Endothelial Cells and Extracellular Calmodulin Inhibit Monocyte Tumor Necrosis Factor Release and Augment Neutrophil Elastase Release

Houston, Donald S.; Carson, Craig W.; Esmon, Charles T.

doi:10.1074/jbc.272.18.11778

Cited by 38 publications

(25 citation statements)

References 39 publications

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“…It is known that AAT suppresses neutrophil function, including IL-8 release and adherence to endothelial cells (24,25). Indeed, the absence of elastase had no effect on neutrophil recruitment (26), which supports our findings.…”

Section: Discussionsupporting

confidence: 82%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

222

148

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The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastasedeficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastasedeficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40-to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.is the prototypic member of the serpin superfamily and one of the most abundant serine protease inhibitors in the circulation (1). As an acute-phase protein, AAT is thought to play an important role in limiting host-tissue injury triggered by proteases, particularly neutrophil elastase (NE). The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT, who have increased susceptibility to early-onset pulmonary emphysema, liver and pancreatic diseases, and in rare cases to panniculitis and vasculitis (2). It has been assumed that in AAT-deficiency the protease/antiprotease balance is shifted toward NE, which leads to extensive tissue damage, particularly in causing emphysema. Therefore, augmentation of circulating AAT was introduced 25 y ago to treat emphysema patients with severe PiZZ (Glu342Lys) AAT deficiency (3). Because clinical trials of AAT augmentation therapy use historical data as controls, the benefit of AAT therapy for PiZZ patients remains under debate (4-6), although in most cases therapy offers disease stabilization. The uncertainty surrounding the efficacy of augmentation therapy also reflects the incomplete understanding of the properties of the AAT protein, which can be affected by the isolation methods from plasma.Although the a...

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Section: Discussionsupporting

confidence: 82%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

222

148

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“…Neutrophils can be stimulated to release elastase upon exposure to various cytokines and chemoattractants, including TNFa [24], interleukin-8, complement component 5a [25], lipopolysaccharide [26], and a tripeptide derived from bacterial walls (N-formyl-methionyl-leucylphenylalanine) [27]. In the physiological state, neutrophil elastase includes most components of the extracellular matrix (e.g., collagen, fibronectin, and laminin) as well as a wide range of other proteins such as cytokines, clotting factors, adhesion molecules, and components of the complement cascade [28].…”

Section: Discussionmentioning

confidence: 99%

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

et al. 2013

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Background Sivelestat sodium hydrate (sivelestat) is a specific neutrophil elastase inhibitor that is effective in treating acute lung injury associated with systemic inflammatory response syndrome. As such, it may be useful in treating hepatic ischemia-reperfusion injury (IRI), a condition in which neutrophils transmigrate into the interstitium, leading to release of neutrophil elastase from neutrophils and consequent damage to the affected tissue, particularly in cases of hepatic failure after liver transplantation or massive liver resection. Aims The purpose of this study was to examine whether treatment with sivelestat inhibits neutrophil adhesion and migration to the vessel wall and suppresses hepatic IRI. Methods Whether and, if so, the extent to which sivelestat suppresses the adhesion and migration of neutrophils and reduces liver damage in hepatic IRI was examined in a human umbilical vein endothelial cell (HUVEC) model and a rat hepatic IRI model. Results In the HUVEC model, the extent of the adhesion and migration of neutrophils stimulated by platelet-activating factor were found to be dose-dependently inhibited by sivelestat treatment (p \ 0.05). In the rat model, serum liver enzyme levels were significantly lower at 12 h after reperfusion, and the number of neutrophils that had migrated to extravascular sites was significantly less in the treatment group compared to the control group (p \ 0.05). Conclusion Sivelestat inhibits the adhesion and migration of neutrophils to vascular endothelium in hepatic IRI, thereby suppressing liver injury.

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“…Human umbilical vein endothelial cell(s) (HUVEC) were cultured with endothelial cell growth factor, heparin, and heat-inactivated bovine calf serum as described (21).…”

Section: Methodsmentioning

confidence: 99%

Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

Esmon

1999

Journal of Biological Chemistry

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Blocking protein C binding to the endothelial cell protein C receptor (EPCR) on the endothelium is known to reduce protein C activation rates. Now we isolate human EPCR and thrombomodulin (TM) and reconstitute them into phosphatidylcholine vesicles. The EPCR increases protein C activation rates in a concentration-dependent fashion that does not saturate at 14 EPCR molecules/TM. Without EPCR, the protein C concentration dependence fits a single class of sites (K m ‫؍‬ 2.17 ؎ 0.13 M). With EPCR, two classes of sites are apparent (K m ‫؍‬ 20 ؎ 15 nM and K m ‫؍‬ 3.2 ؎ 1.7 M). Increasing the EPCR concentration at a constant TM concentration increases the percentage of high affinity sites. Holding the TM: EPCR ratio constant while decreasing the density of these proteins results in a decrease in the EPCR enhancement of protein C activation, suggesting that there is little affinity of the EPCR for TM. Negatively charged phospholipids also enhance protein C activation. EPCR acceleration of protein C activation is blocked by anti-EPCR antibodies, but not by annexin V, whereas the reverse is true with negatively charged phospholipids. Human umbilical cord endothelium expresses approximately 7 times more EPCR than TM. Anti-EPCR antibody reduces protein C activation rates 7-fold over these cells, whereas annexin V is ineffective, indicating that EPCR rather than negatively charged phospholipid provide the surface for protein C activation. EPCR expression varies dramatically among vascular beds. The present results indicate that the EPCR concentration will determine the effectiveness of the protein C activation complex.

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Endothelial Cells and Extracellular Calmodulin Inhibit Monocyte Tumor Necrosis Factor Release and Augment Neutrophil Elastase Release

Cited by 38 publications

References 39 publications

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

Reconstitution of the Human Endothelial Cell Protein C Receptor with Thrombomodulin in Phosphatidylcholine Vesicles Enhances Protein C Activation

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