1,667 research outputs found
Human lung myofibroblast-derived inducers of alveolar epithelial apoptosis identified as angiotensin peptides
No full textEarlier work from this laboratory found that fibroblasts isolated from fibrotic human lung [human interstitial pulmonary fibrosis (HIPF)] secrete a soluble inducer(s) of apoptosis in alveolar epithelial cells (AECs) in vitro [B. D. Uhal, I. Joshi, A. True, S. Mundle, A. Raza, A. Pardo, and M. Selman. Am. J. Physiol. 269 ( Lung Cell. Mol. Physiol. 13): L819–L828, 1995]. The cultured human fibroblast strains most active in producing the apoptotic activity contained high numbers of stellate cells expressing α-smooth muscle actin, a myofibroblast marker. The apoptotic activity eluted from gel-filtration columns only in fractions corresponding to proteins. Western blotting of the protein fraction identified immunoreactive angiotensinogen (ANGEN), and two-step RT-PCR revealed expression of ANGEN by HIPF fibroblasts but not by normal human lung fibroblasts. Specific ELISA detected angiotensin II (ANG II) at concentrations sixfold higher in HIPF-conditioned medium than in normal fibroblast-conditioned medium. Pretreatment of the concentrated medium with purified renin plus purified angiotensin-converting enzyme (ACE) further increased the ELISA-detectable ANG II eightfold. Apoptosis of AECs in response to HIPF-conditioned medium was completely abrogated by the ANG II receptor antagonist saralasin (50 μg/ml) or anti-ANG II antibodies. These results identify the protein inducers of AEC apoptosis produced by HIPF fibroblasts as ANGEN and its derivative ANG II. They also suggest a mechanism for AEC death adjacent to HIPF myofibroblasts [B. D. Uhal,, I. Joshi, C. Ramos, A. Pardo, and M. Selman. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1192–L1199, 1998].</jats:p
Norepinephrine induces alveolar epithelial apoptosis mediated by α-, β-, and angiotensin receptor activation
No full text Norepinephrine (NE) induces apoptosis in cardiac myocytes, and autocrine production of angiotensin (ANG) II is required for apoptosis of alveolar epithelial cells (AECs) (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 277: L1245–L1250, 1999; Wang R, Alam G, Zagariya A, Gidea C, Pinillos H, Lalude O, Choudhary G, and Uhal BD. J Cell Physiol 185: 253–259, 2000). On this basis, we hypothesized that NE might induce apoptosis of AECs in a manner inhibitable by ANG system antagonists. Purified NE induced apoptosis in the human A549 AEC-derived cell line or in primary cultures of rat AECs, with EC50 values of 200 and 20 nM, respectively. Neither the α-agonist phenylephrine nor the β-agonist isoproterenol could mimic NE when tested alone but when applied together could induce apoptosis with potency equal to NE. Apoptosis and net cell loss (47–59% in 40 h) in response to NE was completely abrogated by the ANG-converting enzyme inhibitor lisinopril or the ANG II receptor antagonist saralasin, each at concentrations capable of blocking Fas- or tumor necrosis factor-α-induced apoptosis. These data suggest that NE induces apoptosis of human and rat AECs through a mechanism involving the combination of α- and β-adrenoceptor activation followed by autocrine generation of ANG II. </jats:p
Jerarquía maya entre los dioses lacandones.. Anales del Instituto Nacional de Antropología e Historia. Num. 47 Tomo XVIII (1965) Sexta Época (1939-1966)
No full textAnónimo a) El Libro de los Libros de Chilam Balam, Trad. por Alfredo Barrera Vásquez y Silvia Rendón. México, 1948.Anónimo b) Popol Vuh, The Sacred Book of the Ancient Quiché Maya, English version by Delia Goetz and Sylvanus G. Morley from the translation of Adrián Recinos. University of Oklahoma Press. Norman, 1950.Bruce S., R. D. a) The Book of Chan Kin. (Inédito).Bruce S., R. D. b) Gramática del Lacandón, Tesis profesional, Escuela Nacional de Antropología e Historia. México, 1965. (lnédito).Landa, Fr. D. de. Relación de las Cosas de Yucatán. México, 1959.Marimon y Tudo, S. Fray Antonio Margil über die Lacandonen, 1695. Zeitschrift für Ethnologie, XIV, pp. 130-32. Stuttgart, 1882.Morley, S. G. La Civilización Maya, versión española de Adrián Recinos. México, 1947.Villa Rojas, A. Los Lacandones. (Inédito)
Fas-induced apoptosis of alveolar epithelial cells requires ANG II generation and receptor interaction
