Neutrophil elastase and acute lung injury: Prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics

Zeiher, Bernhardt; Matsuoka, Shozo; Kawabata, Kazuhito; Repine, John E.

doi:10.1097/00003246-200205001-00018

Cited by 116 publications

(85 citation statements)

References 34 publications

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“…The secretion of LTB 4 may serve as a potent neutrophil chemotactic molecule (34). The role that neutrophils play in fibrotic responses is unclear, but certainly the release of reactive oxygen species and neutrophil elastase may contribute to local tissue injury (35). The fact that CysLTs are elevated in fibrotic lungs is well documented in both murine and human studies (12,17) and in the mouse, CysLTs are the predominant LT generated in the lung (17).…”

Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Vannella¹,

McMillan

Charbeneau

et al. 2007

The Journal of Immunology

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Pulmonary fibrosis is characterized by the accumulation of fibroblasts and myofibroblasts. These cells may accumulate from three potential sources: the expansion of resident lung fibroblasts, the process of epithelial-mesenchymal transition, or the recruitment and differentiation of circulating mesenchymal precursors known as fibrocytes. We have previously demonstrated that fibrocytes participate in lung fibrogenesis following administration of FITC to mice. We now demonstrate that leukotriene-deficient 5-LO−/− mice are protected from FITC-induced fibrosis. Both murine and human fibrocytes express both cysteinyl leukotriene receptor (CysLT) 1 and CysLT2. In addition, fibrocytes are capable of producing CysLTs and can be regulated via the autocrine or paracrine secretion of these lipid mediators. Exogenous administration of leukotriene (LT) D4, but not LTC4 induces proliferation of both murine and human fibrocytes in a dose-dependent manner. Consistent with this result, CysLT1 receptor antagonists are able to block the mitogenic effects of exogenous LTD4 on fibrocytes. Endogenous production of CysLTs contributes to basal fibrocyte proliferation, but does not alter fibrocyte responses to basic fibroblast growth factor. Although CysLTs can induce the migration of fibrocytes in vitro, they do not appear to be essential for fibrocyte recruitment to the lung in vivo, possibly due to compensatory chemokine-mediated recruitment signals. However, CysLTs do appear to regulate the proliferation of fibrocytes once they are recruited to the lung. These data provide mechanistic insight into the therapeutic benefit of leukotriene synthesis inhibitors and CysLT1 receptor antagonists in animal models of fibrosis.

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Section: Discussionmentioning

confidence: 99%

Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Vannella¹,

McMillan

Charbeneau

et al. 2007

The Journal of Immunology

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“…Reactive oxygen species cause tissue injury in local as well as systemic inflammatory conditions. Pulmonary or systemic insults may result in acute lung injury or ARDS, the most severe form of acute lung injury, both of which are associated with a high rate of mortality (25)(26)(27)(28). Patients with ARDS have increased levels of H 2 O 2 in their breath condensate (9,29,30).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, it slightly but significantly increased TCC formation to 36 MFI (23-66; p Ͻ 0.05). No change in TCC formation was seen for the isotype-matched control antibody [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38]]. …”

