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Changes in Clara Cell 10 kDa Protein (CC10)-positive Cell Distribution in Acute Lung Injury Following Repeated Lipopolysaccharide Challenge in the Rat
1 Department of Pathology, Safety Assessment UK, AstraZeneca R&D Charnwood, Loughborough, Leicestershire LE11 5RH, United Kingdom Correspondence: Address correspondence to: Dr. Sarah Jane Bolton, Department of Pathology, Safety Assessment UK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, United Kingdom; e-mail:Sarahj.Bolton{at}astrazeneca.com
Clara cell 10 kDa protein (CC10) is the major secretory protein of Clara cells and is thought to play a protective role in the lung owing to its anti-inflammatory properties. There is little information on the anatomical distribution of CC10-positive cells in rat lung following lipopolysaccharide (LPS) challenge. We have determined the expression of CC10 along the tracheobronchial tree in saline-treated and LPS-treated rats. Saline-treated rats showed sporadic CC10 staining in central airways and abundant staining in bronchioles. In transitional airways, most cells were positive except for squamous cells. Following LPS challenge, there was a reduction in staining in the upper airways but little change within bronchioles. Squamous epithelia within the transitional airways now showed positive staining. These cells also co-stained for pancytokeratin and appeared to co-localize with surfactant D- and Ki67-positive cells, indicating the presence of a dedifferentiated cell type with both epithelial and pneumocyte phenotypes. These data show that diffuse inflammatory injury results in generalized loss of CC10 in central airways. Conversely, the transitional airways showed evidence of a dedifferentiated population of squamous cells that now stained for CC10. We hypothesize that this is an attempt by peripheral lung to maintain alveolar sac integrity during an inflammatory episode.
Key Words: rat • lung • CC10 • tracheobronchial tree • LPS • repair Abbreviations: CC10, Clara cell 10 kDa protein • LPS, lipopolysaccharide • CK, cytokeratin • BALF, bronchoalveolar lavage fluid • KO, knockout • OVA, ovalbumin • SP-D or SP-C, surfactant protein D or C
Clara cell 10 kDa protein (CC10) is the major secretory protein of the Clara cell, a nonciliated secretory epithelial cell present throughout the tracheobronchial tree. It has a variety of names, including CCSP, CC16, uteroglobin, and SCGB1A1, and is part of the family of secretoglobins (Klug et al. 2000). CC10 is known to be steroid inducible and to exhibit anti-inflammatory and immunomodulatory functions, which have been documented in both humans and animals. It is now recognized that CC10 is a sensitive marker of lung injury, and it has been proposed as a peripheral biomarker of airway disease. It is now well established that CC10-positive cells are found throughout the tracheobronchial tree, including the bronchi, in a variety of species including humans, monkeys, and rodents (Barth et al. 2000; Boers et al. 1999; Coppens et al. 2007; Dodge et al. 1993). It has been documented that "classic" CC10-positive Clara cells (i.e., nonciliated, dome-shaped cells), are the predominant cell type in the lower respiratory tree (Jensen et al. 1994; Boers et al., 1999), and there is speculation that the CC10-positive cells seen in the human and rodent bronchi are not true Clara cells but may represent a subset of Clara cells (Broers et al. 1992; Dodge et al. 1993). Clara cells secrete proteins into the epithelial lining fluid of the airways, including CC10 and surfactant proteins A (and D), which are essential for maintaining airway patency in the parenchyma. In addition to their secretory function, Clara cells are thought to be progenitor cells of terminally differentiated bronchiolar epithelium, and it has been shown that the location of the Clara cell can influence this role (Ji et al. 1995; Boers et al. 1999). Clara cells in the bronchi and bronchioles of human airways are not proliferative (Boers et al. 1999; Barth et al. 2000), whereas in terminal bronchioles, Clara cells contributed 15% of the proliferative cells and this fraction rose to 44% in the respiratory bronchioles (Boers et al. 1999). In hyperproliferation of the conducting airways, such as hyperplasia and metaplasia, there is a decrease in CC10 in humans (Jensen et al. 1994; Barth et al. 2000) mice (Hicks et al. 2003) and rats (S. Bolton, unpublished observations). In contrast, peripheral tumors induced in mice under control of the surfactant promoter did not show a reduction in CC10 (Wikenheiser and Whitsett 1997). This finding would suggest that CC10 may have different functions at different anatomical locations. Clara cells are not found in the alveolar bed, but the resident Type II