Epithelial Cell Modulation of Airway Fibrosis in Asthma

The increase in large airways wall thickness seen in patients lated that airway basement membrane thickening may actuwith asthma is a consequence of expansion of the matrix, ally protect against airway narrowing and air trapping by the cellular, and the vascular tissue compartments. Analysis increasing the load on airway smooth muscle (6). Thus, of the subepithelial basement membrane area in the large further well controlled studies designed to understand the airways of patients with asthma, using immunohistochemical clinical and physiologic significance of the dense layer of staining for type III collagen, demonstrates a 50% increase collagen fibrils in the lamina recticularis are encouraged. in its thickness above that in normal subjects (1). Further- The airway epithelial cell layer is altered in asthma. First, more, in the subgroup with clinically severe asthma, a thicker there is shedding of columnar cells, seen as clumps in spubasement membrane layer correlated with airway eosino- tum (Creola bodies), with retention of the basal cells of the philia and an increase in the number of submucosal cells pseudostratified epithelial layer (7). Second, epithelial cells expressing the profibrotic cytokine, transforming growth in asthma are biochemically different, with increases in exfactor- (TGF-) (2). Subepithelial basement membrane pression of heat shock proteins, activation of transcription thickening is somewhat of a misnomer, as electron micro- factors (AP-1, NF-B, STAT-1), and increases in epidermal scopic evaluation of asthmatic airways demonstrates a struc- growth factor (EGF) receptor (7). Epithelial cells, under turally normal true basement membrane, with an abnormally certain circumstances, will elaborate a number of inflamthick and dense layer of fibrillar material subjacent to the mation-modulating cytokines, chemokines, and growth factrue basement membrane (Figure 1) (3). This dense material tors in vitro, and thereby potentially drive the airway inwas devoid of the basement membrane components collagen flammatory process itself. Some unique phenotypic findings type IV and laminin, but rich in interstitial matrix compo- in primary cultures of epithelial cells from individuals with nents, including collagens (Type I and III) and fibronectin asthma have shown persistence upon serial passage in cul(3). Together, these observations imply that mesenchymal ture, suggesting that the cells are altered in a manner indecells, not epithelial cells, within the airway wall are responsi- pendent of their immediate proinflammatory microenvironble for the matrix deposition in the lamina recticularis layer ment. Furthermore, a host of stimuli, including enzymatic of the airway. Although the precise effector cells for this activity of allergens, proteases, oxidants, infectious agents, process have yet to be conclusively identified, cells located and mechanical deformation, will activate epithelial cells subjacent to the epithelial basement membrane that contain in vitro (7). a contractile apparatus and express myofibroblast antigens The capacity of epithelial cells to respond to exogenous are seen in increased numbers in asthma (4, 5). chemical or mechanical stimuli in vitro by elaborating proAlthough the histopathologic evidence demonstrating a fibrogenic factors into the basolateral compartment is also thickened lamina recticularis is clear, its contribution to demonstrable using a three-dimensional co-culture model the pathobiology of airway distension, airway hyperrespon- where epithelial cells are grown as a monolayer on top of siveness, airway inflammation, asthma clinical severity, or collagen gels that are seeded with myofibroblasts (7). In this response to therapy remains unproven. It has been hypothe- model, increases in collagen gene expression and enhanced sized that the basement membrane thickening may contrib- proliferation of the myofibroblasts are a consequence of ute to the limited capacity for airway distension during deep the combined effects of FGF-2, IGF-1, PDGF-BB, TGF-, inspiration seen in asthma. However, others have specu- and endothelin (ET)-1 after the epithelial cells are mechani