The Experts below are selected from a list of 132 Experts worldwide ranked by ideXlab platform
Steven D Shapiro - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Elastase induces trail mediated tumor cell death through its carboxy terminal domain
American Journal of Respiratory and Critical Care Medicine, 2017Co-Authors: Nadine Dandachi, Neil J Kelly, Adriana S Leme, John P Wood, Christine L Burton, Josiah E Radder, Alyssa D Gregory, Steven D ShapiroAbstract:Rationale: Macrophage Elastase (matrix metalloproteinase [MMP]-12) is a potent protease that contributes to the lung destruction that accompanies cigarette smoking; it simultaneously inhibits lung tumor angiogenesis and metastasis by catalyzing the formation of antiangiogenic peptides. Recent studies have revealed novel nonproteolytic functions of MMP12, including antimicrobial activity through a peptide within its C-terminal domain (CTD).Objectives: To determine whether the MMP12 CTD contributes to its antitumor activity in lung cancer.Methods: We used recombinant MMP12 peptide fragments, including its catalytic domain, CTD, and a 20 amino acid peptide within the CTD (SR20), in an in vitro system to delineate their effects on non–small cell lung cancer cell proliferation and apoptosis. We translated our findings to two murine models of lung cancer, including orthotopic human xenograft and KrasLSL/G12D mouse models of lung cancer.Measurements and Main Results: We show that SR20 triggers tumor apoptosis by...
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Macrophage Elastase suppresses white adipose tissue expansion with cigarette smoking
American Journal of Respiratory Cell and Molecular Biology, 2014Co-Authors: Takao Tsuji, Mcgarry A Houghton, Neil J Kelly, Saeko Takahashi, Adriana S Leme, Steven D ShapiroAbstract:Macrophage Elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight suppressing effects of smoking are a major hindrance to cessation efforts, and MMP12 is known to suppress the vascularization on which adipose tissue growth depends by catalyzing the formation of antiangiogenic peptides endostatin and angiostatin. The goal of this study was to determine the role of MMP12 in adipose tissue growth and smoking-related suppression of weight gain. Whole body weights and white adipose depots from wild-type and Mmp12-deficient mice were collected during early postnatal development and after chronic CS exposure. Adipose tissue specimens were analyzed for angiogenic and adipocytic markers and for content of the antiangiogenic peptides endostatin and angiostatin. Cultured 3T3-L1 adipocytes were treated with adipose tissue homogenate to examine its effects on vascular endothelial growth factor (VEGF) expression and sec...
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Macrophage Elastase kills bacteria within murine Macrophages
Nature, 2009Co-Authors: Mcgarry A Houghton, William O Hartzell, Clinton S Robbins, Xavier F Gomisruth, Steven D ShapiroAbstract:Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. Here, Macrophage Elastase, an enzyme implicated in several disease processes including emphysema, is shown to have direct antimicrobial activity against Gram-positive and Gram-negative bacteria.
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Macrophage Elastase kills bacteria within murine Macrophages
Nature, 2009Co-Authors: Mcgarry A Houghton, William O Hartzell, Clinton S Robbins, Xavier F Gomisruth, Steven D ShapiroAbstract:Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that Macrophage-derived proteinases may contribute to the antimicrobial properties of Macrophages. Macrophage Elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue Macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12(-/-) mice exhibit impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at Macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to Macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.
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cd8 t cells are required for inflammation and destruction in cigarette smoke induced emphysema in mice
Journal of Immunology, 2007Co-Authors: Mcgarry A Houghton, Steven D Shapiro, Pablo A Quintero, Toshitaka Maeno, Sandra Grumelli, Caroline A OwenAbstract:Increased numbers of T lymphocytes are observed in the lungs of patients with chronic obstructive pulmonary disease, but their role in the disease process is not known. We investigated the role of CD8+ T cells in inflammatory cell recruitment and lung destruction in a cigarette smoke-induced murine model of emphysema. In contrast to wild-type C57BL/6J mice that displayed Macrophage, lymphocyte, and neutrophil recruitment to the lung followed by emphysema in response to cigarette smoke, CD8+ T cell-deficient (CD8-/-) mice had a blunted inflammatory response and did not develop emphysema when exposed to long-term cigarette smoke. Further studies supported a pathogenetic pathway whereby the CD8+ T cell product, IFN-gamma-inducible protein-10, induces production of Macrophage Elastase (matrix metalloproteinase 12) that degrades elastin, both causing lung destruction directly and generating elastin fragments that serve as monocyte chemokines augmenting Macrophage-mediated lung destruction. These studies demonstrate a requirement for CD8+ T cells for the development of cigarette smoke-induced emphysema and they provide a unifying pathway whereby CD8+ T cells are a central regulator of the inflammatory network in chronic obstructive pulmonary disease.
