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At least 19 recordsLinked to original sources
PubMed2003

Isolation of a putative progenitor subpopulation of alveolar epithelial type 2 cells.

Alveolar epithelial type 2 cells (AEC2) isolated from hyperoxia-treated animals exhibit increases in both proliferation and DNA damage in response to culture. AEC2 express the zonula adherens proteins E-cadherin, -, - and -catenin, desmoglein, and pp120, as demonstrated by Western blotting. Immunohistochemical analysis of cultured AEC2 showed expression of E-cadherin on cytoplasmic membranes varying from strongly to weakly staining. When cultured AEC2 placed in suspension were labeled with fluorescent-tagged antibodies to E-cadherin, cells could be sorted into at least two subpopulations, either dim or brightly staining for this marker. With the use of antibody to E-cadherin bound to magnetic beads, cells were physically separated into E-cadherin-positive and -negative subpopulations, which were then analyzed for differences in proliferation and DNA damage. The E-cadherin-positive subpopulation contained the majority of damaged cells, was quiescent, and expressed low levels of telomerase activity, whereas the E-cadherin-negative subpopulation was undamaged, proliferative, and expressed high levels of telomerase activity.

Adherens Junctions↗
PubMed1978

Explant culture of human peripheral lung. I. Metabolism of benzo[alpha]pyrene.

Human lung explants have been maintained in vitro for a period of 25 days. Autoradiographic studies indicated that the broncholar epithelial cells, type 2 alveolar epithelial cells, and stromal fibroblasts incorporated 3H-thymidine during the culture. After 7 to 10 days, type 2 cells were the predominant alveolar epithelial cell type. Lamellar inclusion bodies were released from the type 2 cells and accumulated in the alveolar spaces. The metabolism of benzo[alpha]pyrene (BP) in human lung explants cultured for up to 7 days was investigated. Human lung explants had measurable aryl hydrocarbon hydroxylase activity and could metabolize BP into forms that were bound to cellular DNA and protein. Peripheral lung had significantly lower aryl hydrocarbon hydroxylase activity than cultured bronchus but both tissues had similar binding levels of BP to DNA. Radioautographic studies indicated that all cell types in the peripheral lung can metabolize BP. The major ethylacetate extractable metabolites of BP formed by peripheral lung were tetrols and trans-7,8-diol. The primary water-soluble metabolite released with arylsulfatase and beta-glucuronidase was 3-hydroxybenzo[alpha]pyrene.

Aryl Hydrocarbon Hydroxylases↗
PubMed1998

Antioxidant activity in alveolar epithelial type 2 cells of rats during the development of bleomycin injury.

Bleomycin (BLM) induces lung inflammation and subsequent fibrosis in human and in animal models. Alveolar epithelial type 2 cells (T2 cells) are known to play a crucial role in the repair process after BLM injury. We hypothesized that resistance of T2 cells to BLM-damage was associated with an increase in their antioxidant system activity. We developed an animal model of lung lesions preceding fibrosis, using daily intraperitoneal administration of BLM (1.5 mg/day over 7 and 14 days). We observed a body weight stabilization in BLM-treated rats from the third day. After 14 days of BLM treatment, the number of cells recovered by bronchoalveolar lavage was significantly increased (p < 0.05), with a dramatic increase (p < 0.01) in the percentage of neutrophils associated with a decrease in macrophage percentage (p < 0.01) No evidence of fibrosis was seen by microscopic studies at this time. However, T2 cells in 14-day-treated rats were swollen with enlarged lamellar inclusion bodies. Biochemical study of freshly isolated T2 cells displayed a significant decrease of lactate dehydrogenase (LDH) released by these cells when isolated from 14-day-treated rats as compared with 7-day. By contrast, BLM induced an increase in superoxide dismutase (SOD) and glutathione peroxidase activities. Cell content of glutathione was decreased and gamma-glutamyl transpeptidase activity was markedly increased. These results show that BLM induces changes in the antioxidant system of T2 cells, particularly in the glutathione system.

Animals↗
PubMed1972

Alterations in cell proliferation in mouse lung following urethane exposure. 3. Effects of chronic exposure on type 2 alveolar epithelial cell.

The effect of chronic urethane exposure on proliferation of Type 2 alveolar epithelium was investigated by autoradiography. Control mice and mice exposed for 10 weeks to urethane in drinking water were injected with (3)H thymidine and killed at intervals for 7 days. Mean grain counts of Type 2 alveolar cells in the 2 groups showed that the cell cycle time of test mice was prolonged when compared with an estimated 22-hour cycle for controls; this was accompanied by a fivefold increase in labeling index in test animals.

