Airway Smooth Muscle Cell Proliferation Is Increased in Asthma

Johnson, Patricia A.; Roth, Michael; Tamm, Michael; Hughes, Margaret; Ge, Qi; King, Greg; Burgess, Janette K.; Black, Judith L.

doi:10.1164/ajrccm.164.3.2010109

Cited by 475 publications

(413 citation statements)

References 17 publications

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“…It was considered that the inflammatory mediators and cytokines released by accumulated eosinophils in airway resulted in mucus hypersecretion, increased vascular permeability, bronchial hyperresponsiveness, smooth muscle contraction [19,20] . Furthermore, cytokines and growth factors released by inflammatory cells such as neutrophils are also involved in initiation of airway remodeling which is characterized by airway smooth muscle proliferation [21] . In this study, we investigated the therapeutic effect of rosiglitazone in OVA-induced asthma and possible mechanisms involved.…”

Section: Discussionmentioning

confidence: 99%

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

Zhu

Wang

et al. 2015

Acta Pharmacol Sin

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Aim: Rosiglitazone is one of the specific PPARγ agonists showing potential therapeutic effects in asthma. Though PPARγ activation was considered protective in inhibiting airway inflammation and remodeling in asthma, the specific mechanisms are still unclear. This study was aimed to investigate whether heme oxygenase-1 (HO-1) related pathways were involved in rosiglitazone-activated PPARγ signaling in asthma treatment. Methods: Asthma was induced in mice by multiple exposures to ovalbumin (OVA) in 8 weeks. Prior to every OVA challenge, the mice received rosiglitazone (5 mg/kg, po). After the mice were sacrificed, the bronchoalveolar lavage fluid (BALF), blood samples and lungs were collected for analyses. The activities of HO-1, MMP-2 and MMP-9 in airway tissue were assessed, and the expression of PPARγ, HO-1 and p21 proteins was also examined. Results: Rosiglitazone administration significantly attenuated airway inflammation and remodeling in mice with OVA-induced asthma, which were evidenced by decreased counts of total cells, eosinophils and neutrophils, and decreased levels of IL-5 and IL-13 in BALF, and by decreased airway smooth muscle layer thickness and reduced airway collagen deposition. Furthermore, rosiglitazone administration significantly increased PPARγ, HO-1 and p21 expression and HO-1 activity, decreased MMP-2 and MMP-9 activities in airway tissue. All the therapeutic effects of rosiglitazone were significantly impaired by co-administration of the HO-1 inhibitor ZnPP. Conclusion: Rosiglitazone effectively attenuates airway inflammation and remodeling in OVA-induced asthma of mice by activating PPARγ/HO-1 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

Zhu

Wang

et al. 2015

Acta Pharmacol Sin

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“…Airway smooth muscle bundles were dissected free from surrounding tissues, and the cells were grown in culture at 37°C in a humidified 5% CO2 in air atmosphere, as previously described (10). Cells established in culture from each lung donor were checked for the presence of the airway smooth muscle contractile proteins ␣-smooth muscle actin and h-calponin by immunohistochemistry (12). At the time of plating, the average viability of each cell line was 96.2 Ϯ 1.1% (average Ϯ SE, n ϭ 11) as tested by trypan blue dye exclusion testing.…”

Section: Human Asmcmentioning

confidence: 99%

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Lalor¹,

Truong²,

Henness³

et al. 2004

American Journal of Physiology-Lung Cellular and Molecular Phys

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Inflammation and vascular leakage are prevalent in asthma. This study aimed to elucidate the mechanisms involved in serum potentiation of cytokine-induced granulocyte macrophage colony stimulating factor (GM-CSF) production by human airway smooth muscle cells and to identify possible factors responsible. Serum-deprived cells at low density were stimulated with TNF-α and IL-1β for 24 h. Human AB serum (10%), inhibitors of RNA and protein synthesis or specific signaling molecules, or known smooth muscle mitogens were then added for 24 h. Culture supernatants were analyzed for GM-CSF levels, and cells were harvested to assess viability, cell cycle progression, GM-CSF-specific mRNA content, and p38 phosphorylation. Serum potentiated GM-CSF release when added before, together with (maximal), or after the cytokines. The potentiation involved both new GM-CSF-specific mRNA production and protein synthesis. The mitogens IGF, PDGF, and thrombin all potentiated GM-CSF release, and neutralizing antibodies for EGF, IGF, and PDGF reduced the serum potentiation. Inhibitor studies ruled as unlikely the involvement of p70S6kinase and the MAPK p42/p44, two signaling pathways implicated in proliferation, and the involvement of the MAPK JNK, while establishing roles for p38 MAPK and NF-κB in the potentiation of GM-CSF release. Detection of significant p38 phosphorylation in response to serum stimulation, through Western blotting, further demonstrated the involvement of p38. These studies have provided evidence to support p38 being targeted to interrupt the cycle of inflammation, vascular leakage and cytokine production in asthma.

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“…The first evidence for an intrinsic abnormality of ASM cells came from the observation that ASM cells from patients with asthma proliferate significantly faster than cells from control subjects (19). Indeed, a recent report demonstrated reduction of asthma symptoms and improved lung function after removal of ASM bundles (20).…”

Section: Bronchial Hyperresponsivenessmentioning

confidence: 99%

“…Compelling evidence now suggests that ASM plays an important role in regulating bronchomotor tone, in perpetuating airway inflammation, and in airway remodeling (32). Several publications have demonstrated that ASM, in addition to having contractile and proliferative properties, is also an important source of pro-inflammatory cytokines, chemokines and growth factors, as well as extracellular matrix components (19,35,36,42,43).…”

Section: Airway Inflammationmentioning

confidence: 99%

Asthma: where is it going?

Faffe¹

2008

Braz J Med Biol Res

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Asthma is characterized by reversible airway obstruction, airway hyperresponsiveness, and airway inflammation. Although our understanding of its pathophysiological mechanisms continues to evolve, the relative contributions of airway hyperresponsiveness and inflammation are still debated. The first mechanism identified as important for asthma was bronchial hyperresponsiveness. In a second step, asthma was recognized also as an inflammatory disease, with chronic inflammation inducing structural changes or remodeling. However, persistence of airway dysfunction despite inflammatory control is observed in chronic severe asthma of both adults and children. More recently, a potential role for epithelial-mesenchymal communication or transition is emerging, with epithelial injury often resulting in a self-sustaining phenotype of wound repair modulation by activation/ reactivation of the epithelial-mesenchymal trophic unit, suggesting that chronic asthma can be more than an inflammatory disease. It is noteworthy that the gene-environmental interactions critical for the development of a full asthma phenotype involve processes similar to those occurring in branching morphogenesis. In addition, a central role for airway smooth muscle in the pathogenesis of the disease has been explored, highlighting its secretory function as well as different intrinsic properties compared to normal subjects. These new concepts can potentially shed light on the mechanisms underlying some asthma phenotypes and improve our understanding of the disease in terms of the therapeutic strategies to be applied. How we understand asthma and its mechanisms along time will be the focus of this overview.

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Airway Smooth Muscle Cell Proliferation Is Increased in Asthma

Abstract: asthma; human airway smooth muscle; cell culture; cell proliferation; hyperplasia

Cited by 475 publications

References 17 publications

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

The PPARγ agonist, rosiglitazone, attenuates airway inflammation and remodeling via heme oxygenase-1 in murine model of asthma

Mechanisms of serum potentiation of GM-CSF production by human airway smooth muscle cells

Asthma: where is it going?

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