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Robert M. Strieter - One of the best experts on this subject based on the ideXlab platform.
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neutralization of the cxc chemokine Macrophage Inflammatory Protein 2 attenuates bleomycin induced pulmonary fibrosis
Journal of Immunology, 1999Co-Authors: Michael P Keane, Steven L. Kunkel, Marie D. Burdick, John A Belperio, Thomas A Moore, Bethany B Moore, Douglas A Arenberg, Robert E Smith, Robert M. StrieterAbstract:Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis. For fibroplasia and deposition of extracellular matrix to occur, there must be a geometric increase in neovascularization. We hypothesized that net angiogenesis during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis are dependent in part upon an overexpression of the angiogenic CXC chemokine, Macrophage Inflammatory Protein-2 (MIP-2). To test this hypothesis, we measured MIP-2 by specific ELISA in whole lung homogenates in either bleomycin-treated or control CBA/J mice and correlated these levels with lung hydroxyproline. We found that lung tissue from mice treated with bleomycin, compared with that from saline-treated controls, demonstrated a significant increase in the presence of MIP-2 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Neutralizing anti-MIP-2 Abs inhibited the angiogenic activity of day 16 bleomycin-treated lung specimens using an in vivo angiogenesis bioassay. Furthermore, when MIP-2 was depleted in vivo by passive immunization, bleomycin-induced pulmonary fibrosis was significantly reduced without a change in the presence of pulmonary neutrophils, fibroblast proliferation, or collagen gene expression. This was also paralleled by a reduction in angiogenesis. These results demonstrate that the angiogenic CXC chemokine, MIP-2, is an important factor that regulates angiogenesis/fibrosis in pulmonary fibrosis.
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Macrophage Inflammatory Protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury
Gene Therapy, 1999Co-Authors: Cory M. Hogaboam, Kenneth J. Simpson, Stephen W. Chensue, Matthew L. Steinhauser, N. W. Lukacs, Jack Gauldie, Robert M. Strieter, S L KunkelAbstract:Macrophage Inflammatory Protein-2 gene therapy attenuates adenovirus- and acetaminophen-mediated hepatic injury
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neutralization of Macrophage Inflammatory Protein 2 attenuates neutrophil recruitment and bacterial clearance in murine klebsiella pneumonia
The Journal of Infectious Diseases, 1996Co-Authors: Marc J Greenberger, Robert M. Strieter, Steven L. Kunkel, J M Danforth, Lauri L Laichalk, Daniel C Mcgillicuddy, Theodore J. StandifordAbstract:: The role of Macrophage Inflammatory Protein-2 (MIP-2) in bacterial pneumonia was characterized. Mice were challenged with Klebsiella pneumoniae intratracheally, and organs were harvested at 8, 24, and 48 h. Inoculation with K. pneumoniae resulted in the time-dependent expression of MIP-2 mRNA and Protein within the lung, which was maximal 48 h after inoculation. Mice were then passively immunized with rabbit anti-murine MIP-2 serum intraperitoneally 2 h before administration of K. pneumoniae. Treatment with anti-MIP-2 serum resulted in a 60% decrease in lung neutrophil (PMNL) influx and a significant increase in K. pneumoniae colony-forming units in both lung and liver homogenates. Finally, treatment with anti-MIP-2 serum decreased early (48-72 h) but not late (after 72 h) survival in animals with Klebsiella pneumonia. This study indicates that MIP-2 is produced during Klebsiella pneumonia and inhibition of MIP-2 bioactivity in vivo results in decreased PMNL influx and lung bacterial clearance in murine Klebsiella pneumonia. MIP-2 is produced during Klebsiella pneumonia and inhibition of MIP-2 bioactivity in vivo results in decreased PMNL influx and lung bacterial clearance in murine Klebsiella pneumonia.
