expression, and cell proliferation in cultured canine ASM cells. In confluent ASM cells, histamine significantly increased incorporation of [35S]-methionine in protein. Maintenance of the proportion of smooth muscle-specific myosin heavy chain to total myosin heavy chain suggested a nonspecific increase in contractile protein expression. DNA synthesis, as measured by [3H]thymidine incorporation, was significantly increased by histamine in a concentration-dependent manner. Cell proliferation paralleled [3H]thymidine incorporation; histamine significantly increased cell numbers at 24 and 48 h of stimulation. Because growth of mesenchymal-derived cells is associated with transcription of c-fos mRNA, we examined whether histamine altered expression of this proto-oncogene. Histamine-treated cells showed marked increases in expressions of steady-state c-fos mRNA, with a time course of mRNA induction similar to cells exposed to platelet-derived growth factor or serum, known smooth muscle and fibroblast cell mitogens. Therefore, histamine is an ASM mitogen with an action similar to other mesenchymal cell growth factors and may play a role in the hyperplasia of ASM in asthma.

scholarly journals Cytokines and Growth Factors Promote Airway Smooth Muscle Cell Proliferation

2012 ◽  
Vol 2012 ◽  
pp. 1-13 ◽  
Author(s):  
R. Stamatiou ◽  
E. Paraskeva ◽  
K. Gourgoulianis ◽  
P.-A. Molyvdas ◽  
A. Hatziefthimiou
Keyword(s):  
Smooth Muscle ◽  
Growth Factors ◽  
Smooth Muscle Cell ◽  
Airway Smooth Muscle ◽  
Muscle Cell ◽  
Thymidine Incorporation ◽  
Cell Number ◽  
Airway Smooth Muscle Cell ◽  
Specific Cell ◽  
Dependent Manner

Chronic airway diseases, such as asthma or chronic obstructive pulmonary disease, are characterized by the presence in the airways of inflammation factors, growth factors and cytokines, which promote airway wall remodelling. The aim of this study was to investigate the effect of cytokines and growth factors on airway smooth muscle cell (ASMC) proliferation, phenotype and responsiveness. Incubation of serum starved human bronchial ASMCs with TNF-α, TGF, bFGF, and PDGF, but not IL-1β, increased methyl-[3H]thymidine incorporation and cell number, mediated by the PI3K and MAPK signalling pathways. Regarding rabbit tracheal ASMC proliferation, TNF-α, IL-1β, TGF, and PDGF increased methyl-[3H]thymidine incorporation in a PI3K- and MAPK-dependent manner. bFGF increased both methyl-[3H]thymidine incorporation and cell number. Moreover, incubation with TGF, bFGF and PDGF appears to drive human ASMCs towards a synthetic phenotype, as shown by the reduction of the percentage of cells expressing SM-α actin. In addition, the responsiveness of epithelium-denuded rabbit tracheal strips to carbachol was not significantly altered after 3-day treatment with bFGF. In conclusion, all the tested cytokines and growth factors increased ASMC proliferation to a different degree, depending on the specific cell type, with bronchial ASMCs being more prone to proliferation than tracheal ASMCs.

VIP inhibits basal and histamine-stimulated proliferation of human airway smooth muscle cells

1995 ◽  
Vol 268 (6) ◽  
pp. L1047-L1051 ◽  
Author(s):  
K. Maruno ◽  
A. Absood ◽  
S. I. Said
Keyword(s):  
Smooth Muscle ◽  
Airway Smooth Muscle ◽  
Thymidine Incorporation ◽  
Inhibitory Effect ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Cyclic Monophosphate ◽  
Cell Counts ◽  
Dependent Protein ◽  
Camp Levels

Airway smooth muscle (ASM) cell proliferation contributes to increased airway resistance in bronchial asthma. We have examined the modulation of ASM proliferation by vasoactive intestinal peptide (VIP), a cotransmitter of airway relaxation. Human ASM cells were grown in culture as a monolayer. VIP (1.0 nM-1.0 microM) inhibited proliferation in a dose-dependent manner by up to 82% on day 2, but the related peptide glucagon had no effect. Histamine (100 nM-100 microM) increased cell counts by 66%, but in the presence of VIP, cell counts and [3H]thymidine incorporation were reduced by up to 55%. Adenosine 3',5'-cyclic monophosphate (cAMP)-promoting agents, including 3-isobutyl-1-methylxanthine, forskolin, and 8-bromo-adenosine 3',5'-cyclic monophosphate, alone and especially combined with VIP, reduced cell counts and [3H]thymidine incorporation, in correlation with cAMP levels. KT-5720 (1.0 nM-1.0 microM), a selective inhibitor of cAMP-dependent protein kinase A (PKA), abolished the inhibitory effect of VIP. The results show that VIP selectively and potently inhibits human ASM cell growth and multiplication, and nullifies the mitogenic effect of histamine, by a PKA-mediated mechanism. A deficiency of VIP may lead to ASM hyperplasia due to unopposed stimulation by endogenous mitogens.