pneumocytes share several key functions with Clara cells, such as proliferative capacity (regarded as stem cell population) and secretion of surfactant (Castranova et al. 1988). CC10 protein is also thought to play a protective role in the lung owing to its anti-inflammatory properties. Studies have shown modulation of CC10 levels in bronchoalveolar lavage fluid (BALF) and plasma during lung inflammation in both human and animal studies, which may represent a common sequela of airway damage. The levels of CC10 were reduced in both serum and BALF of healthy smokers compared to controls (Shijubo et al. 1997; Shijubo et al. 1999), and this finding was reflected in a reduction in the numbers of CC10-positive cells in the airways (Shijubo et al. 1997). In contrast to the BALF data, a recent study showed that there was no alteration in levels of CC10 in sputum from asthmatics (de Burbure et al. 2007), although this result could possibly be attributed to a difference in the areas of lung sampled compared to BALF. Similar reductions in CC10 have been reported in various human lung diseases (reviewed in Shijubo et al. 2003), including non-small cell lung carcinoma (Linnoila et al. 1992; Jensen et al. 1994), asthma (Laing et al. 2000; Shijubo et al. 1999), and sarcoidosis (Ohchi et al., 2004). It has also been demonstrated that a polymorphism in the CC10 gene led to decreased levels of CC10 and was associated with development of the airway disease (Laing et al. 2000; Mansur et al. 2002; Ohchi et al. 2004). Animal studies have shown that CC10 exerts its anti-inflammatory effects by inhibition of phospholipases A and C (Mantile et al. 1993) and PGD2 (Mandal et al. 2004), which are known to be involved in animal models of allergic and inflammatory disease. In the CC10 knock-out (KO) mouse, there was an exaggerated inflammatory response to ovalbumin (OVA) (Chen et al. 2001; Hung et al. 2004; Mandal et al. 2004; Wang et al. 2001) that could be inhibited by treatment with recombinant CC10 (Hung et al. 2004; Mandal et al. 2004), consistent with the proposed anti-inflammatory protective role for CC10. These studies also showed that CC10 could directly modulate cytokine responses (Chen et al. 2001) specifically from Th2 cells (Hung et al. 2004), which putatively drive the OVA-induced pathology. In contrast to the chronic allergic models, acute inflammation induced by lipopolysaccharide (LPS) instillation into rats led to a decrease in CC10-positive epithelial cells in bronchioles (Arsalane et al. 2000; Ooi et al. 1994), which was accompanied by a decrease in CC10 levels in BALF and an increase in serum, owing to leakage across the alveolocapillary barrier (Arsalane et al. 2000). Presence of CC10 in plasma has also been shown in humans following a single inhaled challenge of LPS (Michel et al. 2005). Changes in the levels of CC10, as an indicator of epithelial barrier integrity, can therefore be detected and monitored in blood and lung fluids. Clara cells are also target cells for toxicants such as naphthalene owing to high levels of the cytochrome P450 required for their metabolism (Devereux et al. 1989). In mice exposed to either intraperitoneal or inhaled naphthalene, there was epithelial vacuolation and necrosis accompanied by epithelial sloughing (Plopper et al. 1992; West et al. 2001). Effects on Clara cells and CC10 have been seen in other models of acute lung injury where animals are exposed to other toxicants such as tobacco smoke (Van Miert et al. 2005), ipomeanol (Hermans et al. 1999), ozone (Pinkerton et al. 1993), and LPS (Michel et al. 2005). The Clara cell is a known target for LPS injury following a single exposure (Ooi et al. 1994; Arsalane et al. 2000; Elder et al. 2000; Elizur et al. 2007). Repeat dosing of LPS in rodents is known to induce a level of adaptation or tolerance in the airways that is typified by a reduction in the infiltrating neutrophils, with an increase in macrophages with each subsequent exposure (Elder et al. 2000; Elizur et al. 2007). There are no published reports on the effect of repeat LPS challenge on the resident cells such as Clara cells or expression of CC10 throughout the tracheobronchial tree. Previous studies in rats have described changes in only the bronchioles after a single challenge of LPS (Ooi et al. 1994; Arsalane et al. 2000). We have examined, using an immunohistochemical approach, the phenotype and distribution of CC10-positive cells throughout the tracheobronchial tree in rats exposed to aerosolized LPS for five days. These cells were further characterized for expression of cytokeratin (epithelial marker), surfactant D (SP-D, type II pneumocyte marker), and Ki67 (a proliferative marker) in an attempt to determine the origins and proliferative capacity of these CC10-positive cells.