Animals↗
PubMed2004

In vivo inosine protects alveolar epithelial type 2 cells against hyperoxia-induced DNA damage through MAP kinase signaling.

Inosine, a naturally occurring purine with anti-inflammatory properties, was assessed as a possible modulator of hyperoxic damage to the pulmonary alveolar epithelium. Rats were treated with inosine, 200 mg/kg ip, twice daily during 48-h exposure to >90% oxygen. The alveolar epithelial type 2 cells (AEC2) were then isolated and cultured. AEC2 isolated from inosine-treated hyperoxic rats had less DNA damage and had increased antioxidant status compared with AEC2 from hyperoxic rats. Inosine treatment during hyperoxia also reduced the proportion of AEC2 in S and G2/M phases of the cell cycle and increased levels of the DNA repair enzyme 8-oxoguanine DNA glycosylase. Bronchoalveolar lavage (BAL) recovered from hyperoxic, inosine-treated rats contained threefold higher levels of active transforming growth factor-beta than BAL from rats exposed to hyperoxia alone, and Smad2 was activated in AEC2 isolated from these animals. ERK1/2 was activated both in freshly isolated and 24-h-cultured AEC2 by in vivo inosine treatment, whereas blockade of the MAPK pathway in vitro reduced the protective effect of in the vivo inosine treatment. Together, the data suggest that inosine treatment during hyperoxic exposure results in protective signaling mediated through pathways downstream of MEK. Thus inosine may deserve further evaluation for its potential to reduce hyperoxic damage to the pulmonary alveolar epithelium.

Animals↗
PubMed1998

Apoptosis and DNA damage in type 2 alveolar epithelial cells cultured from hyperoxic rats.

Apoptosis is a genetically controlled cellular response to developmental stimuli and environmental insult that culminates in cell death. Sublethal hyperoxic injury in rodents is characterized by a complex but reproducible pattern of lung injury and repair during which the alveolar surface is damaged, denuded, and finally repopulated by type 2 alveolar epithelial cells (AEC2). Postulating that apoptosis might occur in AEC2 after hyperoxic injury, we looked for the hallmarks of apoptosis in AEC2 from hyperoxic rats. A pattern of increased DNA end labeling, DNA laddering, and induction of p53, p21, and Bax proteins, strongly suggestive of apoptosis, was seen in AEC2 cultured from hyperoxic rats when compared with control AEC2. In contrast, significant apoptosis was not detected in freshly isolated AEC2 from oxygen-treated rats. Thus the basal culture conditions appeared to be insufficient to ensure the ex vivo survival of AEC2 damaged in vivo. The oxygen-induced DNA strand breaks were blocked by the addition of 20 ng/ml of keratinocyte growth factor (KGF) to the culture medium from the time of plating and were partly inhibited by Matrigel or a soluble extract of Matrigel. KGF treatment resulted in a partial reduction in the expression of the p21, p53, and Bax proteins but had no effect on DNA laddering. We conclude that sublethal doses of oxygen in vivo cause damage to AEC2, resulting in apoptosis in ex vivo culture, and that KGF can reduce the oxygen-induced DNA damage. We speculate that KGF plays a role as a survival factor in AEC2 by limiting apoptosis in the lung after acute hyperoxic injury.

Animals↗
PubMed1990

Growth-related gene expression in type 2 alveolar epithelial cells.

Our laboratory is studying mechanisms of growth control in alveolar type 2 cells. This highly differentiated cell is induced to proliferate in lungs of animals of all ages during various forms of growth and during the repair process after lung injury. Using type 2 (T2) cells isolated from adult and neonatal rat lungs and an SV40-T transfected T2 cell line, we have shown tha growth-arrested T2 cells constitutively express genes associated with G1 and S phase of the cell cycle, yet they do not efficiently translate the proteins encoded by these genes. This block of growth-related gene expression is post-transcriptional and appears to involve mechanisms that control translation, perhaps at the level of initiation. Furthermore, growth-arrested T2 cells initiate DNA synthesis; however, the cells do not complete the cell cycle, suggesting that they are arrested in a late stage, perhaps the G1/S border. Differential screening of a cDNA library of growth-arrested T2 cells with DNA from growing and growth-arrested T2 cells has identified four families of genes preferentially expressed in the growth-arrested cells. These genes, which are in the process of being characterized, may be responsible for the unusual type of growth arrest demonstrated by T2 cells.

Animals↗
PubMed2005

Contribution of proliferation and DNA damage repair to alveolar epithelial type 2 cell recovery from hyperoxia.