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Macrophage Inflammatory Protein-Iβ: A C-C Chemokine in Osteoarthritis
Clinical Immunology and Immunopathology, 1995Co-Authors: Alisa E. Koch, Steven L. Kunkel, Manisha R. Shah, Rebekah Fu, Daphne D. Mazarakis, G. Kenneth Haines, Marie D. Burdick, Richard M. Pope, Robert M. StrieterAbstract:Abstract The aim of this study was to determine whether the cytokine Macrophage Inflammatory Protein-1β (MIP1β) is present and functionally active in the arthritic joint. We used immunoassays and bioassays to assess the presence and function of MIP-1β using samples obtained from 62 arthritic patients. MIP-1β levels were increased in synovial fluids (SFs) from patients with osteoarthritis (OA) (18.0 ± 8.9 ng/ml) (SD) compared to patients with rheumatoid arthritis (RA) (6.1 ± 2.9 ng/ml) or other forms of arthritis (10.4 ± 7.0 ng/ml) (P
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production and function of murine Macrophage Inflammatory Protein 1 alpha in bleomycin induced lung injury
Journal of Immunology, 1994Co-Authors: Robert E Smith, Robert M. Strieter, Marie D. Burdick, Sem H Phan, Nicholas W Lukacs, Gary B Huffnagle, Carol A Wilke, Pamela M Lincoln, Holly L Evanoff, Steven L. KunkelAbstract:We investigated the role of Macrophage Inflammatory Protein-1 alpha (MIP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary Inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha Protein levels both in whole-lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the lung. In addition, immunohistochemical staining identified alveolar Macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha Protein is expressed in the lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.
Philip M Murphy - One of the best experts on this subject based on the ideXlab platform.
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differential effects of leukotactin 1 and Macrophage Inflammatory Protein 1α on neutrophils mediated by ccr1
Journal of Immunology, 1999Co-Authors: Shangming Zhang, Philip M Murphy, Byungs Youn, Byoung S KwonAbstract:The human CC chemokine leukotactin-1 (Lkn-1) is both a strong chemoattractant for neutrophils, monocytes, and lymphocytes and a potent agonist for CCR1 and CCR3. However, human neutrophils do not migrate when the cells are stimulated with other human CC chemokines, such as human Macrophage Inflammatory Protein-1α (hMIP-1α) and eotaxin, which also use the CCR1 and CCR3 as their receptors. In this report, we demonstrate that while hMIP-1α induced a negligible level of calcium flux and chemotaxis, Lkn-1 produced a high level of calcium flux and chemotaxis in human neutrophils. Lkn-1 cross-desensitized hMIP-1α-induced calcium flux, but hMIP-1α had little effect on the Lkn-1-induced response in human neutrophils. The same pattern was observed in peritoneal neutrophils from wild-type mice, whereas neutrophils from CCR1−/− mice failed to respond to either MIP-1α or Lkn-1. Scatchard analysis revealed a single class of receptor for both hMIP-1α and Lkn-1 on human neutrophils with dissociation constants (Kd) of 3.2 nM and 1.1 nM, respectively. We conclude that CCR1 is a receptor mediating responses to both MIP-1α and Lkn-1 on neutrophils and produces different biological responses depending on the ligand bound.
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structure and functional expression of the human Macrophage Inflammatory Protein 1 alpha rantes receptor
Journal of Experimental Medicine, 1993Co-Authors: Douglas B Kuhns, H L Tiffany, David H Mcdermott, Xu Li, Uta Francke, Philip M MurphyAbstract:The chemokine beta family is comprised of at least six distinct cytokines that regulate trafficking of phagocytes and lymphocytes in mammalian species; at least one of these, Macrophage Inflammatory Protein 1 alpha (MIP-1 alpha), also regulates the growth of hematopoietic stem cells. We now show that MIP-1 alpha and the related beta chemokine, RANTES, induce transient alterations in intracellular Ca2+ concentration in polymorphonuclear leukocytes that can be reciprocally and specifically desensitized, suggesting a common receptor. Moreover, we have now cloned both the cDNA and the gene for this receptor, functionally expressed the receptor in Xenopus oocytes, and mapped the gene to human chromosome 3p21. Transcripts for the receptor were found in mature and immature myeloid cells as well as B cells. The receptor is a member of the G Protein-coupled receptor superfamily. It has approximately 33% amino acid identity with receptors for the alpha chemokine, interleukin 8, and may be the human homologue of the product of US28, an open reading frame of human cytomegalovirus.
