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Impact Of Hyperoxia On Ciliated Cells Biology Essay

Elevated oxygen fraction or hyperoxia is commonly used in the treatment of critically ill patients around the world. However, excessive exposure to high oxygen concentration has an adverse impact. Studies have shown that hyperoxia significantly affects cellular physiology by promoting the formation of reactive oxygen species (ROS), increasing expression of pro-inflammatory cytokines and by activating cell death pathways by altering oxidative signalling (Lee and Choi, 2003, Altemeier W.A. and S.E., 2007). Both in vitro and in vivo studies have demonstrated histopathological changes such as high permeability oedema, hyaline membrane formation, pulmonary vascular lesions, pulmonary fibrosis, and loss of cilia coverage and function (Jones et al., 1984, Kay et al., 2002). These histological and physiological changes have been assumed to be caused by excessive production of ROS such as superoxide anion (.O2-), hydrogen peroxide (H2O2), and hydroxyl radical (.OH) (Dean et al., 2004).

Most of the surface of the respiratory tract is covered with ciliated epithelium; each ciliated cell has about 200 cilia, each being 5-7 µm in length with a configuration of axonemal microtubules (Rautiainen et al., 1990). Ciliary action clears the mucus and associated trapped particles via the mucociliary transport to the pharynx. The deleterious effect of hyperoxia has been reflected both indirectly by the effect on mucociliary clearance and directly in cilia function or loss (Rutman et al., 1993, Rankin et al., 2007).

1-Histological structure of respiratory tract

The respiratory system carrys out the task of supplying the body with oxygen. The respiratory tract can be divided into the upper and lower respiratory tract. The upper tract consists of nostrils, nasal cavities, pharynx, epiglottis, and the larynx while the lower tract contains the trachea, bronchi, bronchioles and the lungs (Figure 1) (Cormack, 1998). The tissue in the respiratory tract is organized in four main layers; these are mucosa, which is divided into epithelium and lamina propria, sub mucosa, cartilage and smooth muscle layer. Most of the respiratory tract is lined by ciliated pseudostratified columnar epithelium which is a single layer consisting of different cell types (Junqueira et al., 1989). These types are columnar ciliated cells covered with cilia, goblet cells which secrete mucus as coating protective liquid and moisten the air and basal cells. Basal cells are short cells lying on the basement membrane but not extending to the lumen of the tract. These cells subsequently differentiate into other cells types (Moran and J.C., 1988). Bronchioles are lined by simple cuboidal epithelium with scattered goblet cells with appearance of Clara cells, which secrete proteins that protect the epithelium against oxidative pollutants and inflammation (Junqueira and Carneiro, 2005). Alveoli are lined by two types of cells: squamous epithelium cell (type I) which covers 93% of the airway surface and cuboidal epithelial cells (type II) which covers 7% of the surface area (Hazinski, 2002). Also bronchioles have specific regions called neuroepithelial bodies made up by groups of cells (80-100) containing granules and supplied with cholinergic nerve endings; they are chemoreceptors that respond to changes in gas composition within the airway and also contribute to the reparative process of airway epithelial cell renewal after injury (Junqueira and Carneiro, 2005).

1-1.Cilia structure

Cilia are hair like extensions from the surface of columnar epithelial cells. They move with a wave motion (metachronal wave) (Moran and J.C., 1988) to propel the mucus and other particles toward the throat. The ciliary beat cycle has two active parts, the effective or power stroke where the cilium is fully extended and moves through an arc perpendicular to the cell surface, and the recovery or preparatory stroke where the cilium swings near the cell surface (Sleigh et al., 1988). Each cilium ends at the base in a basal body attached to the cytoskeleton (Sleigh and Silvester, 1983). The basal body has a lateral foot, all of the basal feet in each cell are oriented in the same direction Thus, the effective strokes of all cilia in the cell have a common orientation (Holley and Afzelius, 1986). Therefore, the basal feet or the central microtubules are used in studies of cilia orientation (Rautiainen et al., 1986).