In this study, C57BL/6J mice were exposed to hyperoxia and allowed to recover in room air. The sublethal dose of hyperoxia for C57BL/6J was 48 h. Distal lung cellular isolates from treated animals were characterized as 98% epithelial, with minor fibroblast and endothelial cell contaminants. Cells were then verified as 95% pure alveolar epithelial type II cells (AEC2) by surfactant protein C (SP-C) expression. After hyperoxia exposure in vivo, fresh, uncultured AEC2 were analyzed for proliferation by cell yield, cell cycle, PCNA expression, and telomerase activity. DNA damage was assessed by TdT-dUTP nick-end labeling, whereas induction of DNA repair was evaluated by GADD-153 expression. A baseline level for proliferation and damage was observed in cells from control animals that did not alter significantly during acute hyperoxia exposure. However, a rise in these markers was observed 24 h into recovery. Over 72 h of recovery, markers for proliferation remained elevated, whereas those for DNA damage and repair peaked at 48 h and then returned back to baseline. The expression of GADD-153 followed a distinct course, rising significantly during acute exposure and peaking at 48 h recovery. These data demonstrate that in healthy, adult male C57BL/6J mice, AEC2 proliferation, damage, and repair follow separate courses during hyperoxia recovery and that both proliferation and efficient repair may be required to ensure AEC2 survival.

Animals↗
PubMed2002

GATA6 regulates differentiation of distal lung epithelium.

GATA6 is a member of the GATA family of zinc-finger transcriptional regulators and is the only known GATA factor expressed in the distal epithelium of the lung during development. To define the role that GATA6 plays during lung epithelial cell development, we expressed a GATA6-Engrailed dominant-negative fusion protein in the distal lung epithelium of transgenic mice. Transgenic embryos lacked detectable alveolar epithelial type 1 cells in the distal airway epithelium. These embryos also exhibited increased Foxp2 gene expression, suggesting a disruption in late alveolar epithelial differentiation. Alveolar epithelial type 2 cells, which are progenitors of alveolar epithelial type 1 cells, were correctly specified as shown by normal thyroid transcription factor 1 and surfactant protein A gene expression. However, attenuated endogenous surfactant protein C expression indicated that alveolar epithelial type 2 cell differentiation was perturbed in transgenic embryos. The number of proximal airway tubules is also reduced in these embryos, suggesting a role for GATA6 in regulating distal-proximal airway development. Finally, a functional role for GATA factor function in alveolar epithelial type 1 cell gene regulation is supported by the ability of GATA6 to trans-activate the mouse aquaporin-5 promoter. Together, these data implicate GATA6 as an important regulator of distal epithelial cell differentiation and proximal airway development in the mouse.

Animals↗
PubMed1994

Synthesis and release of amphipathic gamma-glutamyl transferase by the pulmonary alveolar type 2 cell. Its redistribution throughout the gas exchange portion of the lung indicates a new role for surfactant.

gamma-Glutamyl transferase (gamma-GT) catalyzes a transpeptidation reaction which is involved in the metabolism of glutathione. Glutathione is abundant within the epithelial lining fluid of the lung. However, little is known about gamma-GT expression in the epithelial cells of the lung alveolus. Herein we show that the pulmonary alveolar epithelial type 2 cell expresses the gene for gamma-GT. We were unable to detect expression in the pulmonary alveolar epithelial type 1 cell or in the pulmonary alveolar macrophage. gamma-GT expression in the pulmonary alveolar epithelial type 2 cell is via mRNA III, a transcript that was initially cloned from the liver. This cell synthesizes gamma-GT protein and releases enzyme activity into a surfactant-associated pool within the lung alveolus. The specific activity of this surfactant-associated enzyme is almost 10-fold higher than that of whole lung. This activity results from amphipathic gamma-GT since it partitions with lung surfactant phospholipid and with the detergent phase of Triton X-114. Activity can be dissociated from each by papain proteolysis. These results demonstrate that gamma-GT is expressed in the differentiated pulmonary alveolar epithelial type 2 cell and that amphipathic gamma-GT protein is released by this cell along with lung surfactant. These results suggest that surfactant may serve an expanded role in lung cell biology as the vehicle for the redistribution of amphipathic signal anchored proteins throughout the gas exchange surface of the lung.

Animals↗
PubMed1993

The accumulation of pentamidine and the toxic effects of the drug, its selected analogues and metabolites on isolated alveolar cells.