No full text Recent works from this laboratory demonstrated potent inhibition of Fas-induced apoptosis in alveolar epithelial cells (AECs) by the angiotensin-converting enzyme (ACE) inhibitor captopril [B. D. Uhal, C. Gidea, R. Bargout, A. Bifero, O. Ibarra-Sunga, M. Papp, K. Flynn, and G. Filippatos. Am. J. Physiol. 275 ( Lung Cell. Mol. Physiol. 19): L1013–L1017, 1998] and induction of dose-dependent apoptosis in AECs by purified angiotensin (ANG) II [R. Wang, A. Zagariya, O. Ibarra-Sunga, C. Gidea, E. Ang, S. Deshmukh, G. Chaudhary, J. Baraboutis, G. Filippatos and B. D. Uhal. Am. J. Physiol. 276 ( Lung Cell. Mol. Physiol. 20): L885–L889, 1999]. These findings led us to hypothesize that the synthesis and binding of ANG II to its receptor might be involved in the induction of AEC apoptosis by Fas. Apoptosis was induced in the AEC-derived human lung carcinoma cell line A549 or in primary AECs isolated from adult rats with receptor-activating anti-Fas antibodies or purified recombinant Fas ligand, respectively. Apoptosis in response to either Fas activator was inhibited in a dose-dependent manner by the nonthiol ACE inhibitor lisinopril or the nonselective ANG II receptor antagonist saralasin, with maximal inhibitions of 82 and 93% at doses of 0.5 and 5 μg/ml, respectively. In both cell types, activation of Fas caused a significant increase in the abundance of mRNA for angiotensinogen (ANGEN) that was unaffected by saralasin. Transfection with antisense oligonucleotides against ANGEN mRNA inhibited the subsequent induction of Fas-stimulated apoptosis by 70% in A549 cells and 87% in primary AECs (both P < 0.01). Activation of Fas increased the concentration of ANG II in the serum-free extracellular medium 3-fold in primary AECs and 10-fold in A549 cells. Apoptosis in response to either Fas activator was completely abrogated by neutralizing antibodies specific for ANG II ( P < 0.01), but isotype-matched nonimmune immunoglobulins had no significant effect. These data indicate that the induction of AEC apoptosis by Fas requires a functional renin-angiotensin system in the target cell. They also suggest that therapeutic control of AEC apoptosis is feasible through pharmacological manipulation of the local renin-angiotensin system. </jats:p
Angiotensin 1-7/Mas promotes alveolar epithelial cell survival through upregulation of map kinase phosphatase-2
No full textApoptosis is now known to be an important regulator of maintaining normal organ homeostasis. However, in recent years experimental studies support the concept that excessive alveolar epithelial cell (AEC) apoptosis contributes to pathogenic conditions in lung. Studies show that local activation of angiotensin system (ANG) in the lung plays a major role in AEC apoptosis. Autocrine generation of angiotensin II (ANGII) an effector peptide, initiates AEC apoptosis through AT1 receptor, phosphorylating c-Jun-N-terminal kinase (pJNK), both of which are required events in AEC apoptosis. Angiotensin converting enzyme-2 (ACE-2) is a vital enzyme that converts ANGII to angiotensin 1-7 (ANG1-7), promoting cell survival by limiting the accumulation of ANGII. Although the downstream signaling mechanisms of ANG1-7/Mas are unclear, experimental studies have shown anti-apoptotic effects of ANG1-7 in AECs.In this study, the molecular mechanisms by which ANG1-7 and its receptor Mas promote AEC survival are investigated. Previous studies from the Uhal laboratory indicated that under normal conditions ANG1-7 levels are higher than ANGII levels in the AEC culture. Hence, it was theorized that ANG1-7 activates a map kinase phosphatase-2 (MKP-2) and maintains low pJNK levels, as a cell survival mechanism in AECs.The data show blockade of the Mas receptor diminished the induction of MKP-2 by ANG1-7 which confirmed that Mas acts through MKP-2. Further, silencing MKP-2 abolished the ability of ANG1-7 to block ANGII-induced phospho-JNK and apoptosis. Silencing of MKP-2 significantly prevented the blockade of all apoptotic markers such as caspase-9, loss of mitochondrial membrane potential (MMP) and DNA fragmentation by ANG1-7. These data support the theory that ANG1-7 upregulates the phosphatase MKP-2 through Mas and thereby maintains low phospho-JNK levels to promote AEC survival.In conclusion, this study implies that ANG1-7/Mas activation inhibits JNK phosphorylation and apoptosis by constitutively activating MKP-2, and further demonstrates the critical role of the ANG1-7 receptor Mas in AEC survival.Thesis (Ph. D.)--Michigan State University. Biochemistry and Molecular Biology, 2015Includes bibliographical references (pages 110-125
Opening Up an Intelligent Tutoring System Development Environment for Extensible Student Modeling
No full textITS authoring tools make creating intelligent tutoring systems more cost effective, but few authoring tools make it easy to flexibly incorporate an open-ended range of student modeling methods and learning analytics tools. To support a cumulative science of student modeling and enhance the impact of real-world tutoring systems, it is critical to extend ITS authoring tools so they easily accommodate novel student modeling methods. We report on extensions to the CTAT/Tutorshop architecture to support a plug-in approach to extensible student modeling, which gives an author full control over the content of the student model. The extensions enhance the range of adaptive tutoring behaviors that can be authored and support building external, student- or teacher-facing real-time analytics tools. The contributions of this work are: (1) an open architecture to support the plugging in, sharing, re-mixing, and use of advanced student modeling techniques, ITSs, and dashboards; and (2) case studies illustrating diverse ways authors have used the architecture