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Structure and functional expression of the human Macrophage Inflammatory Protein 1 alpha/RANTES receptor.
Journal of Experimental Medicine, 1993Co-Authors: Douglas B Kuhns, H L Tiffany, David H Mcdermott, Xu Li, Uta Francke, Philip M MurphyAbstract:The chemokine beta family is comprised of at least six distinct cytokines that regulate trafficking of phagocytes and lymphocytes in mammalian species; at least one of these, Macrophage Inflammatory Protein 1 alpha (MIP-1 alpha), also regulates the growth of hematopoietic stem cells. We now show that MIP-1 alpha and the related beta chemokine, RANTES, induce transient alterations in intracellular Ca2+ concentration in polymorphonuclear leukocytes that can be reciprocally and specifically desensitized, suggesting a common receptor. Moreover, we have now cloned both the cDNA and the gene for this receptor, functionally expressed the receptor in Xenopus oocytes, and mapped the gene to human chromosome 3p21. Transcripts for the receptor were found in mature and immature myeloid cells as well as B cells. The receptor is a member of the G Protein-coupled receptor superfamily. It has approximately 33% amino acid identity with receptors for the alpha chemokine, interleukin 8, and may be the human homologue of the product of US28, an open reading frame of human cytomegalovirus.
Steven L. Kunkel - One of the best experts on this subject based on the ideXlab platform.
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The role of CCL3/Macrophage Inflammatory Protein-1α in experimental colitis
European Journal of Pharmacology, 2004Co-Authors: Maureen N. Ajuebor, Steven L. Kunkel, Cory M. HogaboamAbstract:CCL3/Macrophage Inflammatory Protein (MIP-1)-1alpha is elevated in the rectal biopsies of patients with active Inflammatory bowel diseases, but its role remains undefined. The present study examined the role of CCL3/MIP-1alpha during trinitrobenzene sulfonic acid (TNBS)-induced colitis in the rat. Colonic CCL3/MIP-1alpha levels were elevated (>20-fold above control) within 24 h and remained elevated to day 7 of colitis induction by TNBS administration. In addition, significant increases in colonic neutrophil accumulation were observed within 24 h to day 7 of TNBS treatment. Pre-treatment of rats with a single dose of CCL3/MIP-1alpha antibody significantly reduced (47%) colonic neutrophil accumulation during the early (24 h) phase of TNBS-induced colitis. In contrast, chronic (repeated) administration of CCL3/MIP-1alpha antibody did not attenuate colonic neutrophil accumulation during the late phase (day 7) of TNBS-induced colitis. These results suggest a role for CCL3/MIP-1alpha in promoting colonic neutrophil accumulation during the early (24 h) phase of TNBS-induced colitis.
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neutralization of the cxc chemokine Macrophage Inflammatory Protein 2 attenuates bleomycin induced pulmonary fibrosis
Journal of Immunology, 1999Co-Authors: Michael P Keane, Steven L. Kunkel, Marie D. Burdick, John A Belperio, Thomas A Moore, Bethany B Moore, Douglas A Arenberg, Robert E Smith, Robert M. StrieterAbstract:Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis. For fibroplasia and deposition of extracellular matrix to occur, there must be a geometric increase in neovascularization. We hypothesized that net angiogenesis during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis are dependent in part upon an overexpression of the angiogenic CXC chemokine, Macrophage Inflammatory Protein-2 (MIP-2). To test this hypothesis, we measured MIP-2 by specific ELISA in whole lung homogenates in either bleomycin-treated or control CBA/J mice and correlated these levels with lung hydroxyproline. We found that lung tissue from mice treated with bleomycin, compared with that from saline-treated controls, demonstrated a significant increase in the presence of MIP-2 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Neutralizing anti-MIP-2 Abs inhibited the angiogenic activity of day 16 bleomycin-treated lung specimens using an in vivo angiogenesis bioassay. Furthermore, when MIP-2 was depleted in vivo by passive immunization, bleomycin-induced pulmonary fibrosis was significantly reduced without a change in the presence of pulmonary neutrophils, fibroblast proliferation, or collagen gene expression. This was also paralleled by a reduction in angiogenesis. These results demonstrate that the angiogenic CXC chemokine, MIP-2, is an important factor that regulates angiogenesis/fibrosis in pulmonary fibrosis.
