IL-17A mediates a selective gene expression profile in asthmatic human airway smooth muscle cells.

Airway smooth muscle (ASM) cells are thought to contribute to the pathogenesis of allergic asthma by orchestrating and perpetuating airway inflammation and remodeling responses. In this study, we evaluated the IL-17RA signal transduction and gene expression profile in ASM cells from subjects with mild asthma and healthy individuals. Human primary ASM cells were treated with IL-17A and probed by the Affymetrix GeneChip array, and gene targets were validated by real-time quantitative RT-PCR.

Measurement and impact of remodeling in the lung: airway neovascularization in asthma.

Expansion of the airway wall vascular compartment has recently been established as a feature of asthma involving both enlargement of existing vascular structures and the formation of new vessels (angiogenesis). Both processes are likely to occur together and are fundamental for supporting the many aspects of tissue inflammation and remodeling manifest in the clinical symptoms of airway disease. Multiple growth factors are implicated in airway angiogenesis, with vascular endothelial growth factor among the most important.

Matrix metalloproteinase-19 deficiency promotes tenascin-C accumulation and allergen-induced airway inflammation.

Matrix metalloproteinases (MMPs) recently appeared as key regulators of inflammation, allowing the recruitment and clearance of inflammatory cells and modifying the biological activity of many peptide mediators by cleavage. MMP-19 is newly described, and it preferentially cleaves matrix proteins such as collagens and tenascin-C. The role of MMP-19 in asthma has not been described to date.

Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthma.

Phenotypic modulation of airway smooth muscle (ASM) is an important feature of airway remodeling in asthma that is characterized by enhanced proliferation and secretion of pro-inflammatory chemokines. These activities are regulated by the concentration of free Ca(2+) in the cytosol ([Ca(2+)](i)). A rise in [Ca(2+)](i) is normalized by rapid reuptake of Ca(2+) into sarcoplasmic reticulum (SR) stores by the sarco/endoplasmic reticulum Ca(2+) (SERCA) pump.

Airway vascular reactivity and vascularisation in human chronic airway disease.

Altered bronchial vascular reactivity and remodelling including angiogenesis are documented features of asthma and other chronic inflammatory airway diseases. Expansion of the bronchial vasculature under these conditions involves both functional (vasodilation, hyperperfusion, increased microvascular permeability, oedema formation, and inflammatory cell recruitment) and structural changes (tissue and vascular remodelling) in the airways. These changes in airway vascular reactivity and vascularisation have significant pathophysiological consequences, which are manifest in the clinical symptoms of airway disease.

Animal models of airway inflammation and airway smooth muscle remodelling in asthma.

Asthma is a complex disease that involves chronic inflammation and subsequent decline in airway function. The widespread use of animal models has greatly contributed to our understanding of the cellular and molecular pathways underlying human allergic asthma. Animal models of allergic asthma include smaller animal models which offer 'ease of use' and availability of reagents, and larger animal models that may be used to address aspects of allergic airways disease not possible in humans or smaller animal models.

The effect of asthma therapeutics on signalling and transcriptional regulation of airway smooth muscle function.

Our knowledge of the multifunctional nature of airway smooth muscle (ASM) has expanded rapidly in the last decade, but the underlying molecular mechanisms and how current therapies for obstructive airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), affect these are still being elucidated. Our current knowledge has built on the pharmacology of human ASM contraction and relaxation established prior to that and which is reviewed in detail elsewhere in this issue. The advent of methods to isolate and culture ASM cells, especially human ASM cells, has made it possible to study how they may contribute to airway remodelling through their synthetic, proliferative, and migratory capacities.

Induction of angiogenesis by airway smooth muscle from patients with asthma.

Rationale: Airway remodeling in asthma involves accumulation of airway smooth muscle (ASM) and increased vascularity due to angiogenesis. Bronchial blood vessels and ASM are found in close proximity, and ASM releases multiple proinflammatory mediators, including vascular endothelial growth factor (VEGF).

Objectives: We examined whether release of proangiogenic mediators is increased in ASM from subjects with asthma and whether this is translated to induction of angiogenesis.

Proangiogenic activity in bronchoalveolar lavage fluid from patients with asthma.

Rationale: Asthmatic airways have an increased number and size of vascular structures, which contribute to airflow obstruction and hyperresponsiveness.

Objectives: We examined whether proangiogenic mediators are elevated in bronchoalveolar lavage fluid (BALF) from subjects with asthma and if this translated to induction of angiogenesis.

Methods: Angiogenic activity in BALF from 12 healthy, nonatopic subjects and 10 atopic subjects with mild asthma was evaluated by examining tubule formation at 11 days in cocultures of human endothelial cells with dermal fibroblasts.

Repeated allergen inhalation induces cytoskeletal remodeling in smooth muscle from rat bronchioles.

Airway hyperresponsiveness (AHR) is associated with airway wall structural remodeling and alterations in airway smooth muscle (ASM) function. Previously, in bronchioles from Brown Norway rats challenged by repeated ovalbumin (OVA) inhalation, we have reported increased force generation and depletion of smooth muscle contractile proteins. Here, we investigated if cytoskeletal changes in smooth muscle could account for this paradox.

Extracellular matrix regulates enhanced eotaxin expression in asthmatic airway smooth muscle cells.

Rationale: Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with fibronectin and collagen are key features of asthma. Previously, we have reported these ECM proteins enhance ASM synthetic function.

Objective: We compared ASM cultured from endobronchial biopsies from subjects with and without asthma to assess if asthmatic cells were hypersecretory and determined whether the underlying mechanism involved autocrine ECM production.

Some structural determinants of the antiproliferative effect of heparin-like molecules on human airway smooth muscle.

