The Experts below are selected from a list of 252 Experts worldwide ranked by ideXlab platform
Eun Joo Chung - One of the best experts on this subject based on the ideXlab platform.
-
igf 1 receptor signaling regulates Type II Pneumocyte senescence and resulting macrophage polarization in lung fibrosis
International Journal of Radiation Oncology Biology Physics, 2020Co-Authors: Eun Joo Chung, Jessica L. Reedy, Seokjoo Kwon, Ayla O. White, Joon Seon Song, Ilseon Hwang, Joonyong Chung, Kris YlayaAbstract:PURPOSE Type II Pneumocyte (alveolar epithelial cells Type II [AECII]) senescence has been implicated in the progression of lung fibrosis. The capacity of senescent cells to modulate pulmonary macrophages to drive fibrosis is unexplored. Insulin-like growth factor-1 receptor (IGF-1R) signaling has been implicated as a regulator of senescence and aging. METHODS AND MATERIALS Mice with an AECII-specific deletion of IGF-1R received thoracic irradiation (n ≥ 5 per condition), and the effect of IGF-1R deficiency on radiation-induced AECII senescence and macrophage polarization to an alternatively activated phenoType (M2) was investigated. IGF-1R signaling, macrophage polarization, and senescence were evaluated in surgically resected human lung (n = 63). RESULTS IGF-1R deficient mice demonstrated reduced AECII senescence (senescent AECII/field; intact: 7.25% ± 3.5% [mean ± SD], deficient: 2.75% ± 2.8%, P = .0001), reduced accumulation of M2 macrophages (intact: 24.7 ± 2.2 cells/field, deficient: 15.5 ± 1.2 cells/field, P = .0086), and fibrosis (hydroxyproline content; intact: 71.9 ± 21.7 μg/lung, deficient: 31.7 ± 7.9, P = .0485) after irradiation. Senescent AECII enhanced M2 polarization in a paracrine fashion (relative Arg1 mRNA, 0 Gy: 1.0 ± 0.4, 17.5 Gy: 7.34 ± 0.5, P < .0001). Evaluation of surgical samples from patients treated with chemoradiation demonstrated increased expression of IGF-1 (unirradiated: 10.2% ± 4.9% area, irradiated: 15.1% ± 11.5%, P = .0377), p21 (unirradiated: 0.013 ± 0.02 histoscore, irradiated: 0.084 ± 0.09 histoscore, P = .0002), IL-13 (unirradiated: 13.7% ± 2.8% area, irradiated: 21.7% ± 3.8%, P < .0001), and M2 macrophages in fibrotic regions relative to nonfibrotic regions (unirradiated: 11.4 ± 12.2 CD163 + cells/core, irradiated: 43.1 ± 40.9 cells/core, P = .0011), consistent with findings from animal models of lung fibrosis. CONCLUSIONS This study demonstrates that senescent AECII are necessary for the progression of pulmonary fibrosis and serve as a targetable, chronic stimuli for macrophage activation in fibrotic lung.
-
12-Lipoxygenase is a Critical Mediator of Type II Pneumocyte Senescence, Macrophage Polarization and Pulmonary Fibrosis after Irradiation.
Radiation research, 2019Co-Authors: Eun Joo Chung, Jessica L. Reedy, Seokjoo Kwon, Shilpa S. Patil, L. Valle, Ayla O. White, Deborah CitrinAbstract:Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of Type II Pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-Type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-Type mice. Conditioned media from irradiated or 12S-HETE-treated primary Pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated Pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 Type polarization when AECIIs were derived from wild-Type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.
-
role of Type II Pneumocyte senescence in radiation induced lung fibrosis
Journal of the National Cancer Institute, 2013Co-Authors: Deborah Citrin, Ayla O. White, Uma Shankavaram, Jason A Horton, William Shield, Shuping Zhao, Hiroaki Asano, Anastasia L Sowers, Angela Thetford, Eun Joo ChungAbstract:Background Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood.
Bruce D. Uhal - One of the best experts on this subject based on the ideXlab platform.