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neutralization of Macrophage Inflammatory Protein 2 attenuates neutrophil recruitment and bacterial clearance in murine klebsiella pneumonia
The Journal of Infectious Diseases, 1996Co-Authors: Marc J Greenberger, Robert M. Strieter, Steven L. Kunkel, J M Danforth, Lauri L Laichalk, Daniel C Mcgillicuddy, Theodore J. StandifordAbstract:: The role of Macrophage Inflammatory Protein-2 (MIP-2) in bacterial pneumonia was characterized. Mice were challenged with Klebsiella pneumoniae intratracheally, and organs were harvested at 8, 24, and 48 h. Inoculation with K. pneumoniae resulted in the time-dependent expression of MIP-2 mRNA and Protein within the lung, which was maximal 48 h after inoculation. Mice were then passively immunized with rabbit anti-murine MIP-2 serum intraperitoneally 2 h before administration of K. pneumoniae. Treatment with anti-MIP-2 serum resulted in a 60% decrease in lung neutrophil (PMNL) influx and a significant increase in K. pneumoniae colony-forming units in both lung and liver homogenates. Finally, treatment with anti-MIP-2 serum decreased early (48-72 h) but not late (after 72 h) survival in animals with Klebsiella pneumonia. This study indicates that MIP-2 is produced during Klebsiella pneumonia and inhibition of MIP-2 bioactivity in vivo results in decreased PMNL influx and lung bacterial clearance in murine Klebsiella pneumonia. MIP-2 is produced during Klebsiella pneumonia and inhibition of MIP-2 bioactivity in vivo results in decreased PMNL influx and lung bacterial clearance in murine Klebsiella pneumonia.
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Macrophage Inflammatory Protein-Iβ: A C-C Chemokine in Osteoarthritis
Clinical Immunology and Immunopathology, 1995Co-Authors: Alisa E. Koch, Steven L. Kunkel, Manisha R. Shah, Rebekah Fu, Daphne D. Mazarakis, G. Kenneth Haines, Marie D. Burdick, Richard M. Pope, Robert M. StrieterAbstract:Abstract The aim of this study was to determine whether the cytokine Macrophage Inflammatory Protein-1β (MIP1β) is present and functionally active in the arthritic joint. We used immunoassays and bioassays to assess the presence and function of MIP-1β using samples obtained from 62 arthritic patients. MIP-1β levels were increased in synovial fluids (SFs) from patients with osteoarthritis (OA) (18.0 ± 8.9 ng/ml) (SD) compared to patients with rheumatoid arthritis (RA) (6.1 ± 2.9 ng/ml) or other forms of arthritis (10.4 ± 7.0 ng/ml) (P
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production and function of murine Macrophage Inflammatory Protein 1 alpha in bleomycin induced lung injury
Journal of Immunology, 1994Co-Authors: Robert E Smith, Robert M. Strieter, Marie D. Burdick, Sem H Phan, Nicholas W Lukacs, Gary B Huffnagle, Carol A Wilke, Pamela M Lincoln, Holly L Evanoff, Steven L. KunkelAbstract:We investigated the role of Macrophage Inflammatory Protein-1 alpha (MIP-1 alpha) in bleomycin-induced lung injury, a model of interstitial lung disease. Bleomycin stimulates a T cell-dependent pulmonary Inflammatory response characterized by an increase in leukocyte infiltration, fibroblast proliferation, and collagen synthesis. Intratracheal challenge of CBA/J mice with bleomycin resulted in a significant time-dependent increase in MIP-1 alpha Protein levels both in whole-lung homogenates and bronchoalveolar lavage fluid. The kinetics of MIP-1 alpha expression were biphasic, with the first peak occurring at 2 days postinstillation and the second peak at 16 days. These levels of Ag expression temporally correlated with the accumulation of granulocytes, lymphocytes, and mononuclear phagocytes in the lung. In addition, immunohistochemical staining identified alveolar Macrophages and bronchial epithelial cells as the primary cellular sources of MIP-1 alpha production. Interestingly, passive immunization of bleomycin-challenged mice with anti-MIP-1 alpha Abs significantly reduced pulmonary mononuclear phagocyte accumulation and fibrosis. These experiments establish that MIP-1 alpha Protein is expressed in the lungs of bleomycin-treated mice and provide evidence that MIP-1 alpha promotes leukocyte accumulation and activation. Furthermore, these findings support the notion that leukocyte accumulation and activation are linked to fibrosis.