The normal length of cilia is about 5-7 µm in large airways and 2-3 µm in small airways with a diameter about 0.25-0.33 µm; this normal length is essential for mucociliary transport (Rautiainen et al. 1990). Cilia are contain an axoneme; a cylindrical shape built from a (9+2) arrangement of microtubules. Each doublet has a complete A-subfibre (13 protofilaments) associated with an incomplete B-subfibre (11 protofilaments) (Wanner et al., 1996). The cilial apical region, which is called the ciliary crown, has a specialised structure. This is made up of single A-subfibre instead of the nine outer doublets of microtubule. Thus, it be narrower and stiff for better clearance (Kubo et al., 2008). Three types of connectors link the microtubules together. They are:

Radial spokes that are connected the subfibre (A) to the central microtubules.

Nexin a highly elastic protein connected to the adjacent peripheral microtubules.

Dynein a motor protein connected the subfibre A with subfibre B between to adjacent microtubules (Lodish et al., 2000). Dynein is an armlike structure affixed to the A subfibre. There are two dynein arms, the outer arm with a periodicity of 24 nm, and the inner dynein arm with a periodicity of 96 nm (Reed et al., 2000). Ciliary motility is a result of tubule sliding caused by changes in dynein arms and cyclical attachment between adjacent microtubules (Rutland et al., 1983).

Beneath the epithelium, there is a lamina propria which is a thin vascular layer of connective tissue. Together the epithelium and lamina propria make up the mucosa. The second layer, sub mucosa, is a layer of loose connective tissue; sub-mucosal mixed glands are found in this layer (Cormack, 1998). The mucous granules contain glycoproteins, sialic acid and sulphate groups, while the serous granules which are smaller than mucous granules in diameter contain glycoproteins (Jeffery et al., 1992). The cartilage type in the respiratory tract is hyaline cartilage. The cartilage shapes range from small irregular plates in the bronchi to C- shapes in the trachea (Cormack, 1998). In bronchi with a diameter less than 1 mm, cartilage disappears (Erlandsen and Magney, 1992). The tubes from the trachea to the alveolar ducts are surrounded with a sheet of smooth muscle fibre, which by its contraction, reduces the diameter of conducting tubules, thus, the air flow is regulated during inhalation (Junqueira et al., 1989).

1-2.Cell adhesion

Cell junctions including cell-cell junctions and cell-matrix junctions are essential to tissue integrity and function (Shasby, 2007). These junctions make the cells act as an integrated system. Cell-cell junctions are classified into four groups, gap junctions, tight junctions, adherens junctions and desmosomes; cell-matrix junctions contain two groups, hemidesmosomes and focal adhesion (Figure 5) (Flamme and Kowalczyk, 2008). Gap junctions are channels 1.5-2 nm in diameter. These permit the passage of molecules and ions from one cell to the adjacent cell. These molecules include metabolites (ATP), antioxidants (glutathione), signaling molecules (cAMP, inositol tris phosphate) and ions (Sherwood, 2005). Tight junctions use the occludin and claudin families as linkage proteins. They have two important functions; firstly they regulate the transport and diffusion of molecules and ions between cells. Secondly, they prevent the movement of integral membrane proteins (Morin, 2005). Adherens junctions and desmosomes use cadherin as linkage protein (Flamme and Kowalczyk 2008). These junctions hold cells tightly together. Hemidesmosomes are patches that hold the epithelial cells to the basement membrane. These attachment plaques contain integrins (Alberts et al., 2002). Focal adhesion complex such as integrins, focal adhesion kinase, paxillin and talin provide a structural basis for anchoring the cells to their surrounding (Lodish et al., 2000).

2- Effect of hyperoxia on the respiratory tract

Although elevated oxygen fraction is used in intensive care unit with patients in the critical case, pathological changes in the pulmonary tissue have been shown to occur, and prolonged exposure to high concentrations of oxygen might cause acute or chronic lung injury (Zaher et al., 2007) due to enhanced generation of reactive oxygen species (ROS) (Dean et al., 2004).

ROS such as superoxide (-O•2), hydrogen peroxide (H2O2), and hydroxyl radical (•OH) are formed as a natural products of the normal metabolism of oxygen, and have critical roles in cell signaling. There is a robust antioxidant defence system by which ROS are controlled. When the level of ROS exceed the capacity of the defence system, oxidative damage can result (Turi et al., 2002). ROS may cause lipid peroxidation in cells, protein leakage into the alveolar spaces, alteration of amino acids in structural or functional proteins, alteration of cellular metabolism, DNA strand breakage, less leukocyte influx and an increase in oxidized glutathione (Dedhia and Banks, 1994, Wright et al., 1994, Olive, 1998, Ahmed et al., 2003) (Figure 2).. As well, ciliary activity may be reduced and bronchial mucus transport velocity depressed (Wolfe et al., 1972, Konrad et al., 1995).