Mcgarry A Houghton - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Elastase suppresses white adipose tissue expansion with cigarette smoking
American Journal of Respiratory Cell and Molecular Biology, 2014Co-Authors: Takao Tsuji, Mcgarry A Houghton, Neil J Kelly, Saeko Takahashi, Adriana S Leme, Steven D ShapiroAbstract:Macrophage Elastase (MMP12) is a key mediator of cigarette smoke (CS)-induced emphysema, yet its role in other smoking related pathologies remains unclear. The weight suppressing effects of smoking are a major hindrance to cessation efforts, and MMP12 is known to suppress the vascularization on which adipose tissue growth depends by catalyzing the formation of antiangiogenic peptides endostatin and angiostatin. The goal of this study was to determine the role of MMP12 in adipose tissue growth and smoking-related suppression of weight gain. Whole body weights and white adipose depots from wild-type and Mmp12-deficient mice were collected during early postnatal development and after chronic CS exposure. Adipose tissue specimens were analyzed for angiogenic and adipocytic markers and for content of the antiangiogenic peptides endostatin and angiostatin. Cultured 3T3-L1 adipocytes were treated with adipose tissue homogenate to examine its effects on vascular endothelial growth factor (VEGF) expression and sec...
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Macrophage Elastase kills bacteria within murine Macrophages
Nature, 2009Co-Authors: Mcgarry A Houghton, William O Hartzell, Clinton S Robbins, Xavier F Gomisruth, Steven D ShapiroAbstract:Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. Here, Macrophage Elastase, an enzyme implicated in several disease processes including emphysema, is shown to have direct antimicrobial activity against Gram-positive and Gram-negative bacteria.
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Macrophage Elastase kills bacteria within murine Macrophages
Nature, 2009Co-Authors: Mcgarry A Houghton, William O Hartzell, Clinton S Robbins, Xavier F Gomisruth, Steven D ShapiroAbstract:Macrophages are aptly positioned to function as the primary line of defence against invading pathogens in many organs, including the lung and peritoneum. Their ability to phagocytose and clear microorganisms has been well documented. Macrophages possess several substances with which they can kill bacteria, including reactive oxygen species, nitric oxide, and antimicrobial proteins. We proposed that Macrophage-derived proteinases may contribute to the antimicrobial properties of Macrophages. Macrophage Elastase (also known as matrix metalloproteinase 12 or MMP12) is an enzyme predominantly expressed in mature tissue Macrophages and is implicated in several disease processes, including emphysema. Physiological functions for MMP12 have not been described. Here we show that Mmp12(-/-) mice exhibit impaired bacterial clearance and increased mortality when challenged with both gram-negative and gram-positive bacteria at Macrophage-rich portals of entry, such as the peritoneum and lung. Intracellular stores of MMP12 are mobilized to Macrophage phagolysosomes after the ingestion of bacterial pathogens. Once inside phagolysosomes, MMP12 adheres to bacterial cell walls where it disrupts cellular membranes resulting in bacterial death. The antimicrobial properties of MMP12 do not reside within its catalytic domain, but rather within the carboxy-terminal domain. This domain contains a unique four amino acid sequence on an exposed beta loop of the protein that is required for the observed antimicrobial activity. The present study represents, to our knowledge, the first report of direct antimicrobial activity by a matrix metallopeptidase, and describes a new antimicrobial peptide that is sequentially and structurally unique in nature.
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cd8 t cells are required for inflammation and destruction in cigarette smoke induced emphysema in mice
Journal of Immunology, 2007Co-Authors: Mcgarry A Houghton, Steven D Shapiro, Pablo A Quintero, Toshitaka Maeno, Sandra Grumelli, Caroline A OwenAbstract:Increased numbers of T lymphocytes are observed in the lungs of patients with chronic obstructive pulmonary disease, but their role in the disease process is not known. We investigated the role of CD8+ T cells in inflammatory cell recruitment and lung destruction in a cigarette smoke-induced murine model of emphysema. In contrast to wild-type C57BL/6J mice that displayed Macrophage, lymphocyte, and neutrophil recruitment to the lung followed by emphysema in response to cigarette smoke, CD8+ T cell-deficient (CD8-/-) mice had a blunted inflammatory response and did not develop emphysema when exposed to long-term cigarette smoke. Further studies supported a pathogenetic pathway whereby the CD8+ T cell product, IFN-gamma-inducible protein-10, induces production of Macrophage Elastase (matrix metalloproteinase 12) that degrades elastin, both causing lung destruction directly and generating elastin fragments that serve as monocyte chemokines augmenting Macrophage-mediated lung destruction. These studies demonstrate a requirement for CD8+ T cells for the development of cigarette smoke-induced emphysema and they provide a unifying pathway whereby CD8+ T cells are a central regulator of the inflammatory network in chronic obstructive pulmonary disease.