scholarly journals Mechanical stimuli and IL-13 interact at integrin adhesion complexes to regulate expression of smooth muscle myosin heavy chain in airway smooth muscle tissue

2011 ◽  
Vol 301 (3) ◽  
pp. L275-L284 ◽  
Author(s):  
Leena P. Desai ◽  
Yidi Wu ◽  
Robert S. Tepper ◽  
Susan J. Gunst
Keyword(s):  
Smooth Muscle ◽  
Protein Expression ◽  
Airway Smooth Muscle ◽  
Heavy Chain ◽  
High Load ◽  
Phenotypic Marker ◽  
Akt Activation ◽  
Muscle Tissues ◽  
Low Load ◽  
Muscle Myosin

Airway smooth muscle phenotype may be modulated in response to external stimuli under physiological and pathophysiological conditions. The effect of mechanical forces on airway smooth muscle phenotype were evaluated in vitro by suspending weights of 0.5 or 1 g from the ends of canine tracheal smooth muscle tissues, incubating the weighted tissues for 6 h, and then measuring the expression of the phenotypic marker protein, smooth muscle myosin heavy chain (SmMHC). Incubation of the tissues at a high load significantly increased expression of SmMHC compared with incubation at low load. Incubation of the tissues at a high load also decreased activation of PKB/Akt, as indicated by its phosphorylation at Ser 473. Inhibition of Akt or phosphatidylinositol-3,4,5 triphosphate-kinase increased SmMHC expression in tissues at low load but did not affect SmMHC expression at high load. IL-13 induced a significant increase in Akt activation and suppressed the expression of SmMHC protein at both low and high loads. The role of integrin signaling in mechanotransduction was evaluated by expressing a PINCH (LIM1–2) fragment in the muscle tissues that prevents the membrane localization of the integrin-binding IPP complex (ILK/PINCH/α-parvin), and also by expressing an inactive integrin-linked kinase mutant (ILK S343A) that inhibits endogenous ILK activity. Both mutants inhibited Akt activation and increased expression of SmMHC protein at low load but had no effect at high load. These results suggest that mechanical stress and IL-13 both act through an integrin-mediated signaling pathway to oppositely regulate the expression of phenotypic marker proteins in intact airway smooth muscle tissues. The stimulatory effects of mechanical stress on contractile protein expression oppose the suppression of contractile protein expression mediated by IL-13; thus the imposition of mechanical strain may inhibit changes in airway smooth muscle phenotype induced by inflammatory mediators.

Role of phospholipase C and tyrosine kinase systems in growth response of human airway smooth muscle cells

1996 ◽  
Vol 270 (5) ◽  
pp. L795-L802 ◽  
Author(s):  
S. De ◽  
E. T. Zelazny ◽  
J. F. Souhrada ◽  
M. Souhrada
Keyword(s):  
Smooth Muscle ◽  
Tyrosine Kinase ◽  
Cell Count ◽  
Phospholipase C ◽  
Airway Smooth Muscle ◽  
Thymidine Incorporation ◽  
Airway Smooth Muscle Cells ◽  
Dependent Manner ◽  
Human Airway Smooth Muscle ◽  
Human Airway

The primary culture of confluent human airway smooth muscle (ASM) cells were exposed up to 5 days to human recombinant interleukin (IL)-1 beta in the presence of indomethacin and 1% fetal bovine serum. The proliferation was assessed by a [3H]thymidine incorporation and direct cell count. We found that IL-1 beta significantly increased thymidine incorporation into and cell count of ASM cells in a concentration-dependent manner. Pretreatment of cells with specific polyclonal antibodies against platelet-derived growth factor (PDGF-BB homodimer) completely inhibited the IL-1 beta-induced increase in thymidine incorporation. The PDGF-BB, at the concentrations of 1.5 and 2.5 ng/ml, stimulated the proliferation of ASM cells. The proliferation action of IL-1 beta was potentiated when PDGF-BB was added into the medium in combination with IL-1 beta. Pretreatment of cells with genistein (0.37 microM), a specific tyrosine kinase inhibitor, attenuated the proliferative effect of IL-1 beta and PDGF-BB. To clarify whether these growth stimuli (IL-1 beta and PDGF-BB) activated phospholipase C (PLC), we examined the formation of phosphatidylinositols. We observed that both agents significantly increased phosphoinositide turnover. In contrast, genistein pretreatment (0.37 microM) prevented formation of inositol 1,4,5-trisphosphate (IP3), as induced by IL-1 beta and/or PDGF-BB. This study demonstrates that both IL-1 beta and PDGF-BB could induce proliferation of ASM cells through the activation of tyrosine kinase and PLC, which in turn stimulate the formation of IP3, a second messenger molecule.

