Introduction: The purpose of this review is to describe the significance of the basal cell of the larger lung airway to the field of inhalation toxicology. Systemically administered agents such as naphthalene may also adversely affect lung epithelial cells. Basal cells are now known to be important for many reasons including:

1) Interaction with inflammatory cells and dendritic cells in the lateral intercellular spaces.

2) Attachment mechanism for the rest of the large airway epithelium to the basement membrane or basal lamina.

3) Progenitor cells for the other airway epithelial cells under various conditions.

4) Numerous other functions listed below. The significance of some of these is still not clear.

Basal cells of the lung airway epithelium were thought to serve solely as the stem or progenitor cell of the other epithelial cells until approximately 1990. This was likely due to the assumption that the term "basal" cell meant that these cells in the lung served the same function as the basal cells of skin where they are progenitor cells. The term basal actually refers to the position of the cell at the base of the epithelium. This review summarizes most of the new findings concerning the airway basal cell. Because it takes quite a few years for findings in the literature to make their way into textbooks, most of this information will not yet be found in books.

An earlier review (1) described the origin, distribution and morphology of basal cells in various species and at different airway levels. Basal cells were defined not only by position but also by the presence of hemidesmosomes, cytokeratins 5 and 14, and reacting with lectin Griffonia simplicifolia isolectin B4. Basal cells were derived from undifferentiated columnar epithelium. The conclusion was reached that a function of the basal cell was to attach the epithelium to the basement membrane. Basal cells are physically in a position to interact with all other airway epithelial cells, basement membrane and underlying mesenchymal cells. In addition they can interact with inflammatory cells and dendritic cells in the lateral intercellular spaces.

Progenitor cells: Basal cells have been shown to be progenitor cells of airway epithelium under certain conditions. More recently 2 populations of basal cells were described. One is the usual basal cell and the other, referred to the parabasal cell, is tall and columnar. These may be the indeterminate cells described by others. In normal adults, basal cells have a very slow rate of proliferation. This rate is much higher during development.

Junctional adhesion: It is important to know the mechanisms of columnar cell attachment to the basal lamina in order to understand the etiology of lung injury and diseases involving epithelial sloughing such as smoke inhalation and asthma. When columnar cells are sloughed, basal cells remain attached to the basal lamina. Basal cells have a structural role in attaching the columnar epithelium to the basal lamina. The only cell type in the airway epithelium that forms hemidesmosome junctions with the basement membrane is the basal cell. The columnar cell is attached to the basement membrane with desmosome attachments to basal cells. When desmosomes fail, columnar and basal cells detach and the columnar epithelium may detach and slough. When basal cells are not present, as in smaller airways, columnar cells are attached to the basal lamina with cell adhesion molecules (CAM).

Neurogenic Inflammation: There are axons in the airway epithelium capable of releasing neuropeptides into the lateral intercellular space. This occurs in response to inhaled foreign material and results in what is termed "neurogenic inflammation". The end results of this inflammation include vascular permeability, neutrophil adhesion, vasodilation, ion transport, smooth muscle contraction, and cough among others. Both LIF (leukemic inhibitory factor) and NEP (neutral endopeptidase) are associated with basal cells rather than columnar cells. They are thought to be involved in regulating the process of neurogenic inflammation in the airway.

Inflammation: During an inflammatory response, basal cells upregulate expression of receptors for lymphocytes and migratory inflammatory cells. Some of these receptors include ICAM-1 (intercellular adhesion molecule-1), IgE, LEEP-CAM (lymphocyte endothelial-epithelial cell adhesion molecule), and 4-1BB (part of the TNF superfamily). These are all found in human airway epithelium. The authors suggest that that basal cells interact with inflammatory cells as they migrate through the epithelium via lateral intercellular spaces.

Transepithelial Water Movement: Water channels allow water transfer between cells and the matrix. Basal cells of the rat have a unique aquaporin water channel (AQP3) that is not found in columnar cells. This suggests that basal cells may be unique in acting as fluid modulators of airway surface liquids as well as lateral intercellular space. This leads to the possibility of the presence of cell-specific pathways for transcellular water movement.

