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World Allergy Forum: Immune Intervention

Epithelial Orchestration of Inflammation and Remodelling in Chronic Asthma

Stephen T. Holgate

The bronchial epithelium is a stratified structure designed to protect the delicate tissues of the lung from the wide variety of environmental insults including allergens, viruses and air pollutants. However, in asthma there is evidence that this structure both physically and biochemically is unable to serve this function efficiently.

From a structural standpoint, the epithelium exhibits increased fragility and at worse shows evidence of frank disruption and at best evidence of considerable stress [Figs 1-3]. Increased expression of the epithelial isoform of CD44, the receptor for epidermal growth factor (EGFR) and a range of intracellular markers including transcription factors (NF-kB, AP-1 and STAT-1) and heat shock proteins (HSP) (2). These changes are accompanied by a marked increase in the epithelial production of a large number of mediators and cytokines including those that support Th-2 mediated inflammation (e.g. IL-4, IL-5, GM-CSF and IL-13) and fibrogenic growth factors (e.g. TGF-b1 and -b2, bFGF and endothelin-1) (3).

The unique presence of increased repair collagens Types I, III, V and VI along with b-laminin and tenacin C [Fig 4] in parallel with an increased number of subepithelial myofibroblasts [Figs 5,6] n all types of asthma provides evidence for persistent activation of the epithelial-mesenchymal trophic unit beyond its function to promote branching morphogenesis in the fetus (4) [Figs 7,8]. The existence of increased subepithelial collagen in children up to four years before asthma clinically manifests suggests that secretion of growth factors [Figs 8-10] and metalloproteases by [Fig 11] the trophic unit may be fundamental to the development of asthma, especially in those individuals who are genetically at risk of being atopic (5). We have shown that chemical of physical injury to the overlying epithelium causes release of a range of profibrogenic grows factors some of which promote proliferation (bFGF, IGF-1, ET-1, PDGF) [Figs 10,12-14] while others induce collagen secretion and fibroblast transformation to myofibroblasts (TGF-b2) containing large amounts of a-actin [Fig 15].

Two additional factors are considered important in enhancing the remodelling response in asthma:

  1. An increased sensitivity of the epithelium to stress and injury that persists in cell culture as reflected by a greater dependence upon exogenous growth factors, increased susceptibility to apoptosis in response to injury, decreased adhesion and most importantly increased basal and stimulated production of cytokines e.g. GM-CSF, IL-8, RANTES (4), and

  2. Reduced ability to proliferate following stress and injury as reflected increased by P21waf expression, an inhibitor of cell cycling. In addition to promoting fibrogenic responses, TGF-b is a powerful inhibitor of epithelial proliferation which, through SMAD transcriptional regulation, may compete with repair signals that pass through the MAP-kinase pathway such as EGF and HB-EGF whose receptor, c-erb B1, is over expressed in asthmatic epithelial but in the absence of a proliferative response [Figs 16-20].

A further factor to consider is an interaction between stress and Th-2 mediated signalling in the trophic unit (2). Both IL-4 and IL-13 are important inducers of TGF-b production by epithelial cells with evidence of synergy with stress signals. IL-4 and IL- 13 are also potent profibrogenic cytokines. Polymorphisms of the IL-4 gene or its promoter and of the IL-4 and IL-13a and a2 receptors can greatly influence signalling through STAT-6 which, in severe asthma, is over expressed in the epithelium.

Taken together these findings suggest that for chronic asthma to develop at least two abnormalities are needed - continued activation of the epithelial mesenchymal trophic unit to produce growth factors that promote remodelling via myofibroblasts and polarization of the mucosal T cell response to a Th-2 phenotype (6) [Figs 21,22]. Since it has recently been shown that adenoviral transfer of the GM-CSF gene to the bronchial epithelium in mice can augment Th-2 inflammation or reverse local allergen tolerance, the excess production of this growth factor by an abnormally functioning trophic unit may explain why asthma starts in the first place and occurs in only 1 in 5 of those who are atopic (Figs 23-26).

Taken together, the combination of Th-2 mediated inflammation and activation of the epithelial-mesenchymal trophic unit are likely to underlie disease chronicity and the structural [Figs 4, 27] and functional [Fig 28] changes associated with this.

References:

  1. Montefort S, Roberts JA, Beasley CR, Holgate ST, Roche WR. The site of disruption of the bronchial epithelium in asthmatics and non-asthmatics. Thorax 1992;47:499-503.
  2. Holgate ST, Lackie PM, Davies DE, Roche WR, Walls AF. The bronchial epithelium as a key regulator of airway inflammation and remodelling in asthma. Clin Exp Allergy 1999;29(Suppl.2):90-95.
  3. Chung KF, Barnes PJ. Cytokines in asthma. Thorax 1999;54:825-57
  4. Holgate ST, Davies DE, Lackie PM, Wilson SJ, Puddicombe SM, Lordan JL. Epithelial-mesenchymal interactions in the pathogenesis of asthma. J Allergy Cain Immunol 2000 (in press).
  5. Holgate ST. Genetic and environmental interactions in allergy and asthma. J Allergy Clin Immunol 1999;104:1139-46.
  6. Holgate ST. The epidemic of allergy and asthma. Nature Supplement to Vol.402 1999;B2-B4.

Slide presentation

 

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