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Macrophage Elastase matrix metalloproteinase 12 suppresses growth of lung metastases
Cancer Research, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Dean R Hautamaki, Jay L Grisolano, Mary Baumann, Leslie C Nehring, Lynn A Cornelius, Steven D ShapiroAbstract:Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in Macrophage Elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely Macrophage derived in this model, being expressed by tumor-associated Macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics. (Cancer Res 2006; 66(12): 6149-55)
Dale K Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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Macrophage Elastase matrix metalloproteinase 12 suppresses growth of lung metastases
Cancer Research, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Dean R Hautamaki, Jay L Grisolano, Mary Baumann, Leslie C Nehring, Lynn A Cornelius, Steven D ShapiroAbstract:Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in Macrophage Elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely Macrophage derived in this model, being expressed by tumor-associated Macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics. (Cancer Res 2006; 66(12): 6149-55)
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Macrophage Elastase matrix metalloproteinase 12 suppresses growth of lung metastases
Cancer Research, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Dean R Hautamaki, Jay L Grisolano, Mary Baumann, Leslie C Nehring, Lynn A Cornelius, Steven D ShapiroAbstract:Matrix metalloproteinases (MMP) have been implicated in virtually all aspects of tumor progression. However, the recent failure of clinical trials employing synthetic MMP inhibitors in cancer chemotherapy has led us to hypothesize that some MMPs may actually serve the host in its defense against tumor progression. Here we show that mice deficient in Macrophage Elastase (MMP-12) develop significantly more gross Lewis lung carcinoma pulmonary metastases than their wild-type counterparts both in spontaneous and experimental metastasis models. The numbers of micrometastases between the two groups are equivalent; thus, it seems that MMP-12 affects lung tumor growth, and not metastasis formation, per se. MMP-12 is solely Macrophage derived in this model, being expressed by tumor-associated Macrophages and not by tumor or stromal cells. The presence of MMP-12 is associated with decreased tumor-associated microvessel density in vivo and generates an angiostatic>angiogenic tumor microenvironment that retards lung tumor growth independent of the production of angiostatin. These data define a role for MMP-12 in suppressing the growth of lung metastases and suggest that inhibitors designed to specifically target tumor-promoting MMPs may yet prove effective as cancer therapeutics.
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elastin fragments drive disease progression in a murine model of emphysema
Journal of Clinical Investigation, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Diane G Kelley, Robert P Mecham, Robert M, Pablo A Quintero, David L Perkins, Luiz A Marconcini, Steven D ShapiroAbstract:Mice lacking Macrophage Elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung Macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for Macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from Macrophage Elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic Elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both Macrophage accumulation and airspace enlargement.
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neutrophil Elastase contributes to cigarette smoke induced emphysema in mice
American Journal of Pathology, 2003Co-Authors: Steven D Shapiro, Nir M Goldstein, Mcgarry A Houghton, Dale K Kobayashi, Diane G Kelley, Abderazzaq BelaaouajAbstract:To address the role of neutrophil Elastase in pulmonary emphysema, neutrophil Elastase-deficient mice and wild-type littermate controls were exposed to long-term cigarette smoke. Compared to wild-type littermates, mice that were deficient in neutrophil Elastase were significantly protected (59%) from the development of emphysema. Previously, we demonstrated complete protection from emphysema in the absence of Macrophage Elastase. Further analysis revealed several interactions between these two Elastases. Each Elastase inactivated the endogenous inhibitor of the other, with neutrophil Elastase degrading tissue inhibitor of metalloproteinase-1, and Macrophage Elastase degrading α-1-antitrypsin. Cigarette smoke-induced recruitment of both neutrophils and monocytes was impaired in the absence of neutrophil Elastase. Moreover, there was less Macrophage Elastase activity secondary to decreased Macrophage accumulation in neutrophil Elastase-deficient mice. This study demonstrates a direct role for neutrophil Elastase in emphysema and highlights the interdependence of the proteinases and inflammatory cells that mediate lung destruction in response to cigarette smoke.
