Clara cell antigen in normal and migratory dysplastic Clara cells, and bronchioloalveolar carcinoma of Syrian hamsters induced by N-nitrosomethyl-n-heptylamine

1993 ◽  
Vol 64 (1) ◽  
pp. 181-190 ◽  
Author(s):  
Sabine Rehm ◽  
William Lijinsky ◽  
Barbara J. Thomas ◽  
Barbara H. Kasprzak
Keyword(s):  
Clara Cell ◽  
Bronchioloalveolar Carcinoma ◽  
Clara Cells ◽  
Syrian Hamsters ◽  
Cell Antigen

scholarly journals Squamous Metaplasia of Bronchiolar Cell-derived Adenocarcinoma Induced by N-nitrosomethyl-n-heptylamine in Syrian Hamsters

1994 ◽  
Vol 31 (5) ◽  
pp. 561-571 ◽  
Author(s):  
S. Rehm ◽  
W. Lijinsky
Keyword(s):  
Tumor Cells ◽  
Squamous Cell ◽  
Secretory Granules ◽  
Squamous Metaplasia ◽  
Squamous Cell Carcinomas ◽  
Clara Cell ◽  
Secretory Cells ◽  
Squamous Differentiation ◽  
Syrian Hamsters ◽  
Cell Antigen

Morphology and development of experimental bronchiolar lung tumors were studied in Syrian hamsters, using light and electron microscopic techniques. At the age of 9 weeks, 46 hamsters were each given one weekly gavage of 6.8 mg N-nitrosomethyl- n-heptylamine for 35 weeks, and hamsters were examined at intervals from 2 to 46 weeks. The present report describes the progression of adenocarcinomas of bronchiolar cell origin to adenosquamous and squamous cell carcinomas. Squamous metaplasia was commonly noted at the tumor periphery, i.e., zone of growth. In 20 hamsters, 22 adenosquamous and two squamous cell carcinomas (one a large cell carcinoma) were diagnosed by light microscopy. Overt keratinization was infrequent. Squamous cell metaplasia was not a feature of papillary neoplasms but was seen mainly with acinar structures. Ultrastructurally, squamous differentiation (metaplasia) appeared to develop along two different pathways. First, secretory cells were observed with large numbers of intermediate filaments and tonofilaments, with concurrent loss of organelles such as secretory granules and microvilli. Second, squamous metaplasia also appeared to develop from a progeny of tumor cells that failed to mature into secretory cells. Such cells were often present within the basal layer of secretory acini and resembled basal cells of the tracheobronchial tree. These observations were supported by increased expression of cytokeratins, as revealed by immunohistochemical procedures. Immunoelectron microscopic examination localized hamster Clara cell antigen in secretory granules of neoplastic Clara cells, in the cytoplasm between granules, and at the microvillous border. With the onset of squamous differentiation, Clara cell antigen was progressively lost from secretory cells and was only rarely seen in cells with tonofilaments. No labeling was present in squamous cells arising at the base of tumor acini. These results suggest that pulmonary squamous cell carcinomas may develop by direct squamous differentiation of secretory cells or may proceed from undifferentiated tumor cells.

scholarly journals Plutonium-induced Proliferative Lesions and Pulmonary Epithelial Neoplasms in the Rat: Immunohistochemical and Ultrastructural Evidence for Their Origin from Type II Pneumocytes

1994 ◽  
Vol 31 (3) ◽  
pp. 366-374 ◽  
Author(s):  
R. A. Herbert ◽  
B. S. Stegelmeier ◽  
N. A. Gillett ◽  
A. H. Rebar ◽  
W. W. Carlton ◽  
...  
Keyword(s):  
Clara Cell ◽  
Normal Lung ◽  
Type Ii ◽  
Epithelial Hyperplasia ◽  
Cell Antigen ◽  
Alveolar Epithelial ◽  
Type Ii Pneumocytes ◽  
Epithelial Neoplasms ◽  
Epithelial Lesions ◽  
Surfactant Apoprotein