Reagents and Antibodies LPS, serotype 026:B6, was purchased from Sigma (Poole, Dorset, UK). Antibodies were purchased as follows; rabbit anti-CC10 from Upstate Cell Signalling (Millipore, Chandlers Ford, Hants, UK); mouse anti-pan cytokeratin (pan-CK as marker for epithelial cells; clone C11, cytokeratins 4, 5, 6, 8, 10, 13, 18) from Chemicon (Millipore); mouse anti-rat SP-D (clone SPDE, marker for Type II pneumocytes) from Abcam (Cambridge, Cambs, UK); and mouse anti-Ki67 (clone MM1, proliferation marker) from Vector Labs (Peterborough, Cambs, UK). Isotype control mouse antibodies were purchased from Dako (Ely, Cambs, UK), and rabbit antibodies were purchased from Serotec (Kidlington, Oxon, UK). Alexa-conjugated antibodies were purchased from Molecular Probes (Invitrogen, Paisley, Scotland, UK).
Exposure of Rats to Aerosolized LPS
Tissue Preparation
Immunohistochemistry and Histology
Morphometry
Statistical Analysis
CC10 Expression in Normal Airways CC10 immunostaining was carried out on saline-treated control rats and assessed using standard light microscopy. In the central airways, there was sporadic staining of nonciliated, dome-shaped columnar epithelial cells—typical of the classical Clara cell morphology (Figure 1A, CC). Occasional ciliated columnar epithelial cells were also stained (Figure 1A, CC10 + EC). Within the smaller bronchioles, the staining was more frequent, and the cells showed a typical Clara cell phenotype (Figure 1B), with small, dome-shaped apical caps of CC10-positive material. In transitional airways, typical Clara cells were frequently stained positive (Figure 1C, CC, arrow). At the transitional zone, occasional cuboidal cells were positively stained (Figure 1C, arrow), but not the squamous cells that run into the alveolar bed (Figure 1C, arrowhead). Staining was observed only in epithelial cells, and there was no other positive staining within the alveolar bed apart from the transitional zone. CC10 immunostaining was also carried out on lung samples from naïve rats, with identical results (data not shown). Sections incubated with isotype control rabbit IgG showed no staining (data not shown). Also of note, Ki67 staining (proliferation marker) in the central airways was sparse, with predominantly the basal cell staining positive with no Clara cells showing positive staining (data not shown). Ki67-positive cells in the smaller airways appeared to be a mixture of both Clara cells and basal cells (data not shown).
CC10 Expression Following Repeat LPS Challenge CC10 expression was examined in rats treated once per day for five days with LPS. The aerosolized LPS induced a peribronchial (Figure 2A) and peribronchiolar (Figure 2B) infiltrate of inflammatory cells, which consisted of a mixture of neutrophils and macrophages (Figures 2A and 2B, arrows). Within the transitional airways, the inflammatory cells were seen in the submucosa and within the terminal bifurcation, where there was also a cluster of squamous cells, which were not apparent in control rats (Figure 2C, arrowhead, SqC). In the central airways, there appeared to be a change in the phenotype of some of the CC10-positive cells. Typical Clara cells were still apparent (Figure 2D, CC, arrow), but there were also some CC10-positive epithelial cells without a domed top, which appeared much thinner (Figure 2D, arrowhead). This appearance would suggest that the thin CC10-positive cells represent a subpopulation of CC10-positive cells that have secreted a portion of their CC10 into the airway lumen. Within the bronchioles, there were a few sporadic thin cells, which were not seen in control rats (Figure 2E, arrow; compare to Figure 1B), but the predominant cell type had a Clara cell morphology. Within the transitional airways, the squamous cells at the terminal bifurcation showed positive staining for CC10 (Figure 2F, arrow, SqC). In addition, in some of the cells, the CC10 staining appeared as a ring around the edge of the cell with a clearer zone in the center, suggestive of a secretory morphology (Figure 2F, arrowhead).