-
cholera toxin stimulates Type II Pneumocyte proliferation by a cyclic amp independent mechanism
Biochimica et Biophysica Acta, 1998Co-Authors: Bruce D. Uhal, Michael Papp, Kevin Flynn, Mary E SteckAbstract:Cholera toxin (CT) stimulated DNA synthesis by low-density primary cultures of adult rat Type II Pneumocytes (T2P) in a dose-dependent manner, either in the presence or the absence of serum. In the presence of 1% rat serum, 1 microgram/ml CT also stimulated a 50% increase in cell number over 8 days of incubation (P<0.01); this was in addition to a 2-fold increase in cell number induced by the serum alone (P<0.05). The same dose of CT also elevated intracellular cAMP and the total activity of protein kinase A (both P<0.01), suggesting toxin stimulation of T2P proliferation by a cAMP-dependent mechanism. However, the effect of CT on DNA synthesis could not be mimicked by 8-bromoadenosine 3':5'-cyclic monophosphate (8-bromo-cAMP), nor by N6,2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (dibutyryl-cAMP), each tested over a wide range of concentrations. l-Isoproterenol stimulated surfactant secretion by over 5-fold (P<0. 01), but neither the beta-agonist, forskolin nor 3-isobutyl-1-methylxanthine had any significant effect on DNA synthesis. The purified B-subunit of CT stimulated DNA synthesis to the same degree as did the holotoxin, either in the presence or the absence of rat serum. In contrast, the purified A-subunit had no significant effect. These data suggest that cholera toxin stimulates Type II Pneumocyte proliferation through a mechanism that is independent of cAMP, protein kinase A and toxin-catalyzed ADP-ribosylation.
-
flow cytometric study of the Type II Pneumocyte cell cycle in vivo and in vitro
Cytometry, 1994Co-Authors: Bruce D. UhalAbstract:The Type II Pneumocyte cell cycle was studied in vivo and in vitro through bivariate flow cytometric analysis of DNA content vs. incorporated 5-bromo-2-deoxyuridine (BrdUrd). The cell cycle phase durations Ts (7.8 h) and TG2/M (1.1 h), measured in vivo, agreed well with earlier estimates obtained by thymidine labeling. Left unilateral pneumonectomy increased the BrdUrd labeling index of Type II cells in the remaining lung from an initial value of 1.9 +/- 0.3% to 4.8 +/- 1.0%, but had no effect on Ts or TG2/M in vivo. In both normal and pneumonectomized animals, BrdUrd-positive cells in vivo rapidly completed mitosis but did not enter a second S-phase. These results demonstrate that proliferating Type II cells do not form a continuously cycling population in the normal or regenerating adult lung. When cell cycle parameters were measured in vitro immediately after Type II cell isolation, Ts increased 2-fold and TG2/M rose up to 10-fold above the value obtained in vivo. After 2 d of primary culture under customary plating conditions, Ts had returned to the same value as that in vivo, but TG2/M remained elevated. Little variability was observed in the duration of S-phase within each treatment group. In contrast, Type II cells exhibited considerable heterogeneity in the rate of G2/M-phase traverse, especially in vitro. These data suggest that the inability of adult rat Type II Pneumocytes to proliferate in primary culture is related to delayed G2/M-phase transit and imply the existence of Pneumocyte subpopulations which differ in susceptibility to growth arrest.
-
Type II Pneumocyte proliferation in vitro: problems and future directions.
American Journal of Physiology-Heart and Circulatory Physiology, 1991Co-Authors: Bruce D. Uhal, Kevin M. Flowers, D. Eugene RannelsAbstract:In adult animals, the Type II Pneumocyte is progenitor of both the Type I and Type II alveolar epithelium. In primary culture, however, the fate of this cell is uncertain. Type II cells in culture ...
-
Type II Pneumocyte proliferation in vitro: problems and future directions
1991Co-Authors: Bruce D. Uhal, Kevin M. Flowers, Eugene D. Rannels, Bruce D, Eugene D. RanAbstract:1991.-In adult animals, the Type II Pneumocyte is progenitor of both the Type I and Type II alveolar epithelium. In primary culture, however, the fate of this cell is uncertain. Type II cells in culture lose their differentiated properties and eventually resemble Type I cells, but a lack of specific markers has compli-cated the characterization of the phenoType acquired in vitro. Furthermore, limited proliferation of these cells in vitro has precluded definition of the relationship between Type II cell proliferation and differentiation. Recent work in this labora-tory has involved the correlation of flow cytometric cell cycle analysis with phenoType markers. Initial results indicate that isolation of Type II cells induces cell cycle block similar to that sustained by other cell Types in response to stress. In addition, preliminary evaluation of phenoType suggests that traditional markers become ambiguous beyond the 1st day of primary cul
David Warburton - One of the best experts on this subject based on the ideXlab platform.
