Mechanisms of chemically induced respiratory toxicities
Philippe Camus, Edward C Rosenow in Drug-induced and Iatrogenic Respiratory Disease, 2010
Substantial evidence has accrued to establish the bronchiolar Clara cell as a cell type with enhanced susceptibility to chemically induced cytotoxicities. This is due, in part, to the localization within the Clara cells of high concentrations of cytochrome P450 enzymes that are responsible for the metabolic activation of a wide variety of chemicals. For the majority of potentially cytotoxic chemicals, cytochrome P450-dependent metabolic activation takes place in situ within the Clara cells. The oxidative metabolism of these chemicals yields electrophilic derivatives that are highly reactive and that bind to nucleophilic sites on tissue constituents at the site of formation, leading to necrosis of the Clara cells. Alternately, metabolic activation of chemicals within the Clara cells produces reactive metabolites that bind to DNA, leading to the formation of mutations and initiation of carcinogenicity. Thus, the Clara cell may be a cell of origin of lung tumours induced by chemicals that are metabolically activated in situ in this cell type. Taken together, the vulnerability of the Clara cell is linked to the high concentrations as well as the diversity of cytochrome P450 enzymes that reside in this cell population.
Epithelial Cells
Bruce S. Bochner in Adhesion Molecules in Allergic Disease, 2020
At the bronchiolar level, Clara cells constitute the majority of nonciliated epithelial cells. They are columnar in shape and typically project into the airway lumen (1). Their ultrastructure shows abundant rough endoplasmic reticulum, a prominent Golgi apparatus, and electron-dense granules, all indicative of a secretory role (17,18). Clara cell 16-kD protein (CC16kD, previously referred to as Clara cell 10-kD protein), an inhibitor of elastase (19) and phospholipase A2 (20), is believed to be the major product of these cells (21,22). In addition, they may secrete surfactant-associated glycoprotein (23,24). Clara cells also serve as a site of extrahepatic oxidative metabolism of foreign substances through cytochrome P450-dependent mono-oxygenase reactions (25,26).
Epithelial Function and Airway Responsiveness
Alastair G. Stewart in AIRWAY WALL REMODELLING in ASTHMA, 2020
The Clara cell (nonciliated bronchiolar secretory cell) is highly metabolically active and possesses a variety of enzymes including acid and alkaline phosphatases, nonspecific esterase, hydroxylases, transferases, peroxidases, and catalase, in addition to cytochrome P450 monoxygenase.1,182,183 A primary function of the Clara cell is to metabolise xenobiotic cytotoxic agents that enter the respiratory tract via the air or blood. This is achieved via cytochrome P450–mediated metabolism, a pathway which is more active in the Clara cell than in any other pulmonary cell type.3,184–186
Predicting the likelihood of bronchopulmonary dysplasia in premature neonates
Published in Expert Review of Respiratory Medicine, 2019
Patrick A Philpot, Vineet Bhandari
Biomarkers expressed in pulmonary epithelial cells as well as extracellular matrix proteins represent downstream markers of alveolar hypoplasia in preterm infants. Clara cells (now known as club cells), which are epithelial cells that line the respiratory and terminal bronchioles secrete club cell proteins (CCPs). The level of CCPs in cord blood and infant serum has been shown to be decreased in infants who developed BPD [10] but have been shown to be increased at 2 h of life as well as on day of life 14 in infants who developed BPD [11]. Elevated levels of Kerbs von Lungren 6 antigen (KL-6), a marker of lung injury, and the ratio of matrix metalloproteinase (MMP)-9 to tissue inhibitor of metalloproteinase-1 (TIMP-1) have also been reported to be predictors of moderate to severe BPD [12,13]. Although these markers have been associated with the development of BPD, they have yet to be included in predictive models.
Simulation of respiratory tract lining fluid for in vitro dissolution study
Published in Expert Opinion on Drug Delivery, 2021
Rakesh Bastola, Paul M. Young, Shyamal C. Das
The RTLF is a thin fluid layer that lies on the surfaces of the nasal airways through to the distal airways including the alveolar region. In the nasal and proximal airways, it consists of two layers namely, the sol layer (periciliary sol) that surrounds cilia and the gel layer (mucus blanket) that lies above the cilia [1]. RTLF present in different regions of the respiratory tract is shown in Figure 1. Submucosal glands and goblet cells present in the epithelium secrete mucus in trachea and bronchi [1]; however, the luminal surface of the non-alveolarized portion of respiratory bronchioles does not contain mucus and basal cells but is lined by ciliated and Clara cells [21]. Clara cells provide surfactant proteins (A, B and D) and other specific proteins including Clara cell secretory protein [21].
Nasal mucus proteome and its involvement in allergic rhinitis
Published in Expert Review of Proteomics, 2020
Peter Valentin Tomazic, Barbara Darnhofer, Ruth Birner-Gruenberger
Despite its important role in defending the nose and the entire organism against various pathogens, nasal mucus has been granted less attention than the nasal epithelium. Particularly, nasal mucus proteins, major constituents and functional units of this body fluid, have not been studied extensively. Potential therapeutic targets like surfactant protein (SP-A) or clara cell protein (CC10) have been addressed in mouse models or in vitro models by analyzing their expression in the epithelium [9,10]. SP-A is secreted by type II alveolar epithelial cells into pulmonary surfactant, where it is involved in host defense and immune regulation by inhibiting Th2 cell differentiation, reducing Th2 cytokine levels, and increasing Th1 cytokines. It was also identified in nasal mucosa by immunostaining and PCR, and exogenous application resulted in reduced IL-4 and IL-5 levels in ovalbumin-sensitized mice [9]. These protective effects of SP-A may have therapeutic potential in allergic rhinitis. CC10 is an immunosuppressive protein secreted by nasal epithelial cells upon allergen stimulation. Fexofenadine hydrochloride, an H1 histamine receptor blocker, increased CC10 levels in vitro suggesting that CC10 could be used as a predictor for the efficacy of the agent in the individual patient [10].
Related Knowledge Centers
- Bronchiole
- Epithelium
- Glycosaminoglycan
- Goblet Cell
- Microvillus
- Pulmonary Surfactant
- Lung
- Cytochrome P450
- Cell
- Uteroglobin