Immunohistochemistry and transmission electron microscopy were used to clarify the cellular origin for plutonium-239-induced pulmonary proliferative (preneoplastic) epithelial lesions and epithelial neoplasms in F344 rats. Examples of each histologic type of proliferative lesion and neoplasm were stained by the avidin-biotin complex immunoperoxidase method using antibodies to rat surfactant apoprotein and Clara cell antigen. Rat surfactant apoprotein immunostaining was detected in type II pneumocytes in sections of normal lung, in the cells of the proliferative lesions classified histologically as alveolar epithelial hyperplasia (51) and mixed foci (alveolar epithelial hyperplasia with fibrosis) (30), and in adenomas (2), adenocarcinomas (3), and adenosquamous carcinomas (2). With the exception of one adenosquamous carcinoma, Clara cell antigen immunostaining was not detected in any of the pulmonary lesions but was detected in nonciliated cuboidal epithelial (Clara) cells in normal bronchioles. The epithelial cells of the proliferative lesions and neoplasms had ultrastructural features consistent with type II pneumocytes, i.e., the presence of cytoplasmic lamellar and multivesicular bodies. The results of these studies indicate that the majority of plutonium-induced proliferative epithelial lesions and neoplasms in the rat originate from alveolar type II pneumocytes.

Differential susceptibilities of isolated hamster lung cell types to amiodarone toxicity

1998 ◽  
Vol 76 (7-8) ◽  
pp. 721-727 ◽  
Author(s):  
M W Bolt ◽  
W J Racz ◽  
J F Brien ◽  
T M Bray ◽  
T E Massey
Keyword(s):  
Alveolar Macrophages ◽  
Gradient Centrifugation ◽  
Cell Types ◽  
Clara Cell ◽  
Blue Dye ◽  
Alveolar Type ◽  
Specific Cell ◽  
Type Ii ◽  
Clara Cells

Treatment of cardiac dysrhythmias with the iodinated benzofuran derivative amiodarone (AM) is limited by pulmonary toxicity. The susceptibilities of different lung cell types of male Golden Syrian hamsters to AM-induced cytotoxicity were investigated in vitro. Bronchoalveolar lavage and protease digestion to release cells, followed by centrifugal elutriation and density gradient centrifugation, resulted in preparations enriched with alveolar macrophages (98%), alveolar type II cells (75-85%), and nonciliated bronchiolar epithelial (Clara) cells (35-50%). Alveolar type II cell and Clara cell preparations demonstrated decreased viability (by 0.5% trypan blue dye exclusion) when incubated with 50 µM AM for 36 h, and all AM-treated cell preparations demonstrated decreased viability when incubated with 100 or 200 µM AM. Based on a viability index ((viability of AM-treated cells ÷ viability of controls) × 100%), the Clara cell fraction was significantly (p < 0.05) more susceptible than all of the other cell types to 50 µM AM. However, AM cytotoxicity was greatest (p < 0.05) in alveolar macrophages following incubation with 100 or 200 µM AM. There was no difference between any of the enriched cell preparations in the amount of drug accumulated following 24 h of incubation with 50 µM AM, whereas alveolar macrophages accumulated the most drug during incubation with 100 µM AM. Thus, the most susceptible cell type was dependent on AM concentration. AM-induced cytotoxicity in specific cell types may initiate processes leading to inflammation and pulmonary fibrosis.Key words: amiodarone, susceptibility, alveolar macrophage, accumulation.

scholarly journals Immunolocalization of Sonic Hedgehog (Shh) in Developing Mouse Lung

2001 ◽  
Vol 49 (12) ◽  
pp. 1593-1603 ◽  
Author(s):  
Leigh-Anne D. Miller ◽  
Susan E. Wert ◽  
Jeffrey A. Whitsett
Keyword(s):  
Epithelial Cells ◽  
Sonic Hedgehog ◽  
Normal Development ◽  
Clara Cell ◽  
Mouse Lung ◽  
Lung Hypoplasia ◽  
Hepatocyte Nuclear Factor ◽  
Clara Cells ◽  
Lung Morphogenesis ◽  
Conducting Airways