-
Epidermal growth factor transcription, translation, and signal transduction by rat Type II Pneumocytes in culture.
American journal of respiratory cell and molecular biology, 1992Co-Authors: Lasse Raaberg, Ebba Nexo, Sue Buckley, Wen Luo, Malcolm L. Snead, David WarburtonAbstract:Epidermal growth factor (EGF) is known to induce fetal lung maturation and its receptor is present in the lungs of several species. Recently, EGF has been immunolocalized in Type II Pneumocytes in rat lung. We postulated that EGF is synthesized in Type II Pneumocytes and that, because of its position-restricted distribution within the alveolus, EGF might act as an autocrine regulator of Type II Pneumocyte function. Herein, we have tested the hypothesis using adult rat Type II Pneumocytes in primary culture. In situ hybridization, using an oligonucleotide probe corresponding to amino acid residues 1070 to 1081 of mouse EGF precursor, demonstrated the presence of EGF precursor mRNA. Upon S-200 Sephacryl gel chromatography of Type II Pneumocyte extracts, EGF-reactive protein eluted as a high-molecular-weight form (> 100 kD). EGF immunoreactivity was localized within Type II Pneumocytes in the periphery of groups of 10 to 15 cells in culture. The Type II Pneumocytes bound [125I]EGF in a specific manner, indic...
-
Plasminogen Activator Inhibitor Type 1 Production by Rat Type II Pneumocytes in Culture
American journal of respiratory cell and molecular biology, 1992Co-Authors: Lance A. Parton, David Warburton, Walter E. LaugAbstract:Co-secretion of plasminogen activator inhibitor Type 1 (PAH) and urokinase-Type plasminogen activator was identified in short-term cultures of primary Type II Pneumocytes isolated from adult rats. After separation by sodium dodecyl sulfate (SDS)-PAGE and reverse fibrin autography (reverse FA) of serum-free conditioned medium (SFCM), cellular lysate, and extracellular matrix (ECM), the inhibitor was seen as a zone of spared lysis at an apparent molecular mass of 46 to 48 kD. The plasminogen activator (PA) activity could only be visualized when human instead of bovine fibrin was used in the indicator gel. It presented as a single band of lysis at an apparent molecular mass of 45 kD when tested by regular FA and was found adjacent to PAI-1 when examined by reverse FA. Immunoblot analysis of Type II Pneumocyte SFCM, cellular lysate, and ECM revealed two bands at 46 and 48 kD, consistent with the apparent molecular masses (Mr) reported for rat PAI-1 from HTC hepatoma cells. Type II Pneumocyte PAI-1 formed SDS-...
-
role of inositol triphosphate isomer formation in Type II Pneumocyte signal transduction
American Journal of Respiratory Cell and Molecular Biology, 1991Co-Authors: David Tio, Agnes Tayag, Morris Rehn, David WarburtonAbstract:Adenosine triphosphate (ATP) is a potent agonist of surfactant secretion from Type II Pneumocytes. The extracellular ATP signal is transduced by both P1- and P2-purinergic pathways, which respectively initiate cyclic adenosine monophosphate formation and phosphatidyl inositol hydrolysis to inositol phosphates (Ins P). We investigated the role of inositol triphosphate (Ins P3) isomer formation in this signal transduction pathway. Primary cultures of rat Type II Pneumocytes were labeled with 30 µCi [3H]myoinositol/5 × 106 cells for 48 h. After preincubation with 10 mM LiCl for 20 min, the cells were stimulated with ATP (10−4 M) and then were rapidly frozen with liquid N2. The Ins P3 isomers were analyzed by high performance liquid chromatography. A 4-fold increase in Ins 1,4,5 P3 occurred within 2 s after stimulation with ATP, decreased to half maximum by 60 s, and returned close to baseline values by 2 min. In contrast, Ins 1,3,4 P3 did not increase until 15 s, peaked by 60 s with a 4-fold increase, and re...
Jacob N. Finkelstein - One of the best experts on this subject based on the ideXlab platform.