Cell counts of all airway compartments were carried out, and cells were classified as either CC10-positive, CC10-positive thin (thin without a domed top), or negative. Within the central airways, there was an increase in the numbers of thin CC10 cells after LPS challenge (p = .0428) with a concomitant decrease in normal CC10-positive cells (p = .0056) without any significant change in the overall cell numbers (Figure 3A). In support of this observation, the overall area of CC10 staining was also reduced in the central airways of LPS-treated rats (Figure 3B). In the bronchioles, there were very few thin CC10-positive cells (Figure 3C). However, this number was significantly increased over saline-treated rats, where there were none, although it was not sufficient to affect the overall area of CC10 staining (Figure 3D). The results from the bronchioles were re-analyzed depending on whether there was an inflammatory infiltrate around the epithelial cells, but there was no difference in saline-treated compared to LPS-treated rats (data not shown). No morphometry was done on the transitional airways owing to the presence of the squamous cells, as there was no equivalent cell type in the saline-treated rats.
Characterization of CC10-positive Squamous Cells in Transitional Airways of LPS-treated Rats In many of the transitional airways of LPS-treated rats, there was a cluster of squamous cells at the terminal bifurcation (compare Figure 1C with Figure 2C). We further characterized these cells using double immunofluorescent staining for CC10 and pan-CK. In larger airways, all CC10-positive cells were shown to represent a subset of pan-CK–positive cells (Figure 4A). The squamous cells at the terminal bifurcation of the transitional airways were also CC10-positive and pan-CK–positive (Figure 4B and 4C, F). Staining of sequential sections showed that these cells were also SP-D–positive (Figure 4D) and that some but not all of the cells were also Ki67-positive (Figure 4E).
CC10 Expression in Normal Bronchi We have demonstrated that CC10-positive cells are present throughout the tracheobronchial tree of rats. Staining was sporadic in the central airways, and cells had both a Clara and a non-Clara cell morphology, whereas the cells in the smaller airways appeared to be all Clara cells. Our observations described in this study confirm earlier reports that there exists a population of bronchial epithelial cells that are CC10-positive in both rats (Dodge et al. 1993) and humans (Broers et al. 1992; Barth et al. 2000). However, whether they are classical Clara cells or represent a subset of Clara cells, or indeed whether they are a completely distinct cell type, is unclear. There are several studies, including our own, that lead us to suggest that the bronchial CC10-positive cells are clearly distinct from their bronchiolar counterparts. First, Dodge et al. (1993) demonstrated that rat bronchial CC10-positive cells have a different cellular distribution of CC10 compared to bronchiolar Clara cells. Second, in our study, some of these bronchial CC10-positive cells appeared to have Clara cell morphology and some were ciliated, which would suggest a mixed population of two distinct cell types of Clara and non-Clara cells. Third, human bronchial CC10-positive cells do not show any proliferative capability, unlike their bronchiolar Clara cell counterparts (Barth et al. 2000). Similarly, we also found that Ki67-positive cells in the central airways were restricted mainly to basal cells, indicating that the bronchial CC10-positive cells do not serve a proliferative stem cell role like true Clara cells. Fourth, modulation of CC10-positive cells in the bronchi as opposed to bronchioles or alveolar bed has also been shown in human lung cancer samples (Jensen et al. 1994) and in the current rat study described here, where we found no effect in the bronchioles. Of course, rather than considering them as distinct cell types, it still remains feasible that they are all Clara cells but with slightly different functions, depending on the anatomical location. With regard to the CC10-positive ciliated cells, it is of course feasible that the cilia seen associated with the cells are from adjacent cells. However, the cilia do not appear to have a tangential cut and are arranged perpendicularly to the stained cell, suggesting that they are directly attached.
