Delayed Tumor Necrosis Factor α Blockade Attenuates Pulmonary Dysfunction and Metabolic Acidosis Associated With Experimental Gram-negative Sepsis

Windsor, Alastair; Mullen, Patrick G.; Walsh, Ciaran J.; Fisher, Bernard; Blocher, Charles R.; Jesmok, Gary; Fowler, Alpha A.; Sugerman, Harvey J.

doi:10.1001/archsurg.1994.01420250092012

Cited by 33 publications

(9 citation statements)

References 31 publications

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“…The fourth, and strongest line of evidence supporting a role for TNF-a, is supplied by the marked inhibitory effect of TNFa-Ab on the LPS-induced rise in coronary resistance. This is consistent with the beneficial activity of similar doses of anti-TNF-a antibodies in models of septic shock in mice (Silva et al, 1990), pigs (Windsor et al, 1994) and monkeys (Fiedler et al, 1992). In human sepsis, anti TNF-a therapy did not clearly improve survival (see Natanson et al, 1994), although positive clinical data have been obtained (Vincent et al, 1992).…”

Section: Discussionsupporting

confidence: 74%

The contribution of tumour necrosis factor‐α and endothelin‐1 to the increase of coronary resistance in hearts from rats treated with endotoxin

Hohlfeld

Klemm

Thiemermann

et al. 1995

British J Pharmacology

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1 Inflammatory disease states predispose to myocardial infarction. Here we have investigated the effects of a systemic inflammatory response syndrome, i.e. lipopolysaccharide (LPS)-induced circulatory shock in rats, on coronary vascular tone. 2 Anaesthetized rats were given LPS (10 mg kg-', i.v.) and the hearts excised 180 min later for isolated perfusion at constant flow by the Langendorff technique. Once the ex vivo perfusion was started, the perfusion pressure strongly increased in these hearts compared to hearts from control rats (130+3 vs. 49+3 mmHg after 10 min). This increase in coronary resistance was not associated with a reduction in endothelial cell function, for the vasodilator responses to bradykinin were unchanged. 3 When hearts were removed 30 min after the injection of LPS, the LPS-induced rise in perfusion pressure was delayed. No changes in perfusion pressure were seen when the hearts were removed 15 min after the injection of LPS. Pre-treatment with cycloheximide or an anti-tumour necrosis factor-a (TNF-a) antibody or continuous infusion in vivo and in vitro of the endothelin ETA receptor selective antagonist FR 139317, greatly decreased the increase in coronary vascular resistance induced by LPS. 4 These data suggest that TNF-cx may induce the release of endothelin-1 (ET-1) and that this mediates at least part of the coronary vasoconstriction. This hypothesis is supported by the demonstration that LPS administration increased the circulating levels of both TNF-a and ET-1. 5 We conclude, therefore, that in inflammatory disease states, such as LPS-induced septic shock, there is the sequential release of TNF-a and endothelin-1 which leads to an increase in coronary vascular tone and so a predisposition to myocardial ischaemia. Inactivation of TNF-a by an antibody as well as ETA receptor blockade by a selective antagonist may effectively interfere with this pathway.

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Section: Discussionsupporting

confidence: 74%

The contribution of tumour necrosis factor‐α and endothelin‐1 to the increase of coronary resistance in hearts from rats treated with endotoxin

Hohlfeld

Klemm

Thiemermann

et al. 1995

British J Pharmacology

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“…In addition, tetracycline was found to inhibit TNF-␣ and IL-1␤ secretion from human monocytes in vitro as well as to reduce serum TNF-␣ levels in vivo. TNF-␣ and IL-1␤ are thought to be central mediators in septic shock, and studies using animal models have shown that targeting TNF-␣ or IL-1␤ prevents the clinical manifestation of septic shock (1,4,5,21,23,34,41,47,48,51,55). However, studies using anticytokine strategies in humans were not as successful at saving patients' lives (3).…”

Section: Discussionmentioning

confidence: 99%

Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion

et al. 1996

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Septic shock results from excessive stimulation of host immune cells, particularly monocytes and macrophages, by lipopolysaccharide (LPS) released from gram-negative bacteria. Macrophage-derived cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1 beta), have been identified as central mediators in the pathogenesis of septic shock and the resultant mortality. Therefore, these cytokines were targets for experimental therapy for septic shock. Because of tetracycline's ability to intervene in cellular mechanisms involved in cytokine secretion, we tested the effect of tetracycline on LPS-induced septic shock and inflammatory lesions in mice. Tetracycline was found to protect mice against LPS-induced lethality and to abolish clinical signs of LPS-induced inflammatory lesions. This protection correlates with tetracycline's ability to reduce LPS-induced TNF-alpha levels in serum. Furthermore, tetracycline was found to inhibit LPS-induced TNF-alpha and IL-1 beta secretion, but not cytokine mRNA accumulation, in human monocytes in vitro. The results presented here suggest that tetracycline is a potent drug for LPS-induced pathology and that its mechanism of action involves blockage of posttranscriptional events of cytokine production.

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“…Improved survival and lung function follow pretreatment with anti‐TNF polyclonal antibody in rodent pancreatitis [186]. Delayed antagonism of TNF‐α may be more effective than early treatment, because of the beneficial effect TNF‐α has on regulating the quiescent immune system [187]. IL‐1 blockade with the naturally occurring receptor antagonist, IL‐lra, attenuates the release of TNF‐α, IL‐6, amylase, lipase, neutrophil accumulation in the lung, and pancreatic damage in rodent necrotising pancreatitis.…”

Section: Novel Therapiesmentioning

confidence: 99%

The role of the intestine in the pathophysiology and management of severe acute pancreatitis

Flint

Windsor

2003

HPB

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BackgroundThe outcome of severe acute pancreatitis has scarcely improved in 10 years. Further impact will require new paradigms in pathophysiology and treatment. There is accumulating evidence to support the concept that the intestine has a key role in the pathophysiology of severe acute pancreatitis which goes beyond the notion of secondary pancreatic infection. Intestinal ischaemia and reperfusion and barrier failure are implicated in the development of multiple organ failure. DiscussionConventional management of severe acute pancreatitis has tended to ignore the intestine. More recent attempts to rectify this problem have included 1) resuscitation aimed at restoring intestinal blood¯ow through the use of appropriate¯uids and splanchnic-sparing vasoconstrictors or inotropes; 2) enteral nutrition to help maintain the integrity of the intestinal barrier;3) selective gut decontamination and prophylactic antibiotics to reduce bacterial translocation and secondary infection.Novel therapies are being developed to limit intestinal injury, and these include antioxidants and anti-cytokine agents. This paper focuses on the role of the intestine in the pathogenesis of severe acute pancreatitis and reviews the implications for management.

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Delayed Tumor Necrosis Factor α Blockade Attenuates Pulmonary Dysfunction and Metabolic Acidosis Associated With Experimental Gram-negative Sepsis

Cited by 33 publications

References 31 publications

The contribution of tumour necrosis factor‐α and endothelin‐1 to the increase of coronary resistance in hearts from rats treated with endotoxin

The contribution of tumour necrosis factor‐α and endothelin‐1 to the increase of coronary resistance in hearts from rats treated with endotoxin

Protection against endotoxic shock and lipopolysaccharide-induced local inflammation by tetracycline: correlation with inhibition of cytokine secretion

The role of the intestine in the pathophysiology and management of severe acute pancreatitis

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