With every breath, we are exposed to various environmental pollutants. So, what happens with each exposure? Just like the liver detoxifies what we eat, our lungs have a plan in place to remove impurities from the air we breathe. This job is performed by a special class of cells, known as club cells, that reside at the interface between the external environment and tissue in the respiratory tract.
Club cells, named after their distinct dome-like shape which makes them appear ‘club-like’, were first characterised in 1881 by Rudolph Albert von Kölliker as bronchiolar cells devoid of cilia and mucus. Also known as Clara cells, their significance in humans was studied by the German anatomist Max Clara, who used samples from prisoners in concentration camps. Due to the unethical nature of Max Clara’s studies, researchers have proposed discontinuing the name Clara cells [1].
These cells are heterogeneous, as reflected by their complex ontogeny and functions. Club cells are cuboidal in shape with a characteristic dome-shaped apical surface lined with numerous microvilli, which are protrusions extending from the cell membrane [2]. They are rich in mitochondria and apically concentrated endoplasmic reticulum [3]. Electron microscopy studies have revealed a great diversity in the number of club cells in the epithelial lining, the concentration of secretory granules in each cell, and the type of endoplasmic reticulum found in different mammalian species [4, 5]. This makes it challenging to extrapolate results from animal studies to human studies. Found in the epithelial lining within the respiratory system, where they constitute 11–22% of the cells [6], club cells act as the guardians of the respiratory system by purifying the air and modulating the inflammatory response in the lungs [2].
Club cells purify the air
We are exposed to various toxins and environmental pollutants through the air we breathe. The airway epithelium acts as a barrier against inhaled environmental pollutants. Club cells located within the airways metabolise xenobiotics, which are compounds that are foreign to a living organism such as pollutants. Among them, there are naphthalene from cigarette smoke and diesel exhaust [7], 3-methylindole from cigarette smoke [8], and furan from cigarette smoke, diesel exhaust and processed foods [9]. The expression of enzymes, such as CYP2F1, CYP4B1, and CYP2B6 in humans, in the cytochrome P450 (CYP450) system enables club cells to perform their detoxifying activity. However, further studies are needed to assess how these enzymes are involved in the detoxification of various toxins [2]. Studies performed in animal models have shown that naphthalene can be metabolised by the enzyme CYP2F2 to cytotoxic secondary metabolites which damages the airway epithelium. Interestingly, this damage triggers the proliferation of naphthalene-resistant club cells and stem cells that counteract some of the damage [10, 11]. Other toxins have a similar impact on epithelium airway leading to the pathogenesis of respiratory diseases such as asthma and lung cancer [11].
Club cells fight inflammation
Club cells play an important role in the lung inflammatory response in various situations. Their main secretory protein, known as Clara cell secretory protein (CCSP or CC16), performs several immunomodulatory functions. For example, CC16 has an anti-inflammatory response to acute lung inflammation by inhibiting phospholipase A2 (PLA2) which recruits neutrophils [11]. Studies using mouse models have shown that club cells may play a role in fighting inflammation caused by adenoviral and respiratory infections [12, 13]. However, the mechanism through which club cells reduce lung inflammation remains unclear. Additionally, CC16 also plays an anti-inflammatory response to chronic lung inflammation. Research on mouse models of allergic rhinitis has shown that CC16 performs its anti-allergic function by downregulating eosinophil recruitment and decreasing Th2 cytokine production [13]. A potential mechanism of lowered eosinophil recruitment involves the inhibition of dendritic cells by club cells [14]. In fact, chronic lung diseases have been linked to a decreased number of club cells and proteins secreted by them, suggesting that club cells play a protective role against lung injury [2].
In conclusion, these non-ciliated and non-mucus-producing bronchiolar cells are key players in maintaining the lung’s health. They not only detoxify the air we breathe in but also secrete proteins in response to lung inflammation. Since recent research suggests their role in protecting the lungs against injury, we can hope for more exciting discoveries with club cells as the main characters of the story.
Recognizing and appreciating the labs working in this space
- Whitsett Lab, Division of Pulmonary Biology, Children’s Hospital Medical Center, Ohio, USA. https://www.cincinnatichildrens.org/research/divisions/p/pulmonary-bio/labs/whitsett
- Teresa Fortoul, Department of Cellular and Tisular Biology, School of Medicine, UNAM, Ciudad de México, México.