Expression of sonic hedgehog (Shh) is required for normal development of the lung during embryogenesis. Loss of Shh expression in mice results in tracheoesophageal fistula, lung hypoplasia, and abnormal lung lobulation. To determine whether Shh may play a role later in lung morphogenesis, immunostaining for Shh was performed in mouse lung from embryonic day (E) 10.5 to postnatal day (PD) 24. Shh was detected in the distal epithelium of the developing mouse lung from E10.5 to E16.5. From E16.5 until PD15, Shh was present in epithelial cells in both the peripheral and conducting airways. Although all cells of the developing epithelium uniformly expressed Shh at E10.5, Shh expression was restricted to subsets of epithelial cells by E16.5. Between E16.5 and PD15, non-uniform Shh staining of epithelial cells was observed in the conducting airways in a pattern consistent with the distribution of non-ciliated bronchiolar cells (i.e., Clara cells) and the Clara cell marker CCSP. Shh did not co-localize with hepatocyte nuclear factor/forkhead homologue-4 (HFH-4), β-tubulin, or with the presence of cilia. These results support the concept that Shh plays a distinct regulatory role in the lung later in morphogenesis, when it may influence formation or cytodifferentiation of the conducting airways.

The effect of N-acetylcysteine on Clara cells and Clara cell 16 kDa protein in a murine model of allergen-induced airway inflammation

Respirology ◽  
2005 ◽  
Vol 10 (2) ◽  
pp. 157-163 ◽  
Author(s):  
Xiaomeng NIE ◽  
Qiang LI ◽  
Gang CAI ◽  
Yimin DAI ◽  
Jun ZHANG
Keyword(s):  
Airway Inflammation ◽  
Murine Model ◽  
Clara Cell ◽  
Clara Cells

The lung-specific CC10 gene is regulated by transcription factors from the AP-1, octamer, and hepatocyte nuclear factor 3 families

1993 ◽  
Vol 13 (7) ◽  
pp. 3860-3871
Author(s):  
P L Sawaya ◽  
B R Stripp ◽  
J A Whitsett ◽  
D S Luse
Keyword(s):  
Transcription Factors ◽  
Rat Liver ◽  
Transcription Initiation ◽  
Clara Cell ◽  
Clara Cells ◽  
Mobility Shift ◽  
Specific Expression ◽  
Fetal Sheep ◽  
Region I

We have shown that a large fragment (-2339 to +57) from the rat CC10 gene directed lung-specific expression of a reporter construct in transgenic animals. Upon transfection, a smaller fragment (-165 to +57) supported reporter gene expression exclusively in the Clara cell-like NCI-H441 cell line, suggesting that a Clara cell-specific transcriptional element resided on this fragment (B. R. Stripp, P. L. Sawaya, D. S. Luse, K. A. Wikenheiser, S. E. Wert, J. A. Huffman, D. L. Lattier, G. Singh, S. L. Katyal, and J. A. Whitsett, J. Biol. Chem. 267:14703-14712, 1992). The interactions of nuclear proteins with a particular segment of the CC10 promoter which extends from 79 to 128 bp upstream of the CC10 transcription initiation site (CC10 region I) have now been studied. This sequence can stimulate both in vitro transcription in H441 nuclear extract and transient expression of reporter constructs in H441 cells. Electrophoretic mobility shift assays using extracts from H441, HeLa, rat liver, and fetal sheep lung cells were used to demonstrate that members of the AP-1, octamer, and HNF-3 families bind to CC10 region I. Transcription factors from H441 cells which are capable of binding to CC10 region I are either absent in HeLa, rat liver, and fetal sheep lung extracts or enriched in H441 extracts relative to extracts from non-Clara cells.