D Mazzeo - One of the best experts on this subject based on the ideXlab platform.
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the viral chemokine Macrophage Inflammatory Protein ii is a selective th2 chemoattractant
Blood, 1998Co-Authors: Silvano Sozzani, Timothy N. C. Wells, Walter Luini, Giancarlo Bianchi, Paola Allavena, Monica Napolitano, Giovanni Bernardini, Annunciata Vecchi, Daniele Dambrosio, D MazzeoAbstract:Kaposi’s sarcoma (KS) lesions are characterized by a prominent leukocyte infiltrate composed of mononuclear phagocytes and T cells. KS-associated CD4 + and CD8 + cells showed predominantly a type II cytokine profile. The CC chemokine viral Macrophage Inflammatory Protein-II (vMIP-II) encoded by the KS-associated herpes virus 8 was a selective chemoattractant for T helper 2 (Th2 cells) and for monocytes, whereas it was inactive on other leukocytes, including Th1 cells, dendritic cells, and natural killer (NK) cells. vMIP-II was an agonist for CCR8, a chemokine receptor selectively expressed on CD4 + and CD8 + cells with a type II cytokine profile. Hence, vMIP-II has agonist activity for a chemokine receptor (CCR8), which is preferentially expressed on polarized Th2 cells. The capacity of vMIP-II to attract type II T cells selectively is likely to be a component of the virus strategy to subvert the host immune response.
Robert L Fairchild - One of the best experts on this subject based on the ideXlab platform.
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neutralization of groα and Macrophage Inflammatory Protein 2 attenuates renal ischemia reperfusion injury
American Journal of Pathology, 2001Co-Authors: Masayoshi Miura, Xi Fu, Qiwei Zhang, Daniel G Remick, Robert L FairchildAbstract:Previous studies have provided strong evidence for a role for neutrophils in mediating pathology during reperfusion of ischemic tissues. CXC chemokines including interleukin-8, KC/Groα, and Macrophage Inflammatory Protein (MIP)-2, direct neutrophils to tissue sites of inflammation. In the current study we tested the efficacy of antibodies to KC/Groα and MIP-2 in inhibiting neutrophil infiltration into kidneys during reperfusion after 1 hour of warm ischemia using a mouse model. KC mRNA and Protein were produced within 3 hours after reperfusion of the ischemic kidneys. MIP-2 mRNA and Protein were twofold to fourfold lower than KC and were at low levels until 9 hours after reperfusion. Only 60% of mice subjected to ischemia/reperfusion injury survived to day 3 after reperfusion. Treatment with rabbit neutralizing antibodies to both KC and MIP-2 inhibited neutrophil infiltration into ischemic kidneys during reperfusion, restored renal function as assessed by decreased serum creatinine and urea nitrogen levels to near normal levels, and resulted in complete survival of treated animals. Finally, treatment with both antibodies significantly reduced histologically graded pathology of kidneys subjected to ischemia/reperfusion injury. Collectively, the results indicate the efficacy of neutralizing the chemokines directing neutrophils into ischemic kidneys during reperfusion to inhibit this infiltration and attenuate the resulting pathology.
