Inactivation of the elastase inhibitory activity of alpha 1 antitrypsin in fresh samples of synovial fluid from patients with rheumatoid arthritis.

Chidwick, Keith; Winyard, Paul G.; Zhang, Zhi; Farrell, A J; Blake, David R.

doi:10.1136/ard.50.12.915

Cited by 51 publications

(22 citation statements)

References 10 publications

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“…Okada et al demonstrated the proteolytic inactivation of TIMP-1 by neutrophil elastase [12] and suggested that neutrophils, which infiltrate inflammatory sites, may contribute to TIMP-1 inactivation. The lack of inhibitory capacity of the natural inhibitor of neutrophil elastase, ct-l-proteinase inhibitor, at inflammatory sites has been described [24].…”

Section: Discussionmentioning

confidence: 99%

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Frears¹,

Zhang²,

Blake³

et al. 1996

FEBS Letters

161

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Peroxynitrite (ONOO-) has recently been implicated in connective tissue destruction in vivo. We have studied the effect of ONOO-on the activity of tissue inhibitor of metalloprotelnase-1 (TIMP-1) in vitro. The inactivation of TIMP-1 by ONOO-was dose dependent with 50 ~tM ONOOreducing the inhibitory activity of TIMP-1 towards gelatiuase-A by 50%. High concentrations of ONOO-(500 ~tM-5 mM) caused protein fragmentation whilst lower concentrations (< 250 ~tM) inactivated TIMP-1 without altering the molecular weight. Inactivation could be blocked by ONOO scavengers but not by hydroxyl radical scavengers. Our results show that ONOO-is capable of inactivating TIMP-1, a process which could potentiate metalloproteinase-mediated tissue breakdown.

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Section: Discussionmentioning

confidence: 99%

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Frears¹,

Zhang²,

Blake³

et al. 1996

FEBS Letters

161

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“…Oxidatively and proteolytically inactivated proteinase inhibitors have been detected in vivo in lung secretions from patients with cystic fibrosis [105,110], and in synovial fluid from patients with inflammatory arthritides [111][112][113][114]. Thus it is clear that, during infection and inflammation, oxidants and proteinases released from activated leukocytes and/or bacteria may act synergistically to create microenvironments in which extracellular proteolysis by leukocyte proteinases is facilitated via the inactivation of proteinase inhibitors.…”

Section: Inactivation Of Proteinase Inhibitorsmentioning

confidence: 99%

The cell biology of leukocyte-mediated proteolysis

Owen

Campbell

1999

Journal of Leukocyte Biology

382

399

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Leukocyte-derived proteinases have the capacity to degrade every component of the extracellular matrix, and thereby play fundamental roles in physiological processes. However, if the activity of these proteinases is uncontrolled or dysregulated, they have the capacity to contribute to tissue injury that potentially affects every organ in the body. Although there is a substantial literature on structure and activity of these proteinases when they are free in solution, until recently there has been little information about the cell biology of proteinases and their inhibitors. Recent studies, however, have identified several mechanisms by which inflammatory cells can degrade extracellular proteins in a milieu that contains high-affinity proteinase inhibitors. J. Leukoc. Biol. 65: 137-150; 1999.

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“…20,21 AT contains methionine at the "P1 position," which is located in the reactive site, and determines the specificity of inhibition. Various oxidant radicals such as peroxide, the hydroxyl radical, hypochloride, chloramine, and peroxynitrite 22,23 change the methionine into methionine sulfoxide, and such modified forms of AT lose the inhibitory activity against proteinases.…”

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confidence: 99%

In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL

Mashiba

Wada

Takeya

et al. 2001

ATVB

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Abstract-An inactivated form of ␣ 1 -antitrypsin (AT) and LDL coelutes in gel permeation chromatography. To characterize and to quantify the amount of this fraction of AT, a monoclonal antibody was established against chloramine T-oxidized AT and named OxAT-4. OxAT-4 recognized the oxidatively modified AT, including hexylaldehyde-or 4-hydroxy-2-nonenal-modified AT, but neither normal active AT nor trypsin/AT complex. Comigration of apoB and oxidized AT was demonstrated by Western blotting analysis of AT-LDL by means of anti-apoB monoclonal antibody and OxAT-4. A complex of oxidized AT and LDL (AT-LDL) was isolated from human plasma LDL by affinity column with an OxAT-4 antibody-coated carrier. AT-LDL was degraded 4 times more effectively by mouse peritoneal macrophages, but this was not mediated by scavenger receptor class A type I. Localization of AT-LDL was detected in human atherosclerotic lesions of the coronary artery, but distribution of it was not completely identical to that of macrophages. In situ hybridization revealed AT expression by macrophages, which were present in intimal layers of the coronary artery. From these findings, we concluded that AT is produced and oxidized by macrophages, then attached to LDL in the intimal layer of the arterial wall. Although AT-LDL that escapes into the blood stream can be cleared by hepatocytes, the remaining AT-LDL may be taken up by macrophages and contribute to the lipid accumulation in arterial wall cells as the early stage of atherogenesis. Key Words:erine proteinase activity is regulated by a group of inhibitors of the serine proteinases (also called serpin). ␣ 1 -Antitrypsin (AT) is one of the serpin family proteins. It is produced mainly in the liver, and partly by macrophages stimulated by interleukin-6 or lipopolysaccharide. 1-5 At inflammatory sites, AT protects the tissue against damage caused by proteinases derived from white blood cells; in the lung, AT is produced by monocytes, which are stimulated by endotoxin, interleukin-1, and tumor necrosis factor-␣ and protect the alveolar microstructure against excess activity of proteinases. 6,7 After formation of complexes of AT with serine proteinase, AT is cleaved at the site of the serpin reactive loop and changed into the inactive form. 8,9 The resulting 4-kDa carboxy-terminal fragment of 36 residues (C-36) still binds the complex noncovalently, but under denaturing conditions in vitro, the C-36 fragment dissociates from the complex. 10,11 Recent studies have elucidated the biological activities of the C-36 fragment: upregulation of expression of the LDL receptor in HepG2 cells [12][13][14] and induction of cytokine production and CD36 expression in monocytes. 15 Furthermore, it is involved in neutrophil recruitment. 16,17 Thus, not only AT itself but also the byproducts of its enzymatic inhibition possess biological activities at the locus of inflammation.Oxidized AT is another modified form of ␣ 1 -AT, which is found in inflammatory exudates at levels of Ϸ5% to 10% of total AT 18,19 and inflammatory sy...

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Inactivation of the elastase inhibitory activity of alpha 1 antitrypsin in fresh samples of synovial fluid from patients with rheumatoid arthritis.

Cited by 51 publications

References 10 publications

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

The cell biology of leukocyte-mediated proteolysis

In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL

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Inactivation of the elastase inhibitory activity of alpha 1 antitrypsin in fresh samples of synovial fluid from patients with rheumatoid arthritis.

Cited by 51 publications

References 10 publications

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

Inactivation of tissue inhibitor of metalloproteinase‐1 by peroxynitrite

The cell biology of leukocyte-mediated proteolysis

In Vivo Complex Formation of Oxidized α 1 -Antitrypsin and LDL

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In Vivo Complex Formation of Oxidized α ₁ -Antitrypsin and LDL