Pulmonary cytochrome P-450 monooxygenase system and Clara cell differentiation in rats

1995 ◽  
Vol 269 (3) ◽  
pp. L394-L402 ◽  
Author(s):  
C. M. Ji ◽  
W. V. Cardoso ◽  
A. Gebremichael ◽  
R. M. Philpot ◽  
A. R. Buckpitt ◽  
...  
Keyword(s):  
Protein Expression ◽  
Time Course ◽  
Smooth Endoplasmic Reticulum ◽  
Volume Density ◽  
Clara Cell ◽  
Developmental Expression ◽  
Monooxygenase System ◽  
Clara Cells ◽  
Developmental Patterns ◽  
Species Specific

Because a number of studies suggest that the developmental expression of cytochrome P-450s (CYP) in Clara cells is species specific, this study was designed to compare the developmental patterns of the isoform CYP2B and NADPH reductase protein expression and CYP2B activity with the time course of smooth endoplasmic reticulum (SER) formation in Clara cells of rat lung. Pulmonary CYP2B activity measured as pentoxyresorufin O-dealkylation in lung homogenates was not detectable before 7 days postnatal age, but was detectable at adult levels at 50 days postnatal age. In Clara cells, CYP2B and NADPH reductase were detected immunohistochemically at 4 days postnatal age and at adult levels at 10 days postnatal age. The volume density of SER in Clara cells of terminal bronchioles measured morphometrically increased significantly with postnatal age. We conclude that in the rat 1) CYP2B and NADPH reductase distribution and CYP2B activity are age dependent; 2) the increase in Clara cell SER precedes the expression of CYP2B protein; 3) cellular appearance of CYP2B protein precedes CYP activity; and 4) SER appearance and P-450 protein expression do not occur uniformly in differentiating Clara cells, even within the same bronchiole.

Clara cell secretory protein deficiency increases oxidant stress response in conducting airways

1998 ◽  
Vol 275 (2) ◽  
pp. L348-L356 ◽  
Author(s):  
Gregory W. Mango ◽  
Carl J. Johnston ◽  
Susan D. Reynolds ◽  
Jacob N. Finkelstein ◽  
Charles G. Plopper ◽  
...  
Keyword(s):  
Stress Response ◽  
Mrna Expression ◽  
Molecular Basis ◽  
Oxidant Stress ◽  
Secretory Protein ◽  
Protective Role ◽  
Clara Cell ◽  
Clara Cells ◽  
Clara Cell Secretory Protein ◽  
Oxidant Sensitivity

Little is known about the molecular basis for differential pulmonary oxidant sensitivity observed between genetically disparate members of the same species. We have generated mice that are deficient in Clara cell secretory protein (CCSP −/−) and that exhibit an oxidant-sensitive phenotype. We characterized the kinetics and distribution of altered stress-response [interleukin-6 (IL-6) and metallothionein (MT)] and epithelial cell-specific [cytochrome P-450 2F2 (CYP2F2)] gene expression to further understand the cellular and molecular basis for altered oxidant sensitivity in 129 strain CCSP −/− mice. Increases in IL-6 and MT mRNA abundance were detected by 2 h of exposure to 1 part/million ozone and preceded reductions in Clara cell CYP2F2 mRNA expression. Despite being qualitatively similar, increases in IL-6 and MT mRNA expression were enhanced in CCSP −/− mice with respect to coexposed 129 strain wild-type mice. Increased MT mRNA expression, indicative of the stress response, localized to the airway epithelium, surrounding mesenchyme, and endothelium of blood vessels. These results demonstrate a protective role for Clara cells and their secretions and indicate potential genetic mechanisms that may influence susceptibility to oxidant stress.

Na+ and Cl- transport across rabbit nonciliated bronchiolar epithelial (Clara) cells

1989 ◽  
Vol 256 (4) ◽  
pp. C893-C901 ◽  
Author(s):  
M. R. Van Scott ◽  
C. W. Davis ◽  
R. C. Boucher
Keyword(s):  
Ion Transport ◽  
Short Circuit ◽  
Flux Ratio ◽  
Open Circuit ◽  
Clara Cell ◽  
Clara Cells ◽  
Transport Pathway ◽  
Transport Pathways ◽  
Serum Free ◽  
Significant Difference