The detrimental effects of hyperoxia on the pulmonary architecture have been demonstrated, e.g. decrease in the number and size of alveoli (Appelby and Rheal, 2001); reduction in the cilia numbers associated with apical blebbing appearance in ciliated cells; and loss of cilia coverage (Konradova et al., 2003, Kay et al., 2002), as well as, proliferation of type II alveolar epithelial cells, destruction of type I alveolar epithelial cells, oedema, interstitial fibrosis, hyperplasia and pulmonary vascular remodeling (Quinn et al., 2002). A cell of alveolocapillary barrier damage, alveolar oedema and injury occurs associated with inflammatory response (Barazzone and White, 2000).

3- Effect of hyperoxia on the cells adhesion

Matrix metalloproteinases (MMPs) are groups of proteins that are found in the extracellular matrix, secreted from immune cells particulas leukocytes (Hill, 2002). Many studies have explored the function of these proteins in the pathological and histological changes in the acute lung injury after exposure to high concentrations of oxygen (Ferry et al., 1997, Gibbs et al., 1999). Also, research has demonstrated that MMPs mediate damage tissue caused in some diseases such as atherosclerosis, arthritis, cancer, and ulcerative colitis (Burrage et al., 2006, Rengel et al., 2007). A study by Gushima et al. (2001) has suggested that matrix metalloproteinase play an important role in the pathogenesis of hyperoxic diffuse alveolar damage. The active form of MMP-2, and 9 and the activities of collagenase and gelatinase increased in the bronchoalveolar lavage fluid (BAL) in rats following exposure to hyperoxia (Kohno et al., 2004). In neonatal mouse lung MMP-2, -9 were significantly increased in the mesenchyme and alveolar epithelium (Chetty et al., 2008), whereas Desai et al. (2007) demonstrated that changes in the tyrosine phosphorylation of focal adhesions proteins are associated with decreased adhesion of alveolar type II cells.

In addition, cell junctions can be affected indirectly by hyperoxia through the effects of cytokines, which are proteins secreted to mediate and regulate several amplifying of many immunological actions as a response to tissue damage and pathogens (Heymann et al., 1998). Acute lung inflammation is associated with increased the production of tumor necrosis factor TNF-α which may lead to structural and functional alterations in pulmonary tight junctions in mice (Mazzon and Cuzzocrea, 2007). Also, bronchial epithelial cell apoptosis and loss of cadherin- mediated intercellular adhesion in asthma are associated with secretion of interferon (IFN- gamma) and TNF-α (Trautmann et al., 2005). The expression of the genes for TNF, interleukin-1 beta, interleukin-6, macrophage chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-2 and murine macrophage inflammatory protein-2 (MIP-2) are present and elevated following exposure to high concentrations of oxygen (Jensen et al., 1992, D'Angio et al., 1998, Quinn et al., 2002). Increase in the expression of pro-inflammatory is associated with functional changes and decreasing lung volume (Warner et al., 1998).

4-Cellular defence mechanism

One of the essential mechanism defences against pathogens in the respiratory tract is mucociliary clearance (Rautiainen et al., 1992), which depends on ciliary function, mucus properties and periciliary fluid (Stannard and O'Callaghan, 2006). In addition to its role in trapping the inhaled pathogens and removing them from the tracheobronchial tree, it plays a protective role through the compounds contained in it such as antioxidants. The interaction between the micro-organisms and the inflammatory cells in the surface liquids, prevent them passing through the epithelial airways (Warner et al., 1998).

