Emigration and immigration of mesenchymal cells: a multicultural airway wall

Abstract

Chronic inflammatory disease is accompanied by structural changes that appear to relate to disease severity and duration, and are often considered to be poorly reversible, if at all. The processes underpinning the structural changes are varied, complex and not well understood. It is clear that these structural changes contribute to tissue dysfunction.In asthma, remodelling comprises changes in all compartments of the airway wall, with the epithelium potentially orchestrating a persistent cycle of inflammatory injury and repair [1]. The epithelium is thought to influence the underlying mesenchymal cell network through the release of transforming growth factor-b resulting in the activation of myofibroblasts that secrete excessive amounts of collagen and contribute to the burden of pro-inflammatory cytokines. Such changes in the superficial aspect of the airway recapitulate aspects of the pathogenesis of neointima formation, in which damage to the endothelium initiates a repair response that ultimately may compromise vessel function [2].The most significant cellular component of the airway wall remodelling is an increase in the volume of airway smooth muscle (ASM), which is considered to play a dominant role in the consequences of the airway wall thickening for airway reactivity [3]. The mechanisms of the increase in volume of ASM remain ill-defined despite extensive investigation over the last 15 yrs. Hyperplasia of ASM is well evidenced, but there is also evidence for a more limited hypertrophy [4,5]. The hyperplasia has been ascribed to proliferation in situ of ASM in response to growth factors and inflammatory mediators released during exacerbations of chronic asthma. Several investigations of antigen-induced airway inflammation in experimental animals, particularly those in Brown Norway rats, have demonstrated an increase in proliferation of ASM [6] resulting in an increase in the total number of ASM cells [7]. More recent evidence suggests that a decrease in the rate of ASM apoptosis may also contribute to the hyperplasia [8]. However, recent findings suggest the need to re-evaluate in situ proliferation as the major mechanism underlying the ASM hyperplasia. Neither we [9], nor others [10] have been able to detect increased rates of proliferation of ASM cells in biopsies using Ki67, proliferating cell nuclear antigen or cyclin D1 expression. It may be argued that in chronic asthma the rates of proliferation would be too small to detect an increase over the baseline level of cell turnover. Nevertheless, the lack of evidence for in situ proliferation of ASM in human asthmatic airways is consistent with the antiproliferative nature of the laminin and proteoglycan-rich extracellular matrix (ECM) surrounding the ASM cells in muscle bundles [11,12]. An alternative mechanism for the hyperplasia was identified in a biopsy study by GIZYCKI et al.[13], in which an increase in the number of myofibroblasts was detected within 24 h of segmental challenge of the airways. These myofibroblasts were considered to have differe...

Tissue-engineered endothelial and epithelial implants differentially and synergistically regulate airway repair

“…Airflow was sufficiently restricted by combined brush denudation from within and acellular matrices from without to increase stridor Ͼ4-fold compared with injury alone. The response to our airway injury is reminiscent of inflammatory and proliferative reactions to vascular endothelial denudation that result in intimal hyperplasia, luminal narrowing, and diminished vessel function (15). As in blood vessels in which ME-ECs restored function well before restoring architectural integrity, embedded EPs or EPs/ECs preserved airway health and enhanced repair before restoring airway structure.…”

“…Remodeling can establish an abnormal microenvironment between the epithelium and underlying mesenchyme, finally resulting in a pathophysiological cycle of inflammatory injury and aberrant repair (13,14). These alterations in airway remodeling recapitulate features in the development of neointima formation, where endothelium injury initiates a repair response that can lead to luminal narrowing and diminished vessel function (15).…”

Proliferation is not increased in airway myofibroblasts isolated from asthmatics

“…However, the in vitro observations that cultured airway smooth muscle cells isolated from asthmatic biopsy patients are responsive to mitogen stimulation and are hyperproliferative in culture [5] argue against these asthmatic cells being senescent. Alternative additional mechanisms have been proposed for the increased amount of smooth muscle in the asthmatic airway that may not be detected using cell proliferation markers [34]. These include a decreased rate of muscle apoptosis [35] or migration and differentiation of circulating fibrocytes [36].…”

Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma

“…Interest in migration of smooth muscle is increasing in light of the possibility that smooth muscle proliferation does not appear to take place in the muscle bundle, but rather in the subepithelial tissue, where the source of the proliferating cells may be stem cells recruited from the bone marrow [114], fibroblasts that have undergone differentiation [115] or smooth muscle cells that have migrated off the potentially antiproliferative ECM that is rich in proteoglycans and laminins [89]. Migration is required for each of these alternative mechanisms for smooth muscle hyperplasia.…”

“…Reduced apoptosis could in part explain increased ASM mass in asthmatics and account for limited evidence of increased proliferation of ASM cells in situ [89]. Peptide growth factors, which are elevated in asthmatic airways, play pivotal roles in modulating cell survival, proliferation and migration in the lung [90].…”