-
Membrane Phospholipid Methylation is Associated with Surfactant Secretion in Rabbit Type II Alveolar Epithelial Cells
Experimental Lung Research, 2009Co-Authors: Karen D. Hendricks-muoz, Jacob N. Finkelstein, Donald L. ShapiroAbstract:We investigated the involvement of membrane phospholipid methylation in receptor-mediated secretion of surfactant in adult rabbit Type II alveolar epithelial cells (Type II Pneumocyte). Phospholipid methyltransferase activity was found in Type II Pneumocyte microsomes. Cell cultures of adult rabbit Type II Pneumocytes were then used to assay methyltransferase activity in the presence of the β-adrenergic agonist, terbutaline, and the methyltransferase inhibitor, 3-deazaadenosine. Terbutaline predictably stimulated adenylate cyclase activity and surfactant secretion. It was also found to stimulate incorporation of methyl groups into phosphatidylcholine and to increase β-adrenergic receptor availability as assayed by binding of dihydroalprenolol (DHA). Surfactant secretion, as well as adenylate cyclase activity, were stimulated by terbutaline and were inhibited by 3-deazaadenosine. 3-Deazaadenosine did not inhibit DHA binding. These results suggest that phospholipid methylation plays a role in stimulus-secre...
-
tyrosine kinase activity is necessary for growth factor stimulated rabbit Type II Pneumocyte proliferation
Pediatric Research, 1994Co-Authors: Patricia R Chess, Rita M Ryan, Jacob N. FinkelsteinAbstract:ABSTRACT: Tyrosine kinases are important in the signal transduc-tion of a number of growth factors. As shown previously, transforming growth factor (TGF)-α stimulated proliferation of Type II cells in vitro. The mitogenic effect of TGF-α could be blocked by the addition of the tyrosine kinase inhibitors genistein or tyrphostin. Tyrosine phosphorylation in Type II cells exposed to growth factors was examined using an antiphosphotyrosine antibody. After addition of TGF-α, phosphorylation of a tyrosine protein with a molecular mass of 170 kD, presumed to be the epidermal growth factor receptor (EGF-R), peaked by 5 min, returning to baseline by 30 min. As expected, genistein or tyrphostin decreased the TGF-α -induced phosphorylation of the EGF-R. Addition of TGF-β resulted in no newly phosphorylated tyrosine proteins. TGF-β decreased the TGF-α -induced phosphorylation of the EGF-R. Previous work has shown that TGF-β blocks the TGF-α stimulation of Type II cell proliferation. It appears that TGF-β interferes with TGF-α -induced phosphorylation of the EGF-R.
Deborah Citrin - One of the best experts on this subject based on the ideXlab platform.
-
12-Lipoxygenase is a Critical Mediator of Type II Pneumocyte Senescence, Macrophage Polarization and Pulmonary Fibrosis after Irradiation.
Radiation research, 2019Co-Authors: Eun Joo Chung, Jessica L. Reedy, Seokjoo Kwon, Shilpa S. Patil, L. Valle, Ayla O. White, Deborah CitrinAbstract:Radiation-induced pulmonary fibrosis (RIPF) is a chronic, progressive complication of therapeutic irradiation of the thorax. It has been suggested that senescence of Type II Pneumocytes (AECIIs), an alveolar stem cell, plays a role in the development of RIPF through loss of replicative reserve and via senescent AECII-driven release of proinflammatory and profibrotic cytokines. Within this context, we hypothesized that arachidonate 12-lipoxygenase (12-LOX) is a critical mediator of AECII senescence and RIPF. Treatment of wild-Type AECIIs with 12S-hydroxyeicosateraenoic acid (12S-HETE), a downstream product of 12-LOX, was sufficient to induce senescence in a NADPH oxidase 4 (NOX4)-dependent manner. Mice deficient in 12-LOX exhibited reduced AECII senescence, pulmonary collagen accumulation and accumulation of alternatively activated (M2) macrophages after thoracic irradiation (5 × 6 Gy) compared to wild-Type mice. Conditioned media from irradiated or 12S-HETE-treated primary Pneumocytes contained elevated levels of IL-4 and IL-13 compared to untreated Pneumocytes. Primary macrophages treated with conditioned media from irradiated AECII demonstrated preferential M2 Type polarization when AECIIs were derived from wild-Type mice compared to 12-LOX-deficient mice. Together, these data identified 12-LOX as a critical component of RIPF and a therapeutic target for radiation-induced lung injury.
-
role of Type II Pneumocyte senescence in radiation induced lung fibrosis
Journal of the National Cancer Institute, 2013Co-Authors: Deborah Citrin, Ayla O. White, Uma Shankavaram, Jason A Horton, William Shield, Shuping Zhao, Hiroaki Asano, Anastasia L Sowers, Angela Thetford, Eun Joo ChungAbstract:Background Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood.
