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Airway Smooth Muscle in Bronchomotor Tone, Inflammation, and Remodeling: Advancing from Basic Knowledge to Clinical Relevance

Executive Summary

Goal

The goal of this workshop convened by the National Heart, Lung, and Blood Institute (NHLBI) on September 11-12, 2006 in Bethesda , Maryland was to address the current state of the art and gaps in our knowledge concerning the study of airway smooth muscle function in asthma and chronic obstructive pulmonary disease.

Airway smooth muscle, the critical effector cell modulating bronchomotor tone, may serve a variety of important functions that go beyond modulation of bronchomotor tone including orchestration and perpetuation of airway inflammation, modulation of airway remodeling, and regulation of airway development. It remains a pivotal cell contributing to the pathogenesis of airway diseases. In order to identify the important gaps in our fund of knowledge, key functions of the airway smooth muscle were identified as important topic areas and future research directions were delineated within each of these contexts.

Developmental Biology

Recent studies clearly demonstrate from embryogenesis onward that airway smooth muscle elaborates smooth muscle-specific actin and is mechanically active. New evidence suggests that prenatal airway peristalsis is developmentally regulated during lung growth in a manner that appears dependent on specific growth factors and epithelial-mesenchymal interactions. Important unanswered questions include:

  • What are the local factors that regulate airway smooth muscle cell development in embryogenesis?
  • What are the intracellular signaling pathways that are important in the development of airway smooth muscle?
  • Are any of the developmentally regulated patterns of protein expression in airway smooth muscle recapitulated in the adult in health or in disease?

Excitation-Contraction Coupling

Despite substantial progress in the understanding of ion channels and receptors in airway smooth muscle at the cellular and molecular levels, the mechanisms that underlie spontaneous tone in inflammatory bronchoconstriction remain unclear. Important research directions include:

  • What is the role of spontaneous calcium release events in the generation of airway tone?
  • What are the regulatory molecules that control intracellular calcium channel function?
  • What are the spontaneous release events regulating tone in small airways?
  • What are the differences in ion channel expression between small and large airways?
  • What is the molecular basis of the depolarizing chloride current in airway smooth muscle cells?
  • Do adaptive phenotypes alter the expression and function of sarcolemmal ion channels?
  • What is the role of calcium sensitization in the control of small airway tone?
  • What are the modifications of contractile and cytoskeletal proteins that induce dynamic remodeling and render the airway smooth muscle hyperresponsive?
  • What are the stimuli that elicit mechanical adaptation and the proteins necessary for adaptation that modulates the physical nature of the airway smooth muscle cell?

Cell Proliferation, Growth and Migration

In a variety of diseases, airway smooth muscle mass increases due to the coordinated increase in size (hypertrophy) and number (hyperplasia) of airway smooth muscle cells. Myocyte migration may also serve to regulate airway smooth muscle mass. Important future directions include:

  • What is the physiologic relevance of increasing airway smooth muscle mass?
  • Do increases in airway smooth muscle mass occur throughout the tracheobronchial tree or is it restricted to particular segments?
  • What is the role of transforming growth factor beta in modulating airway smooth muscle mass?
  • What are the critical translational control pathways regulating airway smooth muscle hypertrophy?
  • Concerning myocyte migration, what are the pools of cells responsible for the migration of mesenchymally derived cells into the airway?
  • Do airway smooth muscle cells migrate or are there potentially intravascular pools or hemopoietically derived pools of progenitors that home to airway smooth muscle?
  • What is the physiologic relevance of airway smooth muscle migration?

Immunobiology

Based on in vitro studies, airway smooth muscle cells have been shown to secrete a variety of chemokines and cytokines that can orchestrate and perpetuate airway inflammation. Whether airway smooth muscle secretes chemokines and cytokines in vivo and the relative contribution of this cell type to modulation of airway inflammation remain unknown. Important questions to address include:

  • In vivo , what are the chemokines, cytokines and growth factors expressed by airway smooth muscle?
  • What is the physiologic relevance of airway smooth muscle-derived chemokines and cytokines?
  • Can therapeutic approaches be developed to inhibit airway smooth muscle-derived immunomodulatory molecules and what are the consequences of such therapeutic approaches?
  • Does airway smooth muscle modulate epithelial cell, lymphocyte and mast cell function, and secretion of pro-inflammatory mediators in vivo?

Matrix

Airway smooth muscle serves as an important source of matrix expression and deposition. Both in vivo and cultured human airway smooth muscle are remarkably resistant to apoptosis, suggesting a strong survival signal likely mediated, in part, through cell adhesion-matrix interactions. Further, matrix influences intracellular signaling that modulates excitation-contraction coupling and proliferation of airway smooth muscle. Important unanswered questions remain:

  • How can we define the phenotype of major mesenchymal cell lineages in the airways?
  • Which cells are the major controllers of matrix deposition in the airway in vivo in viral and/or allergen-induced airway hyperresponsiveness models?
  • What are the relative contributions of matrix deposition to airway remodeling, and the development of fixed airway obstruction?
  • Are these changes related to structural changes in matrix in the airway wall, altered cell number or altered cell function?
  • What are the determinants of matrix deposition and turnover in the airway wall?

Working Group Members

Chair

  • Reynold A. Panettieri, Jr., M.D., University of Pennsylvania , Philadelphia , PA

Members

  • Kameswara Badri, Ph.D., Wayne State University School of Medicine, Detroit, MI
  • Jeffrey L. Benovic, Ph.D., Thomas Jefferson University, Philadelphia, PA
  • Alan Fine, M.D., Boston University School of Medicine, Boston, MA
  • Jeffrey J. Fredberg, Ph.D., Harvard School of Public Health, Boston, MA
  • William T. Gerthoffer, Ph.D., University of Nevada School of Medicine, Reno, NV
  • Susan J. Gunst, Ph.D., Indiana University School of Medicine, Indianapolis, IN
  • Ian P. Hall, M.D., University Hospital of Nottingham, Nottingham, UK
  • Marc B. Hershenson, M.D., University of Michigan Health System, Ann Arbor, MI
  • Michael I. Kotlikoff, Ph.D., V.MD., Cornell University, College of Veterinary Medicine, Ithaca, NY
  • Vera P. Krymskaya, Ph.D., University of Pennsylvania, Philadelphia, PA
  • James Martin, M.D., McGill University, Montreal, Quebec, Canada
  • Michael J. Sanderson, Ph.D., University of Massachusetts Medical School, Worcester, MA
  • Julian Solway, M.D., University of Chicago, Chicago, IL
  • Prescott G. Woodruff, M.D., MPH, University of California, San Francisco, CA

NHLBI Staff

  • Susan Banks-Schlegel, Ph.D., Division of Lung Diseases, Bethesda , MD
  • Thomas L. Croxton, M.D., Ph.D., Division of Lung Diseases, Bethesda , MD

November 2006

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