CC10 Expression Following Repeated LPS Challenge: Central Airways and Bronchioles It has been documented in many human studies that chronic pulmonary inflammation, as a result of either cigarette smoke exposure or disease such as asthma, results in a decrease in CC10 levels in BALF and serum (Laing et al. 2000; Mutti et al. 2006; Shijubo et al. 1997; Shijubo et al. 1999). A study by Shijubo (Shijubo et al. 1999) found that the actual numbers of CC10-positive cells were decreased in asthmatics. Unfortunately, as the current study was a retrospective immunohistochemical study on archival material, there was no opportunity to assess the CC10 levels in BALF or blood from these rats. Nevertheless, our study provides evidence that the Clara cell is acutely sensitive to epithelial insult and is reduced in chronic inflammatory conditions, which may help to exacerbate and perpetuate the inflammatory cycle.
CC10 Expression Following Repeated LPS Challenge: Transitional Airways
Characterization of CC10-positive Squamous Cells in Transitional Airways of LPS-treated Rats We have shown the appearance of CC10-positive cells within the transitional airways of rats following repeated LPS challenge. An increase in levels or appearance of CC10 within a cell population may be indicative of either a change in cell maturity or a change in cell phenotype. CC10 appears to be a sensitive indicator of epithelial cell function, and it is conceivable that the increased expression in the peripheral airways is a mechanism to compensate for the loss seen in the central airways after injury. As well as a possible role in inflammation, this finding could also be interpreted as an attempt to maintain alveolar sac patency during an acute inflammatory episode.
Arsalane, K, Broeckaert, F, Knoops, B, Wiedig, M, Toubeau, G, & Bernard, A. (2000). Clara cell specific protein (CC16) expression after acute lung inflammation induced by intratracheal lipopolysaccharide administration. Am J Respir Crit Care Med, 161, 1624-30 Barth, P, Koch, S, Muller, B, Unterstab, F, von Wichert, P, & Moll, R. (2000). Proliferation and number of Clara cell 10 kDa protein (CC10)-reactive epithelial cells and basal cells in normal, hyperplastic and metaplastic bronchial mucosa. Virchows Arch, 437, 648-55[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Boers, JE, Ambergen, AW, & Thunnissen, FBJM. (1999). Number and proliferation of Clara cells in normal human airway epithelium. Am J Respir Crit Care Med, 159, 1585-91 Broers, JLV, Jensen, SM, Travis, WD, Pass, H, Whitsett, JA, Singh, G, et al. (1992). Expression of surfactant associated protein A and Clara cell 10 kilodalton mRNA in neoplastic and nonneoplastic human lung tissue as detected by in situ hybridisation. Lab Invest, 66, 337-46[Web of Science][Medline] [Order article via Infotrieve] Castranova, V, Rabovsky, J, Tucker, JH, & Miles, PR. (1988). The alveolar Type II epithelial cell: A multifunctional pneumocyte. Toxicol Appl Pharmacol, 93, 472-83[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Chen, LC, Zhang, Z, Myers, AC, & Huang, SK. (2001). Cutting edge: altered pulmonary eosinophilic inflammation in mice deficient for Clara cell secretory 10-kDa protein. J Immunol, 167, 3025-28 Coppens, JT, Van Winkle, LS, Pinkerton, KE, & Plopper, CG. (2007). Distribution of Clara cell secretory protein expression in the tracheobronchial airways of rhesus monkeys. Am J Physiol Lung Cell Mol Physiol, 292, L1155-62 de Burbure, C, Pignatti, P, Corradi, M, Malerba, M, Clippe, A, Dumont, X, et al. (2007). Uteroglobin-related protein 1 and Clara cell protein in induced sputum of patients with asthma and rhinitis. Chest, 131, 172-79[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Devereux, TR, Domin, BA, & Philpott, RM. (1989). Xenobiotic metabolism by isolated pulmonary cells. Pharmacol Ther, 