mentioning

confidence: 99%

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Castellheim

Pharo

Fung³

et al. 2005

Pediatr Res

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Meconium aspiration syndrome is a serious condition of the newborn characterized by pulmonary inflammation with substantial neutrophil infiltration. We recently showed that meconium is a potent activator of complement. The aim of the present study was to investigate a possible role for complement in meconiuminduced neutrophil activation. Meconium was incubated in human whole blood anticoagulated with lepirudin, a specific thrombin inhibitor that does not affect complement activation. Complement activation was detected by measuring the terminal complement complex. Neutrophil oxidative burst and changes in CD11b and L-selectin expression were measured by flow cytometry. Complement was inhibited using the MAb 166-32 and 137-26, which block factor D and neutralize C5a, respectively. Meconium markedly activated the neutrophils, as revealed by up-regulation of CD11b, accentuation of L-selectin shedding, and induction of oxidative burst. Complement inhibition using the anti-factor D antibody completely (95-100%) blocked meconium-induced changes in CD11b and L-selectin expression, whereas oxidative burst was reduced by 60 -70%. The anti-C5a antibody inhibited the neutrophil activation to the same extent as anti-factor D. The data suggest that complement activation is largely responsible for the neutrophil inflammatory responses induced by meconium in vitro and that C5a is a key mediator of this response. Abbreviations ARDS, acute respiratory distress syndrome AU, arbitrary units DHR, dihydrorhodamine LPS, lipopolysaccharide MAS, meconium aspiration syndrome MFI, median fluorescence intensity PE, phycoerythrin PMA, phorbol-12-␤-myristat-13-␣-acetate TCC, terminal SC5b-9 complement complex Meconium aspiration syndrome (MAS) may cause a profound lung inflammation similar to acute respiratory distress syndrome (ARDS). A substantial increase in neutrophils in the airways; increased levels of inflammatory cytokines, eicosanoids, superoxide anions, and endothelin-1; expression of inducible nitric oxide synthase and cyclooxygenase-2; and activation of nuclear factor-B have been described in MAS (1-8). A profound inflammatory response and the release of leukocyte cytotoxic products have an important role in initiation and propagation of lung injury in ARDS, in which neutrophils and their cytotoxic products play a crucial role (9).The complement system is a key mediator of inflammation. Complement-mediated activation of neutrophils and monocytes leads to cytokine production; release of lipid mediators and histamine; oxidative burst; and altered expression of adhesion molecules, including increased expression of CD11b and shedding, revealed as decreased expression of CD62L. We showed recently that meconium is a potent activator of the alternative complement pathway in vitro (10). To study the interaction between all participating inflammatory systems, we used an in vitro human whole-blood model that is based on the use of lepirudin, a thrombin-specific anticoagulant that does not interfere with complement activation (11). We hypot...

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“…5,6 Sivelestat is one of the agents which can specifically inhibit NE, 7 and it is used for the treatment of acute lung injury patients or acute respiratory distress syndrome patients. 8,9 Although a few reports showed the possibility that sivelestat might reduce cerebral ischemic damage, 10,11 the detailed protective mechanism of sivelestat in brain tissue has not yet been elucidated.…”

Section: Introductionmentioning

confidence: 99%

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

et al. 2010

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Release of neutrophil elastase is one of the harmful inflammatory reactions in acute cerebral ischemia. Therefore, inhibition of elastase released from neutrophils could be a useful strategy for the treatment of acute stroke. To evaluate this hypothesis, the effect of sivelestat, a selective neutrophil elastase inhibitor was examined in a mouse model of focal ischemia. The results obtained indicate that sivelestat reduced brain edema and vascular permeability, and subsequently improved the neurological deficit in an acute focal ischemia. The architecture of microvessels was analyzed by identifying vascular endothelial cells, which were prelabeled by injecting fluorescein-labeled Griffonia simplicifolia lectin I-isolectin B4 into a tail vein. Most of the microvessels in the infarcted area were structurally destroyed in the control group. In sharp contrast, microvessels in the boundary zone were well maintained in the sivelestat-treated group. Moreover, the expression of angiopoietin-1 was elevated at the ischemic margin in the sivelestat-treated group. Furthermore, the neutrophil elastase inhibitor rescued human brain microvascular endothelial cells in culture from neutrophil elastase-induced damage. These results suggest that neutrophil elastase inhibition could protect blood-brain barrier function in acute cerebral ischemia by augmentation of angiopoietin-1 expression and survival of endothelial cells.

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Neutrophil elastase and acute lung injury: Prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics

Cited by 116 publications

References 34 publications

Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Cysteinyl Leukotrienes Are Autocrine and Paracrine Regulators of Fibrocyte Function

Complement C5a Is a Key Mediator of Meconium-Induced Neutrophil Activation

Neutrophil elastase inhibitor prevents ischemic brain damage via reduction of vasogenic edema

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