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requirement for Macrophage Elastase for cigarette smoke induced emphysema in mice
Science, 1997Co-Authors: Dean R Hautamaki, Dale K Kobayashi, Robert M, Steven D ShapiroAbstract:To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, Macrophage Elastase–deficient (MME −/− ) mice were subjected to cigarette smoke. In contrast to wild-type mice, MME − / − mice did not have increased numbers of Macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME − / − mice that received monthly intratracheal instillations of monocyte chemoattractant protein–1 showed accumulation of alveolar Macrophages but did not develop air space enlargement. Thus, Macrophage Elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
Robert M - One of the best experts on this subject based on the ideXlab platform.
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elastin fragments drive disease progression in a murine model of emphysema
Journal of Clinical Investigation, 2006Co-Authors: Mcgarry A Houghton, Dale K Kobayashi, Diane G Kelley, Robert P Mecham, Robert M, Pablo A Quintero, David L Perkins, Luiz A Marconcini, Steven D ShapiroAbstract:Mice lacking Macrophage Elastase (matrix metalloproteinase-12, or MMP-12) were previously shown to be protected from the development of cigarette smoke-induced emphysema and from the accumulation of lung Macrophages normally induced by chronic exposure to cigarette smoke. To determine the basis for Macrophage accumulation in experimental emphysema, we now show that bronchoalveolar lavage fluid from WT smoke-exposed animals contained chemotactic activity for monocytes in vitro that was absent in lavage fluid from Macrophage Elastase-deficient mice. Fractionation of the bronchoalveolar lavage fluid demonstrated the presence of elastin fragments only in the fractions containing chemotactic activity. An mAb against elastin fragments eliminated both the in vitro chemotactic activity and cigarette smoke-induced monocyte recruitment to the lung in vivo. Porcine pancreatic Elastase was used to recruit monocytes to the lung and to generate emphysema. Elastin fragment antagonism in this model abrogated both Macrophage accumulation and airspace enlargement.
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targeted gene disruption of matrix metalloproteinase 9 gelatinase b suppresses development of experimental abdominal aortic aneurysms
Journal of Clinical Investigation, 2000Co-Authors: Michael J Shipley, Steven D Shapiro, Robert M, John A Curci, Scott J Ziporin, Terri L Ennis, Robert W ThompsonAbstract:: Abdominal aortic aneurysms represent a life-threatening condition characterized by chronic inflammation, destructive remodeling of the extracellular matrix, and increased local expression of matrix metalloproteinases (MMPs). Both 92-kD gelatinase (MMP-9) and Macrophage Elastase (MMP-12) have been implicated in this disease, but it is not known if either is necessary in aneurysmal degeneration. We show here that transient Elastase perfusion of the mouse aorta results in delayed aneurysm development that is temporally associated with transmural mononuclear inflammation, increased local production of several elastolytic MMPs, and progressive destruction of the elastic lamellae. Elastase-induced aneurysmal degeneration was suppressed by treatment with a nonselective MMP inhibitor (doxycycline) and by targeted gene disruption of MMP-9, but not by isolated deficiency of MMP-12. Bone marrow transplantation from wild-type mice prevented the aneurysm-resistant phenotype in MMP-9-deficient animals, and wild-type mice acquired aneurysm resistance after transplantation from MMP-9-deficient donors. These results demonstrate that inflammatory cell expression of MMP-9 plays a critical role in an experimental model of aortic aneurysm disease, suggesting that therapeutic strategies targeting MMP-9 may limit the growth of small abdominal aortic aneurysms.
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requirement for Macrophage Elastase for cigarette smoke induced emphysema in mice
Science, 1997Co-Authors: Dean R Hautamaki, Dale K Kobayashi, Robert M, Steven D ShapiroAbstract:To determine which proteinases are responsible for the lung destruction characteristic of pulmonary emphysema, Macrophage Elastase–deficient (MME −/− ) mice were subjected to cigarette smoke. In contrast to wild-type mice, MME − / − mice did not have increased numbers of Macrophages in their lungs and did not develop emphysema in response to long-term exposure to cigarette smoke. Smoke-exposed MME − / − mice that received monthly intratracheal instillations of monocyte chemoattractant protein–1 showed accumulation of alveolar Macrophages but did not develop air space enlargement. Thus, Macrophage Elastase is probably sufficient for the development of emphysema that results from chronic inhalation of cigarette smoke.
