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Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation.

Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards CK, Schuchman EH, Fuks Z, Kolesnick R - J. Exp. Med. (1997)

Bottom Line: TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses.Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha.These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10021, USA.

ABSTRACT
The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-alpha and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-alpha, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-alpha injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-alpha in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

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Proposed schema  for progression of the endotoxic  response. LPS, released by gram  negative bacteria, interacts with  inflammatory cells leading to  generation of TNF-α and other  cytokines. TNF-α, acting upon  endothelium, stimulates sphingomyelin hydrolysis to ceramide  via an ASMase. Apoptosis of the  endothelium ensues, which can  be blocked by bFGF via inhibition of ceramide generation. We  further propose that endothelial  apoptosis results in generalized  microvascular dysfunction sufficient to compromise the circulation to major organs, leading to  nonendothelial tissue damage,  circulatory collapse, and death.
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Figure 7: Proposed schema for progression of the endotoxic response. LPS, released by gram negative bacteria, interacts with inflammatory cells leading to generation of TNF-α and other cytokines. TNF-α, acting upon endothelium, stimulates sphingomyelin hydrolysis to ceramide via an ASMase. Apoptosis of the endothelium ensues, which can be blocked by bFGF via inhibition of ceramide generation. We further propose that endothelial apoptosis results in generalized microvascular dysfunction sufficient to compromise the circulation to major organs, leading to nonendothelial tissue damage, circulatory collapse, and death.

Mentions: The present studies define a set of early biochemical and biological responses to LPS using a standard model of endotoxic shock. Fig. 7 orders these events. Within 1 h of intraperitoneal injection of LPS, elevation of tissue ceramide content was detected in the intestinal mucosa and lung. Although our evidence supports endothelium as the primary source of the increase in ceramide, it remains formally possible that cells other than endothelium contribute to the ceramide elevation. Ceramide elevation appeared dependent on TNF action since TNF mimicked the LPS effect, and TNF-bp blocked the LPS-induced increase in tissue ceramide. Elevation of ceramide preceded the appearance of a generalized form of apoptosis, expressed initially in the microvascular endothelium of a variety of organs, beginning at 6 h after LPS injection. Both ceramide elevation and endothelial apoptosis preceded damage to nonendothelial parenchymal tissue and the death of the animal, which became apparent at 16 h after a dose of 175 μg LPS/25g mouse. Endothelial apoptosis appeared mandatory for the progression of the endotoxic response, since intravenous injection of bFGF, which specifically protects the endothelium against stress-induced apoptosis, prevented death. Furthermore, ceramide appeared to be a key intracellular mediator of this response, as the ASMase knockout mouse, which is defective in ceramide generation but not in TNF-α production, exhibited decreased endothelial apoptosis and death. Nevertheless, additional models of endotoxic shock must be studied before it can be concluded that these observations are representative of this process in general, as significant species differences have been observed (3).


Lipopolysaccharide induces disseminated endothelial apoptosis requiring ceramide generation.

Haimovitz-Friedman A, Cordon-Cardo C, Bayoumy S, Garzotto M, McLoughlin M, Gallily R, Edwards CK, Schuchman EH, Fuks Z, Kolesnick R - J. Exp. Med. (1997)

Proposed schema  for progression of the endotoxic  response. LPS, released by gram  negative bacteria, interacts with  inflammatory cells leading to  generation of TNF-α and other  cytokines. TNF-α, acting upon  endothelium, stimulates sphingomyelin hydrolysis to ceramide  via an ASMase. Apoptosis of the  endothelium ensues, which can  be blocked by bFGF via inhibition of ceramide generation. We  further propose that endothelial  apoptosis results in generalized  microvascular dysfunction sufficient to compromise the circulation to major organs, leading to  nonendothelial tissue damage,  circulatory collapse, and death.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199151&req=5

Figure 7: Proposed schema for progression of the endotoxic response. LPS, released by gram negative bacteria, interacts with inflammatory cells leading to generation of TNF-α and other cytokines. TNF-α, acting upon endothelium, stimulates sphingomyelin hydrolysis to ceramide via an ASMase. Apoptosis of the endothelium ensues, which can be blocked by bFGF via inhibition of ceramide generation. We further propose that endothelial apoptosis results in generalized microvascular dysfunction sufficient to compromise the circulation to major organs, leading to nonendothelial tissue damage, circulatory collapse, and death.
Mentions: The present studies define a set of early biochemical and biological responses to LPS using a standard model of endotoxic shock. Fig. 7 orders these events. Within 1 h of intraperitoneal injection of LPS, elevation of tissue ceramide content was detected in the intestinal mucosa and lung. Although our evidence supports endothelium as the primary source of the increase in ceramide, it remains formally possible that cells other than endothelium contribute to the ceramide elevation. Ceramide elevation appeared dependent on TNF action since TNF mimicked the LPS effect, and TNF-bp blocked the LPS-induced increase in tissue ceramide. Elevation of ceramide preceded the appearance of a generalized form of apoptosis, expressed initially in the microvascular endothelium of a variety of organs, beginning at 6 h after LPS injection. Both ceramide elevation and endothelial apoptosis preceded damage to nonendothelial parenchymal tissue and the death of the animal, which became apparent at 16 h after a dose of 175 μg LPS/25g mouse. Endothelial apoptosis appeared mandatory for the progression of the endotoxic response, since intravenous injection of bFGF, which specifically protects the endothelium against stress-induced apoptosis, prevented death. Furthermore, ceramide appeared to be a key intracellular mediator of this response, as the ASMase knockout mouse, which is defective in ceramide generation but not in TNF-α production, exhibited decreased endothelial apoptosis and death. Nevertheless, additional models of endotoxic shock must be studied before it can be concluded that these observations are representative of this process in general, as significant species differences have been observed (3).

Bottom Line: TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses.Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha.These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York 10021, USA.

ABSTRACT
The endotoxic shock syndrome is characterized by systemic inflammation, multiple organ damage, circulatory collapse and death. Systemic release of tumor necrosis factor (TNF)-alpha and other cytokines purportedly mediates this process. However, the primary tissue target remains unidentified. The present studies provide evidence that endotoxic shock results from disseminated endothelial apoptosis. Injection of lipopolysaccharide (LPS), and its putative effector TNF-alpha, into C57BL/6 mice induced apoptosis in endothelium of intestine, lung, fat and thymus after 6 h, preceding nonendothelial tissue damage. LPS or TNF-alpha injection was followed within 1 h by tissue generation of the pro-apoptotic lipid ceramide. TNF-binding protein, which protects against LPS-induced death, blocked LPS-induced ceramide generation and endothelial apoptosis, suggesting systemic TNF is required for both responses. Acid sphingomyelinase knockout mice displayed a normal increase in serum TNF-alpha in response to LPS, yet were protected against endothelial apoptosis and animal death, defining a role for ceramide in mediating the endotoxic response. Furthermore, intravenous injection of basic fibroblast growth factor, which acts as an intravascular survival factor for endothelial cells, blocked LPS-induced ceramide elevation, endothelial apoptosis and animal death, but did not affect LPS-induced elevation of serum TNF-alpha. These investigations demonstrate that LPS induces a disseminated form of endothelial apoptosis, mediated sequentially by TNF and ceramide generation, and suggest that this cascade is mandatory for evolution of the endotoxic syndrome.

Show MeSH
Related in: MedlinePlus