- Nathan W Bartlett, Viral Immunology and Respiratory Disease Group, University of Newcastle, New South Wales, Australia. https://www.linkedin.com/in/nathan-bartlett-84851343/?originalSubdomain=au
- Xinxin Ding, Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Arizona, USA. https://www.pharmacy.arizona.edu/person/xinxin-ding
- Lisa Peterson, Masonic Cancer Center, University of Minnesota, Minnesota, USA. https://directory.sph.umn.edu/bio/sph-a-z/lisa-peterson
- Zheng Liu, Department of Otolaryngology-Head and Neck Surgery, Huazhong University of Science and Technology, Wuhan, China.
- Tereza Martinu, Department of Medicine, University of Toronto, Ontario, Canada. https://www.uhnresearch.ca/researcher/tereza-martinu
- Scott M Palmer, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Duke Clinical Research Institute, Durham, North Carolina. https://medicine.duke.edu/profile/scott-michael-palmer
- Stefano Guerra, Asthma and Airway Disease Research Center, University of Arizona, Arizona, USA. https://airways.uahs.arizona.edu/profile/stefano-guerra-md-phd-mph
- Bradley W. Richmond, Department of Cell and Developmental Biology, Vanderbilt University, Tennessee, United States. https://www.vumc.org/viiii/person/bradley-w-richmond-md-phd
References
- López-Valdez, N., et al. “The Multiple Facets of the Club Cell in the Pulmonary Epithelium.” Histol Histopathol 39 8 (2024): 969–982.
- Blackburn, J. B., et al. “An Update in Club Cell Biology and Its Potential Relevance to Chronic Obstructive Pulmonary Disease.” Am J Physiol Lung Cell Mol Physiol 324 5 (2023): L652-l665.
- Karrer, H. E. “Electron Microscopic Study of Bronchiolar Epithelium of Normal Mouse Lung; Preliminary Report.” Exp Cell Res 10 1 (1956): 237–41.
- Plopper, C. G., L. H. Hill, and A. T. Mariassy. “Ultrastructure of the Nonciliated Bronchiolar Epithelial (Clara) Cell of Mammalian Lung. Iii. A Study of Man with Comparison of 15 Mammalian Species.” Exp Lung Res 1 2 (1980): 171–80.
- Plopper, C. G., A. T. Mariassy, and L. H. Hill. “Ultrastructure of the Nonciliated Bronchiolar Epithelial (Clara) Cell of Mammalian Lung: Ii. A Comparison of Horse, Steer, Sheep, Dog, and Cat.” Exp Lung Res 1 2 (1980): 155–69.
- Boers, J. E., A. W. Ambergen, and F. B. Thunnissen. “Number and Proliferation of Clara Cells in Normal Human Airway Epithelium.” Am J Respir Crit Care Med 159 5 Pt 1 (1999): 1585–91.
- Otelea, M. R., et al. “Club Cells-a Guardian against Occupational Hazards.” Biomedicines 12 1 (2023).
- Weems, Jessica M et al. “Potent mutagenicity of 3-methylindole requires pulmonary cytochrome P450-mediated bioactivation: a comparison to the prototype cigarette smoke mutagens B(a)P and NNK.” Chemical research in toxicology vol. 23,11 (2010): 1682–90.
- Tǎbǎran, Alexandru-Flaviu et al. “Inhaled Furan Selectively Damages Club Cells in Lungs of A/J Mice.” Toxicologic pathology vol. 47,7 (2019): 842–850.
- Aoshiba, K., et al. “A Murine Model of Airway Fibrosis Induced by Repeated Naphthalene Exposure.” Exp Toxicol Pathol 66 4 (2014): 169–77
- Harrod, K. S., et al. “Clara Cell Secretory Protein Decreases Lung Inflammation after Acute Virus Infection.” Am J Physiol 275 5 (1998): L924–30.
- Wang, S. Z., et al. “Clara Cell Secretory Protein Modulates Lung Inflammatory and Immune Responses to Respiratory Syncytial Virus Infection.” J Immunol 171 2 (2003): 1051–60.
- Martinu, T., et al. “Club Cell Secretory Protein in Lung Disease: Emerging Concepts and Potential Therapeutics.” Annu Rev Med 74 (2023): 427–441.
- Liu, Y., et al. “Clara Cell 10-Kda Protein Inhibits T(H)17 Responses through Modulating Dendritic Cells in the Setting of Allergic Rhinitis.” J Allergy Clin Immunol 131 2 (2013): 387–94.e1–12.
About the author:
DR. NOWRIN AHMED
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Nowrin Ahmed has a PhD in Behavioral and Neural Sciences from Rutgers University-Newark (NJ, USA) where she studied the interactions between the midline thalamus and the amygdala. Currently, she is a post-doctoral fellow at Rutgers University — Newark where she is studying amygdala circuits. Dr. Nowrin enjoys sharing the beauty of science with diverse audiences.
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The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
