Endotoxin Induces Organ-Specific Endothelial Cell Injury

Maeda, Kaori; Abello, Patricia A.; Abraham, Meena R.; Wetzel, Randall C.; Robotham, James L.; Buchman, Timothy G.

doi:10.1097/00024382-199503010-00007

Cited by 5 publications

(5 citation statements)

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“…Incubation of ECs with IgG from 11 of 23 sera caused the cells to display a proadhesive phenotype over a limited period of time. This phenomenon cannot be attributed to contaminating LPS [28] because all the experiments were performed in the presence of polymyxin B. Our finding that the excess of adhesion molecules was transient accords with the view that their expression declines in advanced vasculitis [29].…”

Section: Discussionsupporting

confidence: 86%

Functional heterogeneity of anti-endothelial cell antibodies

Bordron¹,

Révélen²,

d’Arbonneau³

et al. 2001

Clinical and Experimental Immunology

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SUMMARYWhile it has been claimed that some anti-endothelial cell antibodies (AECA) activate EC, there is also evidence that others trigger apoptosis. To address the issue of whether activation is a prerequisite for AECA-mediated apoptosis of EC, 23 AECA-positive sera were evaluated for their ability to induce activation and/or apoptosis. Activation was defined as an over-expression of E-selectin and intercellular adhesion molecule 1. Optical microscopy, annexin V binding, hypoploid cell enumeration, and determination of poly (ADP-ribose) polymerase cleavage-related products were used to assess apoptosis. Four functional profiles were defined: 10 sera promoted activation and apoptosis (act1/apo1), one was act1/apo-, six act-/apo1, and the remaining six act-/apo-. The reduced membrane expression of thrombomodulin was associated with apoptosis, rather than activation. Caspase-3 was implicated in the two models of apoptosis, the ratios of several survival proteins to Bax decreased, regardless of the ability of apo1 AECA to activate the cells, while radical oxygen species did not appear to be involved. Furthermore, it occurred that macrophages engulfed EC treated with apoptosis-promoting AECA, but not those incubated with AECA that did not induce apoptosis. Hence, AECA represent an extremely heterogeneous family of autoantibodies, not only because of the variety of their target antigens, but also the subsequent diversity of their effects.

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Section: Discussionsupporting

confidence: 86%

Functional heterogeneity of anti-endothelial cell antibodies

Bordron¹,

Révélen²,

d’Arbonneau³

et al. 2001

Clinical and Experimental Immunology

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“…As we have shown previously, such conditions cause endothelial dysfunction with a loss of • NO and PGI 2 by the superoxide-triggered formation of peroxynitrite and its inhibiting effect on PGI 2 synthase (23,25). In connection with endothelial dysfunction, usually an opening of the endothelial barrier (40,41) or even a partial destruction of the endothelium occurs that directly exposes SMC to endotoxin like in the Shwartzman reaction, where detached endothelial cells can be observed (42,43). In contrast, SMC in culture reacted strongly to LPS, but did not undergo cell death as endothelial cells do.…”

Section: Discussionmentioning

confidence: 83%

COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Schildknecht¹,

Bachschmid²,

Baumann³

et al. 2004

FASEB j.

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High levels of prostacyclin (PGI2; measured as 6-keto-PGF1alpha) have been reported in patients under septic shock. Because this was at variance with our previous findings of nitration and inhibition of PGI2 synthase by endotoxin (LPS) in the endothelium, we examined the role of vascular smooth muscle as an alternative source of PGI2. Bovine aortic smooth muscle cells (SMC) in passage 1 contained high levels of PGI2 synthase but no activity and no detectable levels of COX-1 or COX-2. LPS exposure for 3 h caused COX-2 mRNA and protein levels to rise during 8 h together with a large increase in PGI2 synthase activity. In contrast, cytokines lead to only a moderate increase of both PGI2 and PGE2. Specific COX-2 inhibitors completely blocked PGI2 formation but PGE2 synthesis only partially. Unexpectedly, *NO formation remained low over 6-8 h, which may be a reason for the lack of nitration and inhibition of prostacyclin synthase in LPS exposed SMC. Our results can explain the clinical observation of severe hypotension in progressive stages of septic shock as a mechanism to compensate endothelial dysfunction. According to our data, the use of COX-2-specific inhibitors may not be advisable in septic patients. In contrast, administration of COX-1-specific blockers could prevent platelet aggregation during progressed stages of endotoxic shock.

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“…Receptors for TNF-α are present on virtually all cells; the binding of TNF-α to its receptor mediates a variety of reactions including apoptosis [33,34]. In fact, several investigators have reported that TNF-α directly induces apoptosis in endothelial cells [7,9,[13][14][15], while only two studies have shown that LPS induced apoptosis of endothelial cells [6,35]. Recently, it was demonstrated that TNF-binding protein protects against LPS-induced death and endothelial cell apoptosis in mice, suggesting systemic TNF-α is required for both responses [36].…”

Section: Electron Microscopic Findingsmentioning

confidence: 99%

Endothelial Cell Apoptosis in Lipopolysaccharide–Induced Lung Injury in Mice

Fujita

Kuwano

Kunitake

et al. 1998

Int Arch Allergy Immunol

125

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Background: Studies have shown the importance of apoptosis in vascular injury in vitro. We postulated that apoptosis of the endothelium contributes to vascular injury in vivo and may be involved in acute lung injury. Methods: To test this hypothesis, we investigated the incidence of endothelial cell apoptosis in acute lung injury induced in mice by the administration of lipopolysaccharide (LPS). Male ICR mice were administered LPS (20 mg/kg body weight) intravenously and sacrificed at specified times thereafter. Results: Histologic findings were consistent with acute lung injury which increased with time from 3 to 48 h after injection. Electrophoretic analysis of DNA that was extracted from lung tissue and 3'–end–labeled with digoxigenin demonstrated a fragmentation of DNA starting at 6 h. In situ terminal deoxynucleotidyl transferase–mediated dUTP biotin nick end–labeling (TUNEL) demonstrated DNA strand breaks in the endothelial cells. TUNEL also revealed DNA strand breaks in bronchial and alveolar epithelial cells as well as inflammatory cells in the interstitium. These TUNEL–positive cells appeared 6 h after injection. Electron–microscopic examination of the endothelium strongly suggested the morphological characteristics of apoptosis. Conclusion: Apoptosis was induced by LPS administration in endothelial cells in vivo. A role for such apoptosis is suggested in acute lung injury.

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Endotoxin Induces Organ-Specific Endothelial Cell Injury

Cited by 5 publications

References 0 publications

Functional heterogeneity of anti-endothelial cell antibodies

Functional heterogeneity of anti-endothelial cell antibodies

COX‐2 inhibitors selectively block prostacyclin synthesis in endotoxin exposed vascular smooth muscle cells

Endothelial Cell Apoptosis in Lipopolysaccharide–Induced Lung Injury in Mice

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