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elastin degradation by matrix metalloproteinases cleavage site specificity and mechanisms of elastolysis
Journal of Biological Chemistry, 1997Co-Authors: Robert P Mecham, Steven D Shapiro, Thomas J Broekelmann, Catherine J Fliszar, Howard G Welgus, Robert MAbstract:Abstract Insoluble elastin was used as a substrate to characterize the peptide bond specificities of human (HME) and mouse Macrophage Elastase (MME) and to compare these enzymes with other mammalian metalloproteinases and serine Elastases. New amino termini detected by protein sequence analysis in insoluble elastin following proteolytic digestion reveal the P′1 residues in the carboxyl-terminal direction from the scissile bond. The relative proportion of each amino acid in this position reflects the proteolytic preference of the elastolytic enzyme. The predominant amino acids detected by protein sequence analysis following cleavage of insoluble elastin with HME, MME, and 92-kDa gelatinase were Leu, Ile, Ala, Gly, and Val. HME and MME were similar in their substrate specificity and showed a stronger preference for Leu/Ile than did the 92-kDa enzyme. Fibroblast collagenase showed no activity toward elastin. The amino acid residues detected in insoluble elastin following hydrolysis with porcine pancreatic Elastase and human neutrophil Elastase were predominantly Gly and Ala, with lesser amounts of Val, Phe, Ile, and Leu. There were interesting specificity differences between the two enzymes, however. For both the serine and matrix metalloproteinases, catalysis of peptide bond cleavage in insoluble elastin was characterized by temperature effects and water requirements typical of common enzyme-catalyzed reactions, even those involving soluble substrates. In contrast to what has been observed for collagen, the energy requirements for elastolysis were not extraordinary, consistent with cleavage sites in elastin being readily accessible to enzymatic attack.
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molecular cloning chromosomal localization and bacterial expression of a murine Macrophage metalloElastase
Journal of Biological Chemistry, 1992Co-Authors: Steven D Shapiro, Howard G Welgus, Robert M, Gail L Griffin, Debra J Gilbert, Nancy A Jenkins, Neal G Copeland, Timothy J LeyAbstract:Murine Macrophages have previously been shown to secrete a zinc-dependent proteinase that can degrade elastin. In this report, we identify murine Macrophage Elastase (MME) cDNA and show that it is a distinct member of the metalloproteinase gene family. Small amounts of MME were purified to homogeneity, and N-terminal amino acid sequence was obtained. This sequence was used to obtain a partial cDNA clone by the polymerase chain reaction; a cDNA library derived from a mouse Macrophage-like cell line (P388D1) was screened with this probe. A full-length MME cDNA spanning approximately 1.8 kilobases contained an open reading frame of 1386 base pairs; the predicted molecular mass of the MME proenzyme is 53 kDa. The gene encoding MME is represented only once in the mouse genome and is located on chromosome 9. Despite a size that is similar to other metalloproteinases, MME is distinct, sharing only 33-48% amino acid homology with other metalloproteinases. In contrast to other metalloenzymes, MME appears to be rapidly processed to an active truncated form (N-terminal and C-terminal cleavage). We expressed recombinant MME in Escherichia coli and demonstrated that it has significant elastolytic activity that is specifically inhibited by the tissue inhibitor of metalloproteinases. MME is therefore a true metalloproteinase that may be involved in tissue injury and remodeling.
Toshitaka Maeno - One of the best experts on this subject based on the ideXlab platform.
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cd8 t cells are required for inflammation and destruction in cigarette smoke induced emphysema in mice
Journal of Immunology, 2007Co-Authors: Mcgarry A Houghton, Steven D Shapiro, Pablo A Quintero, Toshitaka Maeno, Sandra Grumelli, Caroline A OwenAbstract:Increased numbers of T lymphocytes are observed in the lungs of patients with chronic obstructive pulmonary disease, but their role in the disease process is not known. We investigated the role of CD8+ T cells in inflammatory cell recruitment and lung destruction in a cigarette smoke-induced murine model of emphysema. In contrast to wild-type C57BL/6J mice that displayed Macrophage, lymphocyte, and neutrophil recruitment to the lung followed by emphysema in response to cigarette smoke, CD8+ T cell-deficient (CD8-/-) mice had a blunted inflammatory response and did not develop emphysema when exposed to long-term cigarette smoke. Further studies supported a pathogenetic pathway whereby the CD8+ T cell product, IFN-gamma-inducible protein-10, induces production of Macrophage Elastase (matrix metalloproteinase 12) that degrades elastin, both causing lung destruction directly and generating elastin fragments that serve as monocyte chemokines augmenting Macrophage-mediated lung destruction. These studies demonstrate a requirement for CD8+ T cells for the development of cigarette smoke-induced emphysema and they provide a unifying pathway whereby CD8+ T cells are a central regulator of the inflammatory network in chronic obstructive pulmonary disease.