41, 256 Dodge, DE, Rucker, RB, Singh, G, & Plopper, CG. (1993). Quantitative comparison of intracellular concentration and volume of Clara cell 10 KD protein in rat bronchi and bronchioles based on laser scanning confocal microscopy. J Histochem Cytochem, 41, 1171-83[Abstract] Elder, A, Finkelstein, J, Johnston, C, Gelein, R, & Oberdorster, G. (2000). Induction of adaptation to inhaled lipopolysaccharide in young and old rats and mice. Inhal Toxicol, 12, 225-43[Web of Science][Medline] [Order article via Infotrieve] Elizur, A, Adair-Kirk, TL, Kelley, DG, Griffin, GL, deMello, DE, & Senior, RM. (2007). Clara cells impact the pulmonary innate immune response to LPS. Am J Physiol Lung Cell Mol Physiol, 293, L383-L392 Evans, MJ, Cabral-Anderson, LJ, & Freeman, G. (1978). Role of the Clara cell in renewal of the bronchiolar epithelium. Lab Invest, 38, 648-55[Web of Science][Medline] [Order article via Infotrieve] Guy, J, Dhanireddy, R, & Mukherjee, AB. (1991). Surfactant-producing rabbit pulmonary alveolar type II cells synthesize and secrete an anti-inflammatory protein, uteroglobin. Biochem Biophys Res Comm, 189, 662-69[CrossRef] Hermans, C, Knoops, B, Wiedig, M, Arsalane, K, Toubeau, G, Falmagne, P, et al. (1999). Clara cell protein as a marker of Clara cell damage and bronchoalveolar blood barrier permeability. Eur Resp J, 13, 1014-21[Abstract] Hicks, SM, Vassallo, JD, Dieter, MZ, Lewis, CL, Whiteley, LO, Fix, AS, et al. (2003). Immunohistochemical analysis of Clara cell secretory protein expression in a transgenic model of mouse lung carcinogenesis. Toxicology, 187, 217-28[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Hung, CH, Chen, LC, Zhang, Z, Chowdhury, B, Lee, WL, Plunkett, B, et al. (2004). Regulation of TH2 responses by the pulmonary Clara cell secretory 10-kd protein. J Allergy Clin Immunol, 114, 664-70[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Jensen, SM, Jones, JE, Pass, H, Steinberg, SE, & Linnoila, RI. (1994). Clara cell 1-kDa protein mRNA in normal and atypical regions of human respiratory epithelium. Int J Cancer, 58, 629-37[Web of Science][Medline] [Order article via Infotrieve] Ji, CM, Plopper, CG, & Pinkerton, KE. (1995). Clara cell heterogeneity in differentiation: correlation with proliferation, ultrastructural composition, and cell position in the rat bronchiole. Am J Respir Cell Mol Biol, 13, 144-51[Abstract] Klug, J, Beier, HM, Bernard, A, Chilton, BS, Fleming, TP, Lehrer, RI, et al. (2000). Uteroglobin/Clara cell 10kDa Family of proteins: Nomenclature Committee Report. Ann NY Acad Sci, 923, 348-54[Web of Science][Medline] [Order article via Infotrieve] Laing, AI, Hermans, C, Bernard, A, Burton, PR, Goldblatt, J, & Le Souef, PN. (2000). Association between Plasma CC16 Levels, the A38G Polymorphism, and Asthma. Am J Respir Crit Care Med, 161, 124-27 Linnoila, RI, Jensen, SM, Steinberg, SE, Mulshine, JL, Eggleston, JC, & Gazdar, AF. (1992). Peripheral airway cell marker expression in non-small cell lung carcinoma. Am J Clin Path, 97, 233-43[Web of Science][Medline] [Order article via Infotrieve] Mandal, AK, Zhang, Z, Ray, R, Choi, MS, Chowdhury, B, Pattabiraman, N, et al. (2004). Uteroglobin represses allergen-induced inflammatory response by blocking PGD2 receptor-mediated functions. J Exp Med, 199, 1317-30 Mansur, AH, Fryer, AA, Hepple, M, Strange, RC, & Spiteri, MA. (2002). An association study between the Clara cell secretory protein CC16 A38G polymorphism and asthma phenotypes. Clin Exp Allergy, 32, 994-99[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Mantile, G, Miele, L, Cordella-Miele, E, Singh, G, Katyal, SL, & Mukherjee, AB. (1993). Human Clara cell 10-kDa protein is the counterpart of rabbit uteroglobin. J Biol Chem, 268, 20343-51 Michel, O, Murdoch, R, & Bernard, A. (2005). Inhaled LPS induces blood release of Clara cell