Radiolabelled [3H]pentamidine is accumulated into 48-h and 7-day cultures of alveolar epithelial type 2 cells and alveolar macrophages in a linear, time and dose-dependent manner, with the rate of uptake being 15.3, 13.4 and 17.9 pmol/micrograms protein per 30 min, respectively. Uptake was not affected by metabolic inhibitors. The differential toxicity of the parent drug pentamidine, five analogues and six metabolites was assessed on freshly isolated and type 2 cells maintained in culture over 24 h. Toxicity, determined by the attachment ability of alkaline phosphatase positive cells containing lamellar bodies was greater in freshly isolated cells. Overall, three/four of the analogues proved less damaging to type 2 cells than the pentamidine with one derivative [1,3-bis(4-amidino-2-methoxy)propane], a compound particularly efficacious against pneumocystis in rats, showing minimal toxicity. Five metabolites (chain hydroxylated derivatives) were less toxic than the parent drug. However, one metabolite (N,N-dihydroxy derivative) was much more toxic than pentamidine to both type 2 cells and alveolar macrophages. It is concluded that as the type 2 cell can accumulate the drug, it represents a target cell which is particularly sensitive to pentamidine and/or some of its metabolites.

Alkaline Phosphatase↗
PubMed1990

Localization of inflammation and virions in canine adenovirus type 2 bronchiolitis.

Beagle puppies develop bronchiolar inflammation and histamine hyperresponsiveness with canine adenovirus type 2 (CAV2) infections. We determined the distribution of bronchiolar lesions and correlated inflammation with virions and bronchoalveolar lavage fluid (BALF) cytology. Nineteen beagle puppies were inoculated with tissue culture fluid (control puppies, n = 8), or CAV2 (CAV2, n = 11). The puppies had clinical assessments and measurements of lung resistance (RL), and dynamic compliance (Cdyn) immediately before inoculation (Day zero) and 3 days later (Day 3). The puppies were killed on Day 3, the lungs were removed, and the right intermediate lobe was lavaged. The BALF was assessed for total and differential cell counts. Bronchiolar inflammation was quantitated by bronchiolar inflammation scores (BIS). CAV2 was localized by immunofluorescent antibody staining and electron microscopy. The control puppies remained healthy. The CAV2 puppies had positive cultures for CAV2, respiratory symptoms, and generalized necrotizing bronchiolitis. Alveolar inflammation was quantitatively less prominent than bronchiolar inflammation, and RL and Cdyn were unchanged. The BALF neutrophilia correlated with the BIS. CAV2 was present within bronchiolar epithelium, alveolar epithelial type 2 cells, neutrophils, and macrophages. CAV2 was not found in airways smooth muscles or nerves, nor in any noninflamed tissues of CAV2 puppies or in control animals. Our data suggest that acute CAV2 in beagle puppies produces an inflammation of most bronchioles. Intracellular CAV2 was found in bronchiolar epithelium, macrophages, neutrophils, and alveolar epithelial type 2 cells. Bronchiolar inflammation was reflected in BALF cytology. We conclude that bronchiolar inflammation as indicated by BIS and BALF cytology is related temporarily to histamine hyperresponsiveness in our beagle puppies.

Adenoviridae↗
PubMed1985

Effects of inhalation of 0.12 and 0.25 parts per million ozone on the proximal alveolar region of juvenile and adult rats.

The degree of lung injury caused by prolonged inhalation of low levels of ozone (O3) is of interest since urban environmental levels periodically reach 0.2 to 0.3 ppm. Since the area of the junction of the conductive and respiratory regions of the lung has been reported as the major site of injury due to O3 inhalation, techniques were devised to specifically study alveolar tissue from this region. One-day-old or 6-week-old male rats were exposed to either 0.25 ppm O3 12 hours/day or to continuous room air for 6 weeks. An additional group of 6-week-old rats were exposed to 0.12 ppm O3 for the same time period. All lungs were fixed at the end of the exposure by intratracheal installation of buffered 2% glutaraldehyde. Cylinders of tissue containing a cross-section of a terminal bronchiole were punched out of lung tissue slices using a sharpened cannula. These tissue cylinders were oriented, embedded in Epon, serial sectioned until the first alveolar duct bifurcation was reached, and then thin sectioned for electron microscopy. Qualitative examination of the tissue revealed little observable damage to the proximal alveolar tissues. However, by ultrastructure morphometric analysis, significant changes occurred in the alveolar epithelium of the proximal alveolar region of all exposed animals. In the animals exposed to 0.25 ppm O3 from 1 day of age (juvenile animals), the number of type 1 epithelial cells doubled, their mean surface area decreased 38%, and their mean thickness increased 24%. The number of alveolar type 2 epithelial cells increased, and the number of alveolar macrophages doubled. Adult animals exposed to 0.25 ppm O3 showed similar patterns of changes in the epithelium of the proximal alveolar region and in addition had a doubling of interstitial macrophages, indicating a mild inflammatory stimulus in the interstitium. Adult animals exposed to 0.12 ppm O3 showed smaller, but statistically significant changes in the alveolar type 1 epithelium, suggesting a relatively linear concentration-response relationship. The change in number and size of type 1 cells in all exposed animals is consistent with an increased cell turnover rate due to prolonged O3 inhalation. These results suggest that low concentrations of O3 cause a chronic epithelial injury in the proximal alveolar region and that the extent of these changes occurs in a concentration-dependent manner, even at concentrations as low as 0.12 ppm. No statistically significant age-dependent effects were found.