The tissue angiotensin system in the lung : roles in human pulmonary fibrosis
No full textIdiopathic Pulmonary Fibrosis (IPF) is the most common form of interstitial lung disease with a 3-year median survival upon diagnosis. The lack of effective therapies in treating this disease highlights our incomplete understanding in the pathogenesis of IPF. The prevailing hypothesis is that IPF is a result of abnormal wound healing which consists of persistent injury and apoptosis to alveolar epithelial cells (AECs), aberrant fibroblast proliferation, and the accumulation of extracellular matrix proteins. Our laboratory has implicated a role of the angiotensin (ANG) system in these events. In IPF, both angiotensinogen (AGT), the only known precursor to angiotensin II (ANGII), and Transforming Growth Factor-Beta (TGF-β1) mRNA and protein are up-regulated, as well as the profibrotic peptide, ANGII. In human pulmonary fibroblasts, TGF-β1-inducible AGT transcription is mediated by the core promoter spanning from -46 to +22. At the -20, -18, and -6 positions lies single nucleotide polymorphisms (SNPs) that have been shown to influence its transcription rate in hepatocytes. Our results in human pulmonary fibroblasts parallel those observed in hepatocytes where the CA haplotype at -20 and -6 respectively, had about a 1.5-fold increase in AGT transcription compared to the AG haplotype (p = 0.011). The increase in AGT transcription would result in an increase in ANGII, which we predict to be associated with greater severity of IPF as measured by pulmonary function tests. Studies in IPF cohorts from the United States and Spain demonstrated that the CC genotype at -20 (p = 0.0028 for U.S. and p = 0.017 for Spain), the AA genotype at -6 (p = 0.021 for U.S.), and the CA haplotype (p = 0.0048 for U.S. and p = 0.014 for Spain) predicted lower diffusing capacity. Additionally, the Proline/Proline variant at codon 10 in TGF-β1 was also associated with lower diffusing capacity (p = 0.0014). Surprisingly, the results of both studies were only significant in males, reflecting the male bias of this disease. Preliminary data indicates that in addition to inducing AGT transcription, TGF-β1 also up-regulates cathepsin D and down-regulates ACE-2. Cathepsin D and AGT are both part of the rate-limiting step in the generation of ANGII whereas ACE-2 functions in its removal. This suggests that TGF-β1 may cause an imbalance in the ANG system by favoring the ANGII producing axis. The mechanism by which ACE-2 is down-regulated has not been well studied. However, results from our lab suggests that this down-regulation may be related to ACE-2 ectodomain shedding or through a JNK-mediated mechanism as seen with inducers of ER-stress and cell-cycling in AECs.Thesis (Ph. D.)--Michigan State University. Microbiology and Molecular Genetics, 2014Includes bibliographical reference
Alveolar epithelial cell death adjacent to underlying myofibroblasts in advanced fibrotic human lung
No full text Earlier work from this laboratory showed that abnormal fibroblast phenotypes isolated from fibrotic human lung produce factor(s) capable of inducing apoptosis and necrosis of alveolar epithelial cells in vitro [B. D. Uhal, I. Joshi, A. True, S. Mundle, A. Raza, A. Pardo, and M. Selman. Am. J. Physiol. 269 ( Lung Cell. Mol. Physiol. 13): L819–L828, 1995]. To determine whether epithelial cell death is associated with proximity to abnormal fibroblasts in vivo, the spatial distribution of epithelial cell loss, DNA fragmentation, and myofibroblasts was examined in the same tissue specimens used previously for fibroblast isolation. Paraffin sections of normal and fibrotic human lung were subjected to in situ end labeling (ISEL) of fragmented DNA and simultaneous immunolabeling of α-smooth muscle actin (α-SMA); replicate samples were subjected to electron microscopy and detection of collagens by the picrosirius red technique. Normal human lung exhibited very little labeling except for positive α-SMA immunoreactivity of smooth muscle surrounding bronchi and vessels. In contrast, fibrotic human lung exhibited moderate to heavy ISEL of interstitial, cuboidal epithelial, and free alveolar cells. ISEL of the alveolar epithelium was not distributed uniformly but was most intense immediately adjacent to underlying foci of α-SMA-positive fibroblast-like interstitial cells. Both electron microscopy and picrosirius red confirmed epithelial cell apoptosis, necrosis, and cell loss adjacent to foci of collagen accumulation surrounding fibroblast-like cells. These results demonstrate that the cuboidal epithelium of the fibrotic lung contains dying as well as proliferating cells and support the hypothesis that alveolar epithelial cell death is induced by abnormal lung fibroblasts in vivo as it is in vitro. </jats:p
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