Markers of airway smooth muscle cell phenotype

1996 ◽  
Vol 270 (6) ◽  
pp. L1040-L1051 ◽  
Author(s):  
A. J. Halayko ◽  
H. Salari ◽  
X. MA ◽  
N. L. Stephens
Keyword(s):  
Smooth Muscle ◽  
Myosin Heavy Chain ◽  
Airway Smooth Muscle ◽  
Heavy Chain ◽  
Cytoskeletal Proteins ◽  
Cell Phenotype ◽  
Airway Smooth Muscle Cells ◽  
Mrna Levels ◽  
Alpha Actin ◽  
Muscle Myosin

Airway smooth muscle plays a principal role in the pathogenesis of asthma. Primary cultures are being used to investigate airway myocyte proliferation and cellular pathways regulating contraction. Airway smooth muscle cells (SMC) modulate from a contractile to a noncontractile phenotype in culture, but no systematic study of the concomitant changes in expression of cytocontractile and cytoskeletal proteins has been reported. We measured temporal changes in protein marker expression of canine tracheal SMC in primary culture, using specific antibodies and cDNA probes. Immunoblot analysis revealed that when cells became proliferative after 5 days of culture, the content of smooth muscle myosin heavy chain (sm-MHC), calponin, sm-alpha-actin, and desmin diminished by > 75%; myosin light chain kinase, h-caldesmon, and beta-tropomyosin had also decreased significantly (P < 0.05). Northern blots revealed that mRNA levels for sm-MHC and sm-alpha-actin were also significantly reduced in proliferative SMC. Conversely, immunoblotting demonstrated the content of non-muscle myosin heavy chain, l-caldesmon, vimentin, alpha/beta-protein kinase C (PKC), and CD44 homing cellular adhesion molecule (HCAM) increased one- to sixfold as cells became proliferative. The content of sm-MHC and sm-alpha-actin protein increased after confluence, suggesting that cultured airway SMC are capable of phenotypic plasticity. Marker protein contents were also compared, by immunoblot assay, between SMC dissociated from trachealis or pulmonary arterial media. Cytocontractile protein content was higher in the trachea, which shortens faster than the pulmonary artery. The identification of these markers provides tools for assessing the phenotype of airway SMC in culture and the airways of asthmatic patients.

GSK-3/β-catenin signaling axis in airway smooth muscle: role in mitogenic signaling

2008 ◽  
Vol 294 (6) ◽  
pp. L1110-L1118 ◽  
Author(s):  
Raquel O. Nunes ◽  
Martina Schmidt ◽  
Gordon Dueck ◽  
Hoeke Baarsma ◽  
Andrew J. Halayko ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Smooth Muscle Cells ◽  
Airway Smooth Muscle ◽  
Thymidine Incorporation ◽  
Muscle Cells ◽  
Airway Smooth Muscle Cells ◽  
Mitogenic Signaling ◽  
Signaling Axis

β-Catenin plays a dual role in cellular signaling by stabilizing cadherin-mediated cell-cell contact and by regulating gene transcription associated with cell cycle progression. Nonetheless, its presence and function in airway smooth muscle have not been determined. We hypothesized a central role for β-catenin in mitogenic signaling in airway smooth muscle in response to growth factor stimulation. Immunocytochemical and biochemical analysis revealed that human airway smooth muscle cells indeed express abundant β-catenin, which was localized primarily to the plasma membrane in quiescent cells. Treatment of airway smooth muscle cells with PDGF or FBS induced sustained phosphorylation of glycogen synthase kinase-3 (GSK-3), a negative regulator in its unphosphorylated form that promotes β-catenin degradation. GSK-3 phosphorylation was also increased in airway smooth muscle cells with a proliferative phenotype compared with quiescent airway smooth muscle cells with a mature phenotype. Parallel with the increase in GSK-3 phosphorylation, growth factor treatment induced an increased expression and nuclear presence of β-catenin and activated promitogenic signaling in airway smooth muscle, including the phosphorylation of retinoblastoma protein, DNA synthesis ([3H]thymidine incorporation), and cell proliferation. Importantly, small interfering RNA knockdown of β-catenin strongly reduced retinoblastoma protein phosphorylation, [3H]thymidine incorporation, and cell proliferation induced by PDGF and FBS. Collectively, these data reveal the existence of a GSK-3/β-catenin signaling axis in airway smooth muscle that is regulated by growth factors and of central importance to mitogenic signaling.

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