Aging↗
PubMed1986

Mallory body-like structures in the lung.

Mallory body-like structures (MBLs), which resemble Mallory body (MB) in the liver, were observed in lungs of 4 cases showing interstitial pneumonitis. MBLs were found in the cytoplasm of especially swollen alveolar epithelial cells. MBLs and MBs had almost similar characteristics morphologically and tinctorially under the light microscopy. MBLs were composed of intermediate type fine fibrils which were positive for anti-keratin antibody. These findings suggested that MBLs were a kind of pathological keratinization of alveolar epithelial cells. Although the origin of MBL containing cells could not be clarified, they were closely related to type 2 alveolar epithelial cells.

Aged↗
PubMed1988

Experimental radiation pneumonitis. Corticosteroids increase the replicative activity of alveolar type 2 cells.

Corticosteroid administration during radiation pneumonitis in mice markedly improves the physiologic abnormalities and decreases mortality, an effect that has been attributed to the stimulation of surfactant synthesis and secretion by type 2 alveolar epithelial cells. In the present experiments we explored the effects of corticosteroids on the replicative activity of type 2 cells of lethally irradiated lungs at the height of the radiation reaction. The labeling index of type 2 cells of irradiated mice was increased threefold above that of sham-irradiated controls. Corticosteroids given continuously from 10 weeks after thoracic irradiation further increased the type 2 cell labeling index another threefold above that of irradiated untreated mice. The enhanced reproductive activity of type 2 cells following thoracic irradiation is seen as a protective response that is augmented by corticosteroids, whose effect may be both to improve the physiology of the alveolar surface and to maintain the population of alveolar epithelial cells. The bearing of this result on the controversial role of the type 2 cell as a target in radiation pneumonitis is discussed.

Adrenal Cortex Hormones↗
PubMed1986

Lesions in resected lung parenchyma with regard to possible initial phase of pulmonary emphysema. An ultrastructural study.

Lung tissue appearing macroscopically normal and remote from pathological lesions was examined in semithin and ultrathin sections of surgically excised lobes or entire lungs of 14 patients. Thin areas and apertures were found occupying some of the intercapillary areas of alveolar septa. Thin areas differ from normal intercapillary areas both by their lesser mean thickness and structure; collagenous and elastic fibers, processes of fibrocytes and intercellular substance are absent. Either two layers or only one layer of epithelial lining are encountered in such thin areas. Septal apertures correspond mostly to pores of Kohn by their dimensions. Only some exceed these dimensions or appear in a higher amount per length unit of the alveolar septum. In accordance with other authors we believe that both the thin portions and the apertures of alveolar septa could represent an early phase of destruction in initial stages of pulmonary emphysoma. Continuous epithelial lining in two emphysematous bullae is presented. Structurally, the lining cells are similar to type 2 alveolar epithelial cells, but their bronchiolar origin also has to be considered.

Adult↗
PubMed1977

Experimentally induced bleomycin sulfate pulmonary toxicity: histopathologic and ultrastructural study in the pheasant.

Morphological alterations in the lungs of pheasants after prolonged high-dosage administration of bleomycin sulfate were studied by light and electron microscopy. Nontreated birds acted as controls, and their lungs showed no abnormalities. Lungs of bleomycin-treated pheasants revealed collapse alternating with overexpansion, marked cuboidalization of atrial epithelium, and incipient interstitial fibrosis. There were neither lymphoplasmacytic or eosinophilic infiltrates, nor evidence of vasculitis. Ultrastructurally, type 1 alveolar epithelial cells were either reactive or conspicuously absent in the air capillaries. Type 2 alveolar epithelial cells appeared hyperplastic with numerous lamellar bodies, many of which extruded into air spaces. Immature fibroblasts were noted in the vicinity of collagen fibrils or amorphous material resembling elastin. No immune deposits were present in basement membranes. These findings are consistent with a direct toxic effect of bleomycin to the pheasant lung rather than a drug hypersensitivity reaction. Reproduction of the bleomycin lesion in a nonmammalian species corroborates even further the high propensity of the drug to affect the lung.

Animals↗