specific protein (CC16) in human beings. J Allergy Clin Immunol, 115, 1143-47[CrossRef][Medline] [Order article via Infotrieve] Mutti, A, Corradi, M, Goldoni, M, Vettori, MV, Bernard, A, & Apostoli, P. (2006). Exhaled metallic elements and serum pneumoproteins in asymptomatic smokers and patients with COPD or asthma. Chest, 129, 1288-97[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Ohchi, T, Shijubo, N, Kawabata, I, Ichimiya, S, Inomata, SI, Yamaguchi, A, et al. (2004). Polymorphism of Clara cell 10-kD protein gene of sarcoidosis. Am J Respir Crit Care Med, 169, 180-86 Ooi, H, Arakawa, M, & Ozawa, H. (1994). A morphological study of acute respiratory tract lesions in a lipopolysaccharide instilled rat model. Arch Histol Cytol, 57, 87-105[Web of Science][Medline] [Order article via Infotrieve] Pinkerton, KE, Dodge, DE, Cederdahl-Demmler, J, Wong, VJ, Peake, J, Haselton, CJ, et al. (1993). Differentiated bronchiolar epithelium in alveolar ducts of rats exposed to ozone for 20 months. Am J Pathol, 142, 947-56[Abstract] Plopper, CG, Suverkropp, C, Morin, D, Nishio, S, & Buckpitt, A. (1992). Relationship of cytochrome P-450 activity to Clara cell cytotoxicity. I. Histopathologic comparison of the respiratory tract of mice, rats and hamsters after parenteral administration of naphthalene. J Pharmacol Exper Ther, 261, 353-63 Puchelle, E, Zahm, JM, Tournier, JM, & Coraux, C. (2006). Airway Epithelial Repair, Regeneration, and Remodeling after Injury in Chronic Obstructive Pulmonary Disease. Proc Am Thorac Soc, 3, 726-33 Shijubo, N, Itoh, Y, Yamaguchi, T, Imada, A, Hirasawa, M, Yamada, T, et al. (1999). Clara cell protein-positive epithelial cells are reduced in small airways of asthmatics. Am J Respir Crit Care Med, 160, 930-33 Shijubo, N, Itoh, Y, Yamaguchi, T, Shibuya, Y, Morita, Y, Hirasawa, M, et al. (1997). Serum and BAL Clara cell 10 kDa protein (CC10) levels and CC10-positive bronchiolar cells are decreased in smokers. Eur Resp J, 10, 1108-14[Abstract] Shijubo, N, Kawabata, I, Sato, N, & Itoh, Y. (2003). Clinical aspects of Clara cell 10-kDa protein/uteroglobin (secretoglobin 1A1). Curr Pharm Des, 9, 1139-49[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Shimada, M, Tsukada, H, Ishizuka, O, Kon, Y, Hasegawa, T, Suzuki, E, et al. (2000). Lipopolysaccharide tolerance in relation to intrabronchial influx of neutrophils in the rat. Lung, 178, 235-48[Web of Science][Medline] [Order article via Infotrieve] Van Miert, E, Dumont, X, & Bernard, A. (2005). CC16 as a a marker of lung epithelial hyperpermeability in an acute model of rats exposed to mainstream cigarette smoke. Toxicol Lett, 159, 115-23[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Wang, SZ, Rosenberger, CL, Espindola, TM, Barrett, EG, Tesfaigzi, Y, Bice, DE, et al. (2001). CCSP modulates airway dysfunction and host responses in an Ova-challenged mouse model. Am J Physiol Lung Cell Mol Physiol, 281, L1303-L1311 West, J, Pakenham, G, Morin, D, Fleschner, CA, Buckpitt, A, & Plopper, CG. (2001). Inhaled naphthalene causes dose-dependent Clara cell cytotoxicity in mice but not rats. Toxicol Appl Pharmacol, 173, 114-19[CrossRef][Web of Science][Medline] [Order article via Infotrieve] Wikenheiser, KA, & Whitsett, JA. (1997). Tumor progression and cellular differentiation of pulmonary adenocarcinomas in SV40 large T antigen transgenic mice. Am J Respir Cell Mol Biol, 16, 713-23[Abstract] Wikenheiser, KA, Clark, JC, Linnoila, RI, Stahlman, MT, & Whitsett, JA. (1992). Simian virus 40 large T antigen directed by transcriptional elements of the human surfactant protein C gene produces pulmonary adenocarcinomas in transgenic mice. Cancer Res, 52, 5342-52
This version was published on April
1, 2008 Toxicologic Pathology, Vol. 36, No. 3,
440-448 (2008)
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Abstract
Introduction
