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

Interactions between epithelial, mesenchymal, and neural tissue and also the extracellular matrix are necessary to initiate 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 requires a localized response to a specific stimulus. Fibroblasts, especially those in close proximity to the airway epithelium, 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 connective tissue cells, fibroblasts also produce cytokines and chemokines in response to various stimuli. Their fixed position in the tissue suggests that they can respond in a local manner to bacterial products, tissue injury, or other environmental factors. The relationship between cytokines and inflammatory cells in asthmatic airways also indicates a similar role for fibroblasts. In the asthmatic lung, the fibroblast 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 subepithelial 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 epithelium has not been explored. In 1990, Brewster and associates described a layer of subepithelial fibroblasts in the bronchi of normal and asthmatic human subjects that were positioned to allow close interaction with the epithelium, neural tissues, and extracellular 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 intermeshed 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 endoplasmic reticulum near the nucleus. There were no apparent bundles of microfilaments in the thin or thick portions 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 interstitial 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 fibroblast 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 attenuated fibroblast sheath (Figure 1). The total attenuated fibroblast sheath, with its large surface area and close proximity 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 attenuated fibroblast sheath represents the mesenchymal component of interactions with the epithelium, extracellular matrix, neural tissues, and migratory cells of the inflammatory 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 epithelial–mesenchymal trophic unit would allow local exchange of information between the different tissue elements 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 epithelium instead of being randomly distributed in the lamina propria (2–4). Of the tissues in the epithelial–mesenchymal trophic unit, the least is known about the attenuated fibroblast sheath. Examples of the attenuated fibroblast sheath can be seen in most published electron microscope studies of the upper respiratory tract as a thin layer of attenuated cell processes immediately beneath the epithelium. Present in all animal species examined to date, the attenuated fibroblast sheath extends from the proximal to the distal regions of the conducting airways (5, 6, 8). Conceptually, it continues into the gas exchange region as interstitial fibroblasts in ( Received in original form May 14, 1999 and in revised form July 9, 1999 )