The Attenuated Fibroblast Sheath of the Respiratory Tract Epithelial–Mesenchymal Trophic Unit

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Abstract
Interactions between epithelial, mesenchymal, and neural tissue and also the extracellular matrix are necessary to ini- tiate numerous cellular functions of the lung (1). The most common of these functions include differentiation during lung growth, repair of damaged tissue, and regulation of the inflammatory response. Each of these processes re- quires a localized response to a specific stimulus. Fibro- blasts, especially those in close proximity to the airway ep- ithelium, are likely regulators of local responses. In a recent commentary, Smith and colleagues discussed the possibility that resident fibroblasts may act as sentinel cells for these responses (2). In addition to their role as connec- tive tissue cells, fibroblasts also produce cytokines and chemokines in response to various stimuli. Their fixed po- sition in the tissue suggests that they can respond in a local manner to bacterial products, tissue injury, or other envi- ronmental factors. The relationship between cytokines and inflammatory cells in asthmatic airways also indicates a similar role for fibroblasts. In the asthmatic lung, the fi- broblast plays a key role as a resident mesenchymal cell beneath the epithelium, receiving and sending information to epithelial and inflammatory cells (3, 4). Additionally, these fibroblasts are thought to be responsible for the sub- epithelial fibrosis associated with asthma. The significance of resident fibroblasts in the airway during inflamation has been described; however, the concept of an anatomically distinct group of fibroblasts associated with airway epithe- lium has not been explored. In 1990, Brewster and associates described a layer of subepithelial fibroblasts in the bronchi of normal and asth- matic human subjects that were positioned to allow close interaction with the epithelium, neural tissues, and extra- cellular matrix (5). The population of cells was shown to comprise fibroblasts and myofibroblasts, and individual cells were reported to be as large as 100 m m in diameter. A detailed description of the subepithelial layer of resident fibroblasts in the rat trachea was reported by Evans and coworkers (6). In tissue sections, the cells appear as a layer of attenuated cell processes closely opposed to the lamina reticularis of the basement membrane zone, about 1.9 m m beneath the epithelial basal lamina. The cells are inter- meshed with each other, about 40 m m in diameter with the attenuated portions about 0.55 m m in thickness. The cell is thicker near the nucleus and contains abundant rough en- doplasmic reticulum near the nucleus. There were no ap- parent bundles of microfilaments in the thin or thick por- tions of the cell as there are in myofibroblasts. The cells were determined to be stellate in shape. They exist as a layer of large, flat cells covering about 70% of the intersti- tial surface of the lamina reticularis, and make numerous contacts with the lamina densa of the basement membrane zone (approximately 7,000 times per mm 2 ). This layer of thin mesenchymal cells was named the attenuated fibro- blast sheath (6), with properties of a layer of similar cells in the gut identified as the pericryptal fibroblast sheath (7). On the basis of the data from this previous paper (6), we constructed a three-dimensional model of the attenu- ated fibroblast sheath (Figure 1). The total attenuated fi- broblast sheath, with its large surface area and close prox- imity to the epithelial/environmental interface, defines an anatomic unit of resident fibroblasts that could respond in a local manner to various stimuli. In this role, the attenu- ated fibroblast sheath represents the mesenchymal com- ponent of interactions with the epithelium, extracellular matrix, neural tissues, and migratory cells of the inflamma- tory response. The anatomic and functional relationship between the attenuated fibroblast sheath, epithelial and neural tissue, and also the extracellular matrix appears to serve as an epithelial-mesenchymal trophic unit. The epi- thelial-mesenchymal trophic unit would allow local ex- change of information between the different tissue ele- ments in response to various stimuli. This concept is similar to that of other investigators, with the exception that it recognizes that the subepithelial fibroblasts exist as a specific layer of resident fibroblasts beneath the epithe- lium instead of being randomly distributed in the lamina propria (2-4).

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