Radioisotopic flux measurements were performed on rabbit Clara cell epithelium cultured in serum-free hormone-supplemented medium to identify the major ion transport pathways in the cell type. Clara cells cultured in serum-free hormone-supplemented medium exhibit a large short-circuit current compared with cells maintained in serum-containing medium (45 microA/cm2 vs. 15 microA/cm2). The responses to amiloride and isoproterenol, however, are similar for cells grown in the two media. A net amiloride-sensitive movement of Na+ in the mucosal (M)-to-serosal (S) direction undershort- and open-circuit conditions is detected (1.48 and 0.67 mueq.h-1.cm-2, respectively). No statistically significant difference in the unidirectional fluxes of Cl- is apparent in the basal state, but a net flux of Cl- in the S-to-M direction is observed after exposure of the apical membrane to amiloride (0.93 mueq.h-1.cm-2). The partial ionic conductances for Na+ and Cl- estimated from the fluxes measured in the passive directions (JNaS----M, JClM----S) exceed the total tissue conductance by 20%. Ussing flux ratio analyses of Cl- movements at clamped potentials between -60 and +20 mV show that Cl- movements are not strictly through passive conductive pathways at negative potentials. The movement of Cl- can be modeled by passive diffusion combined with Cl- -Cl- exchange equal to 20% of total passive fluxes of Na+ and Cl-. These observations indicate that 1) Na+ absorption is the major active ion transport pathway across cultured Clara cells, 2) active Cl- secretion is minimal in the basal state, and 3) approximately 20% of the unidirectional Cl- fluxes occur via nonconductive pathways.

scholarly journals Matrix modulation of compensatory lung regrowth and progenitor cell proliferation in mice

2010 ◽  
Vol 298 (2) ◽  
pp. L158-L168 ◽  
Author(s):  
A. M. Hoffman ◽  
A. Shifren ◽  
M. R. Mazan ◽  
A. M. Gruntman ◽  
K. M. Lascola ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Mechanical Stress ◽  
Progenitor Cells ◽  
Stress Responses ◽  
Transpulmonary Pressure ◽  
Alveolar Epithelial Cells ◽  
Clara Cell ◽  
Physical Factors ◽  
Clara Cells ◽  
Elastic Recoil

Mechanical stress is an important modulator of lung morphogenesis, postnatal lung development, and compensatory lung regrowth. The effect of mechanical stress on stem or progenitor cells is unclear. We examined whether proliferative responses of epithelial progenitor cells, including dually immunoreactive (CCSP and proSP-C) progenitor cells (CCSP+/SP-C+) and type II alveolar epithelial cells (ATII), are affected by physical factors found in the lung of emphysematics, including loss of elastic recoil, reduced elastin content, and alveolar destruction. Mice underwent single lung pneumonectomy (PNY) to modulate transpulmonary pressure (mechanical stress) and to stimulate lung regeneration. Control mice underwent sham thoracotomy. Plombage of different levels was employed to partially or completely abolish this mechanical stress. Responses to graded changes in transpulmonary pressure were assessed in elastin-insufficient mice (elastin +/−, ELN+/−) and elastase-treated mice with elastase-induced emphysema. Physiological regrowth, morphometry (linear mean intercept; Lmi), and the proliferative responses of CCSP+/SP-C+, Clara cells, and ATII were evaluated. Plombage following PNY significantly reduced transpulmonary pressure, regrowth, and CCSP+/SP-C+, Clara cell, and ATII proliferation following PNY. In the ELN+/− group, CCSP+/SP-C+ and ATII proliferation responses were completely abolished, although compensatory lung regrowth was not significantly altered. In contrast, in elastase-injured mice, compensatory lung regrowth was significantly reduced, and ATII but not CCSP+/SP-C+ proliferation responses were impaired. Elastase injury also reduced the baseline abundance of CCSP+/SP-C+, and CCSP+/SP-C+ were found to be displaced from the bronchioalveolar duct junction. These data suggest that qualities of the extracellular matrix including elastin content, mechanical stress, and alveolar integrity strongly influence the regenerative capacity of the lung, and the patterns of cell proliferation in the lungs of adult mice.

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