The periciliary liquid layer and mucus are transported along the airways surfaces in one direction via ciliary action (Matsui et al., 1998). It has been reported that patients with chronic mucopurulent sinusitis has slow mucociliary clearance as a result of ciliary disorientation (Rayner et al., 1995). Ciliary disorientation has also been notice in the primary ciliary dyskinesia patients, due to ciliary movement failure as a result of the absence of dynein arms (Rutman et al., 1993). Konradova (2003) has reported that after exposing rabbits to hyperoxia the number of stimulated goblet cells increased significantly and rapid mucus discharge happened due to acceleration in the mechanism of secretion. Then the overstimulated goblet cells degenerated and sloughed off. Mall (2008) noted, in his review, that airway surface liquid (ASL) depletion produced reduced mucus clearance and caused chronic airway disease with mucus obstruction, reduced bacterial clearance, goblet cells metaplasia and pulmonary mortality. Moreover, the number of cilia was decreased with impairment of self-cleaning ability (Konradova et al., 1988).

As reactive oxygen species play a role in simulating inflammatory cell ability to damage the tissues in the airway (Varani and Ward, 1994); neutrophils, for example, impair ciliary function and mucous clearance in the airway, even without observed histological damage (Buman and Martin, 1986).

The antioxidant mechanisms against ROS in the cells can be categorised into non enzymatic and enzymatic antioxidants; the non enzymatic are certain vitamins and low molecular weight compounds (e.g. thiols), while the main enzymatic are superoxide dismutase, catalase and glutathione peoxidase (Wright et al., 1994). Both lipid and water-soluble antioxidant vitamins provide defence against lipid peroxidation, aqueous free radicals and ROS, respectively (Tasinato et al., 1995, Mojon et al., 1994). A study by Jyonouchi (1998) suggested a protective role of antioxidant vitamins E and C in the small airway epithelial cells, after treatment with hyperoxia, they improved that vitamin E prevented the decline of the suppressed of cell proliferation (thymidine incorporation), in sub-confluence and protected against apoptosis changes, in sub-confluent and near-confluent cells. While vitamin C protected against apoptosis in near-confluent small airway epithelial cells. However, Jacobson et al. (1990) found that increasing the tissue antioxidant (vitamin E and butylated hydroxyanisole (BHA)) and antioxidant enzymes (combination of polyethylene glycol (PEG)-superoxide dismutase (SOD) and PEG-catalase), can prevent some of the pulmonary injury due to hyperoxia such as malondialdehyde, alveolar-capillary permeability, and lung weight increase. This result was similar to what was reported by Gurtner (1985), in which pretreatment with antioxidant vitamin E or BHA prevented the loss of vascular reactivity in rabbit lung. Transgenic mice (Tg) which overexpress intracellular antioxidant enzymes (CuZu-SOD and Mn-SOD) are significantly protected from oxygen toxicity (White et al., 1991, Wispe et al., 1992).

5-Epithelia tissue remodeling after injury

Many functions are involve in the protection and preservation of the airway epithelium, these are mechanical clearance of the mucus, homeostasis of ion and water transport, antioxidant, antibacterial and cellular barrier function through the intercellular epithelial junctions (Puchelle et al., 2006a). After injury or wound, epithelial tissue intervention in a series of consecutive processes of repair and regeneration, includes active mitosis, spreading of the basal cells near the wound area, migration, proliferation and then progressive redifferentiation with the emergence of preciliated cells, and ciliogenesis with complete regeneration of the pseudostratified epithelium (Puchelle et al., 2006b) (figure 3).

A study for Zahm (1997) has been shown that the important step in the wound repair process is the spreading and migration of cells in the denuded airway epithelium and the peaked of proliferative cells at 48 h after injury; then the mitotic activity subsided when the wound closure completed. A lot of molecular factors contribute in these remodeling processes such as cytokines and extracellular matrix, growth factors (figure 4). The sours of these factors are mesenchymal cells, macrophagesm endothelial cells, fibroplasts and epithelial cells (Puchelle et al., 2006a) Seeking for the elements participate in tissue repair after hyperoxia, a study to Pagano et al. (2007) suggested a principal role of poly (AND-ribose)polymerase-1 (PARP-1) which is a nuclear enzyme, activated as a response to DNA damage, in alveolar cells repair and tissue remodeling after exposure mice to acute hyperoxia in in vitro and in vivo