Oxidant Defense of the Tissue: Expression of both EC-SOD and MRP transmembrane transporter by basal cells in normal subjects indicates that basal cells have a role in the defense against oxidative stress. EC-SOD (extracellular SOD) mRNA makes the protein SOD that metabolizes free radicals and is probably essential for protection of the extracellular matrix from oxidant damage. Both basal and secretory cells in normal human airways express EC-SOD mRNA. Mulitdrug resistance-protein (MRP) transmembrane transporter is found in normal human bronchial epithelium. However it is expressed differently according to cell type leading to the conclusion that it has specific roles in basal and ciliated cells.

Lateral Intercellular Space: The lateral intercellular space in airway epithelium was first described in1992. It is a distinct space between cells and essential to transepithelial water movement. Interactions between nerves and basal cells, dendritic cells, migratory cells and diffusible molecules occur in the lateral intercellular space of airway epithelium. Human epithelium contains hyaluronan that maintains the hydrated state of intercellular spaces. The hyaluronan is bound to the cell by CD44 adhesion molecules. Asthmatics have twice as many CD44 adhesion molecules on basal cells as normal subjects. Thus it seems that basal cells somehow maintain the lateral intercellular space via binding hyaluronan with CD44 adhesion molecules on the cell surface.

Growth Factors: Growth factors can be bound to receptors on basal cells. Some of these proteins are fibroblast growth factor-2, epidermal growth factor (EGF), endothelin-1, transforming growth factor (TGF) alpha. Growth factors on basal cells are associated with a variety of functions including cell proliferation, induction of DNA synthesis, and stimulation of differentiated functions. Some of these functions also depend upon the species studied.

Adrenomedullin: This is a peptide that regulates vasodilation and bronchodilation in the lung. Adrenomedullin receptor mRNA is found in basal cells of humans. Adrenomedullin itself is stored in the apical region of ciliated cells. It can also stimulate hyaluronan production. Previously it was noted that hyaluron is found in the lateral intracellular space.

Annexin II: Annexin II is a protein associated with intracellular vesicle trafficking and exocytosis. Basal cells contain membrane bound vesicles and although they are not considered to be secretory cells, they are assumed to secret EC-SOD and LIF. There is also evidence that annexin II is related to the lateral intracellular space by stabilizing CD44 adhesion molecules in the basal cell membrane.

Catecholamines: These bind to beta-adrenergic receptors in both basal and columnar cells. Catecholamine functions basal cells are as yet unknown. It has been hypothesized that they regulate gene expression or cell proliferation.

Bcl-2 and Autotaxin: Bcl-2 is an intracellular protein inhibits apoptosis. It is found in 20% of basal cells. The function of autotaxin in basal cells is unclear. It is known to be an autocrine motility-stimulating factor.

Markers of Basal Cells: Galactose or galactosamine-specific lectins are specific to basal cells. The integrin profile of human basal cells has been defined. Some of these integrins are components of hemidesmosomes. Alkaline phosphatase and IgM monoclonal antibody are also unique to basal cells.

Ciliated and nonciliated columnar cells have been studied much more extensively than have basal cells. However basal cells have a central position which can enable them to interact with a variety of other lung, inflammatory and dendritic cells. The lateral intercellular space would appear to be the location of the interactions. These interactions are even more likely to be important because basal cells cover most of the basal lamina as a separate layer of cells. Thus basal cells must serve an important role in the epithelial-mesenchymal- trophic unit. [This structure has been reviewed previously ( ) ]. The authors note that they have attempted to review all the functions and potential functions of basal cells. They have also listed all the molecules associated with basal cells thus far. However, the functions of many of these molecules as related to the basal cell are not yet clear.

References: 1) Evans, MJ, Moller PC: Biology of airway basal cells. Exp Lung Res. 1991; 17:513-531.

By: Susan G. Shami, ScD   Senior Science Editor
http://www.susanshami/index.html

Editorial note:
At first thought, cell biology may not seem particularly important to the field of toxicology especially when considering the recently reviewed studies of inhaled particles. These particle studies seem to be most important for setting guidelines for air pollution standards at the moment. However at some point it will become a question as to how these particles and gases exert their injurious effects on the lungs. This may lead to ways to modify this injury. Some of the papers reviewed already refer to this type of study being imminent  (fibrosis_mouse_ovalbumin.htm) This point will probably come when there is enough descriptive information concerning particle-exposed lungs. It is not only a lack of information on the effects of particles on the lungs but also a lack of information about the lung cells themselves. This one review is the second review since 1990 on the basal cell. Before 1990 this cell was almost completely ignored. 
By: Susan G. Shami, ScD