Accumulation of airway smooth muscle (ASM) and its infiltration by mast cells are key pathological features of airway remodelling in asthma. Heparin, a major component of mast cell granules, inhibits ASM proliferation by an unknown mechanism. Here, unfractionated heparins and related glycosaminoglycans having structurally heterogeneous polysaccharide side chains that varied in molecular weight, sulphation and anionic charge were used to identify features of the heparin molecule that were required for its antiproliferative activity in cultured human ASM cells.

Multiple beta 1 integrins mediate enhancement of human airway smooth muscle cytokine secretion by fibronectin and type I collagen.

Altered airway smooth muscle (ASM) function and enrichment of the extracellular matrix (ECM) with interstitial collagen and fibronectin are major pathological features of airway remodeling in asthma. We have previously shown that these ECM components confer enhanced ASM proliferation in vitro, but their action on its newly characterized secretory function is unknown. Here, we examined the effects of fibronectin and collagen types I, III, and V on IL-1beta-dependent secretory responses of human ASM cells, and characterized the involvement of specific integrins.

On the terminology for describing the length-force relationship and its changes in airway smooth muscle.

The observation that the length-force relationship in airway smooth muscle can be shifted along the length axis by accommodating the muscle at different lengths has stimulated great interest. In light of the recent understanding of the dynamic nature of length-force relationship, many of our concepts regarding smooth muscle mechanical properties, including the notion that the muscle possesses a unique optimal length that correlates to maximal force generation, are likely to be incorrect. To facilitate accurate and efficient communication among scientists interested in the function of airway smooth muscle, a revised and collectively accepted nomenclature describing the adaptive and dynamic nature of the length-force relationship will be invaluable.

Proliferative aspects of airway smooth muscle.

Increased airway smooth muscle (ASM) mass is perhaps the most important component of the airway wall remodeling process in asthma. Known mediators of ASM proliferation in cell culture models fall into 2 categories: those that activate receptors with intrinsic receptor tyrosine kinase activity and those that have their effects through receptors linked to heterotrimeric guanosine triphosphate-binding proteins. The major candidate signaling pathways activated by ASM mitogens are those dependent on extracellular signal-regulated kinase and phosphoinositide 3'-kinase.

Signaling pathways regulating interleukin-13-stimulated chemokine release from airway smooth muscle.

Interleukin (IL)-13 receptor activation on airway smooth muscle cells induces eotaxin release and activates multiple signaling pathways including mitogen-activated protein kinases, and signal transducer and activator of transcription 6 (STAT6). To examine a requirement for STAT6 in mediating IL-13-stimulated eotaxin release we used antisense oligodeoxynucleotides (ODNs) to downregulate endogenous STAT6 protein. STAT6 antisense ODNs were taken up by about 85% of cells.

Regulation of airway smooth muscle cell immunomodulatory function: role in asthma.

General agreement exists that in asthma, airway smooth muscle contracts, narrowing the airway lumen and thereby causing airflow obstruction and dyspnoea. New evidence is emerging that airway smooth muscle may also fulfil an immunomodulatory role by providing a rich source of pro-inflammatory cytokines and chemokines, polypeptide growth factors, extracellular matrix (ECM) proteins, cell adhesion receptors and co-stimulatory molecules. Together, the available data support a role for airway smooth muscle in actively perpetuating airway mucosal inflammatory processes including mast cell and leukocyte (T cell, neutrophil, eosinophil) activation and recruitment.

Contractility and phenotype of human bronchiole smooth muscle after prolonged fetal bovine serum exposure.

Culture of dispersed airway smooth muscle (ASM) cells with fetal bovine serum (FBS) induces rapid growth and modulation from a contractile to a synthetic phenotype, but this may be an artificial situation due to loss of tissue architecture. In this study, structural, functional and biochemical changes of ASM were examined in human intact bronchiole ring segments (200 to 600 micro m internal diameter) after organ culture for up to 6 days in 10% FBS or in D-STIM, an FBS-free medium formulated to maintain a contractile phenotype. ASM content was unchanged after culture for 3 or 6 days with D-STIM or FBS compared with fresh tissues.

Repeated allergen inhalation induces phenotypic modulation of smooth muscle in bronchioles of sensitized rats.

Repeated ovalbumin (OA) or saline exposure of sensitized Brown Norway rats was examined on agonist reactivity, airway smooth muscle (ASM) content, and contractile protein expression in small bronchioles at 24 h, 7 days, and 35 days after challenge. OA increased ASM content (P < 0.05 vs.

Oxygen regulates mitogen-stimulated proliferation of fetal human airway smooth muscle cells.

Increased airway smooth muscle (ASM) content is characteristic of infants with chronic lung disease of prematurity/bronchopulmonary dysplasia. Oxygen therapy, reactive oxygen species (ROS), and immature antioxidant defenses are major risk factors in chronic lung disease of prematurity/bronchopulmonary dysplasia, but their interrelationship is unclear. The direct effects of raised Po2 and modulation of ROS were examined on proliferation of cultured fetal human ASM cells.

Selective induction of eotaxin release by interleukin-13 or interleukin-4 in human airway smooth muscle cells is synergistic with interleukin-1beta and is mediated by the interleukin-4 receptor alpha-chain.

The biologic activities of interleukin (IL)-13 and IL-4 often overlap, and evidence supports their importance in atopic disease and airways hyperresponsiveness. Here, their capacity to release eosinophil-activating cytokines was examined in cultured human airway smooth muscle. IL-13 and IL-4 induced selective release of eotaxin with no effect on granulocyte-macrophage colony-stimulating factor, regulated upon activation, normal T-cell expressed and secreted (RANTES), or IL-8.