MMP participate in the tissues remodeling by involving in the degradation of extracellular matrix (ECM) components and large amounts produced to repair damaged ECM. It has been shown that MMP-9 play a fundamental role in the bronchial epithelial cells migration to repair wound (Corbel et al., 2000). Because MMP-9 has a specific role in the degradation of type IV collagen, it might involve in the epithelial cell movement through basement membranes (Atkinson and Senior, 2003). In vitro studies suggested that basal cells, Clara cells and type II alveoli cells maintain proliferative capacity (Ford and Terzaghi-Howe, 1992, Rice et al., 2002). After recovery from hyperoxia injury proliferation of type II and nonciliated cells increase in lung (Rhonda et al. 2002). Recent studies refute the concept that ciliated and type I alveoli cells are terminally differentiated cells and do not participate to proliferation in the lung (Evans et al., 1986). Park et al. (2006) showed that ciliated cells are remarkable plasticity during redifferentitation process in bronchiolar epithelium when rapidly undergoing squamous metaplasia and transdifferentiation into cuboidal then to columnar cells (ciliated and non-ciliated). Moreover, Coraux et al. found that MM9 and MM7 expression increased in the stage of well-differentiated surface epithelium while IL-8 expression decreased at this stage but it maximal expression occur in step one of regeneration when the cells adhesion and migration. Furthermore, in vitro study to Zalcman et al. (2006) demonstrated the role of transforming growth factor-β 1 in enhanced the airway epithelial repair by increases MMP -2 secreted from epithelial cells.


From the above outlined research, it seems that although mechanical ventilation with hyperoxia is use to treat the patients in intensive care unit, it may cause tissue damage including acute and chronic respiratory injury due to increase the rate of ROS. The redox damaging effects leading to pulmonary epithelial tissue injury and death has been studied, but the specific mechanisms by which hyperoxia causes cilia loss and malfunction remain incompletely understood. Therefore, more studies are needed to investigate the effectiveness of oxygen and its derivatives on the mechanism leading to loss of individual cilia or ciliated cells (sloughing), and to investigate possible solution to the problem of tissue damage in this situation.



Figure 1 Schematic diagram illustrating upper and lower respiratory tract (A), bronchioles, alveoli, and pulmonary net capillaries (B), Gas exchange between capillaries endothelium and alveoli wall(c).Basad on(National and index, 2009).


Figure 2 Schematic diagram illustrate the stimulating of hyperoxia and ROS to different signaling pathways, such as: nuclear factor kB (NFkB), antioxidant enzymes (AOE), tumor necrosis facter (TNF), interleukin (IL), activator protein (AP), heme oxygen (HO), mitogen activated protein kinase (MAPK).Based on (Zaher et al., 2007).

Figure 3 Steps of airway epithelial regeneration of human trachea xenografts in nude mice. Step I, characterized by airway epithelial cell adhesion and migration (a): 4 days after implantation, the regenerating airway epithelium consisted of a monolayer of flattened undifferentiated cells (a). Step II, characterized by epithelial cell proliferation (b): 13 days after implantation, the rat trachea was covered with a squamous epithelium (b). Step III, characterized by pseudo-stratification of the airway epithelium (c): 24 days after implantation, the epithelium became pseudo-stratified (c). Step IV, characterized by complete pseudo-stratification and differentiation of airway epithelium (d): 35 days after engraftment, the human airway epithelium was fully restored and differentiation was complete. The reconstituted epithelium was similar to that of a normal human well-differentiated and pseudo-stratified mucociliary airway surface epithelium (d). Based on (Coraux et al., 2005) .

.Figure 1

Figure 4- Cellular and molecular factors involved in the repair and regeneration of the airway epithelium. These factors, which closely interact during the different steps of airway epithelial regeneration after injury, are modulated by the components of the extracellular matrix; the matrix metalloproteinases (MMPs), cytokines, and growth factors released by the epithelial cells; and by the mesenchymal cells (fibroblasts, inflammatory cells, and chondrocytes Based on (Puchelle et al., 2006a).

Cell junction

Cell-cell junction

Cell-matrix junctionLocation

Gap junction

Tight junction

Adherens junction



Focal adhesion



Claudin occludin






Intermediate filaments


Keratin (intermediate filaments)Intracellular


Cell-cell communication

Regulate transport along cell wall

Structural cell-cell or cell-matrix

Structural cell-cell

Structural cell-matrix

Structural cell-matrix


Figure 5 Cells adhesion based on (Oakes, 2007)

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