Biomedical subjects

H N Langstein

Publications and source records attributed to H N Langstein.

25 records · Page 2Linked to original sources

PubMed1991

Single-dose tumor necrosis factor protection against endotoxin-induced shock and tissue injury in rats.

Tumor necrosis factor (TNF), a macrophage product released in response to endotoxin and other stimuli, has been shown to be a central mediator of endotoxin or septic shock. However, its highly conserved and wide-ranging physiological effects suggest that it may also be an essential cytokine in the host defense against acute bacterial infection or sepsis. A single nontoxic dose of human recombinant TNF administered intravenously 24 h prior to a lethal infusion of Escherichia coli lipopolysaccharide (LPS) completely prevented acute LPS-induced hypotension, ameliorated tissue injury in the lungs and liver, and improved survival in male Fisher 344 rats. The protective effects of TNF were dose dependent and required a 24-h pretreatment interval. After the infusion of LPS, animals in both groups (TNF-treated animals and saline-pretreated controls) initially appeared acutely ill and had a similar severe metabolic acidosis, indicating that TNF did not inactivate or prevent the toxic effects of LPS. Twelve hours after the administration of TNF, the gene for manganous superoxide dismutase, a mitochondrial enzyme which scavenges toxic reactive oxygen species and is induced during conditions which generate a free radical stress, was expressed in liver tissue, suggesting that the induction of manganous superoxide dismutase may be an important in vivo protective mechanism against cellular injury during lethal endotoxemia.

Animals↗

PubMed1991

Treatment with recombinant human tumor necrosis factor-alpha protects rats against the lethality, hypotension, and hypothermia of gram-negative sepsis.

Tumor necrosis factor (TNF) is a peptide secreted by macrophages in response to endotoxin that can produce many of the changes seen in septic shock. After cecal ligation and puncture (CLP) rats gradually develop tachycardia, hypotension, tachypnea, and hypothermia. At 5 h post-CLP, rats have a peak in serum levels of endotoxin and 60% of rats have blood cultures that grow Gram-negative rods (Escherichia coli and Klebsiella pneumonia). At 20 h post-CLP all rats develop positive blood cultures. Serum levels of TNF are not reproducibly measurable in rats following CLP. Rats undergoing CLP have a 50-80% mortality with deaths usually occurring 24-72 h postinjury. Repetitive (twice daily x 6 d) i.p. injection of sublethal doses of recombinant human TNF-alpha (100 micrograms/kg) to rats undergoing CLP 1 d after the treatment period resulted in a significant reduction in mortality compared to control rats previously unexposed to rTNF (P less than 0.03). Animals treated with rTNF had no hypotension or hypothermia after CLP and regained normal food intake faster than control rats. 12 h after CLP the gene expression for manganous superoxide dismutase (MnSOD), an inducible mitochondrial metalloenzyme responsible for cellular resistance to injury from toxic reactive oxygen species, was higher in livers of rats treated with rTNF suggesting that the TNF treatment augmented expression of this protective enzyme. Unlike MnSOD, expression of the gene for copper-zinc SOD was not affected by CLP or rTNF treatment. The results suggest that prior treatment with recombinant TNF can ameliorate the lethality, hypotension, hypothermia, and anorexia of Gram-negative sepsis in rats and that the mechanism may be related to enhanced hepatic expression of the gene for MnSOD. Repeated administration of recombinant TNF may be a strategy to minimize mortality and morbidity of Gram-negative sepsis.

Animals↗

PubMed1991

Mechanisms of cancer cachexia.

It is currently hypothesized that the mechanisms of cancer cachexia involve the host's production of inflammatory cytokines, which in turn orchestrate a series of complex interrelated steps that ultimately lead to a chronic state of wasting, malnourishment, and death (see Fig. 1). The metabolic changes seen in the tumor-bearing host are similar, but not identical, to those seen in sepsis and inflammation and appear to result from a generalized response of the host to the stimulus of invasion--the tumor. Although there are likely to be several humoral factors, of either host or tumor origin (see Fig. 1), involved in cancer cachexia, recombinant DNA methodology has provided sufficient amounts of only a few cytokines to enable careful investigation of their cachectic potential. TNF/cachectin has been most extensively studied and appears to play a clear role, because administration of low-dose continuous or escalating doses simulates changes associated with cancer cachexia. In addition, these cachectic changes have been blocked by a specific antisera. IL-1, IL-6, and interferon-gamma all have potential as mediators of cancer cachexia and more work is clearly indicated. It is possible that, given our current understanding of the mechanisms of cancer cachexia, it can be theorized that TNF, which causes many of the manifestations of cancer cachexia, and IL-1 are released by macrophages in response to tumor (see Fig. 1). Interferon-gamma appears to potentiate these effects and may also be necessary for the complete syndrome of cancer cachexia. IL-6 probably is released as another mediator, principally mediating the acute phase response seen in cancer cachexia. Other factors are certain to be involved. Further study into the mechanisms and possible treatment of cancer cachexia is needed, because a large proportion of cancer patients who are incurable by current therapies continue to suffer from this lethal wasting diathesis. Furthermore, specific strategies to reverse the cachectic changes associated with cancer will likely improve antitumor treatment.

Animals↗

PubMed1990

Prolonged survival of tumor-bearing rats with repetitive low-dose recombinant tumor necrosis factor.

Tumor necrosis factor may be a mediator of the syndrome of cancer cachexia. Tachyphylaxis or tolerance to the cachectic effects of recombinant tumor necrosis factor (rTNF) has been previously described. In this study, we investigate whether repetitive exposure to rTNF can induce similar tolerance in tumor-bearing (TB) rats and ameliorate cachexia induced by the tumor. In experiment 1, non-tumor-bearing (NTB) and TB rats were randomized to either escalating low doses of rTNF or saline i.p. twice daily for 9 consecutive days. NTB rats treated with rTNF demonstrated a significant decline in food intake and weight change (P less than 0.00001) but soon developed tolerance to the cachectic effects of rTNF; they consumed significantly more food than on the first day of treatment and had weight change similar to NTB rats treated with saline. TB rats treated with rTNF showed a similar significant decline in food intake and weight change (P less than 0.0001) and also demonstrated similar tolerance to the cachectic effects of rTNF with continued treatment. Following treatment, TB rats that had been treated with rTNF ate significantly more and lost less weight than TB rats that had been treated with saline (P less than 0.00001). rTNF treatment of TB rats also demonstrated antineoplastic activity, as estimated tumor weight of tumors from rats treated with rTNF were significantly less than controls (P = 0.003). The anticachexia and antineoplastic effects of rTNF resulted in prolonged survival of TB rats treated with rTNF compared to control TB rats (P = 0.015). Experiment 2 utilized two different rTNF treatment regimens in TB rats: one group received 12 days of escalating doses of rTNF, and another group received 15 days of rTNF treatment. TB rats treated with rTNF again had a significantly greater food intake (P less than 0.00001) and delayed weight loss (P = 0.0001) posttreatment that was further augmented by additional doses of rTNF. Antineoplastic activity of rTNF was less clear, and overall tumor growth curves were not affected by rTNF treatment. Survival of TB rats treated with rTNF was again significantly increased in a dose-dependent manner (P = 0.006). Repeated administration of low doses of rTNF to TB rats induces mild reduction in tumor growth, tolerance to the cachectic effects of rTNF that results in tolerance to the cachectic effects of tumor, and prolongation of survival.

Animals↗

PubMed1990

The utility of circulating levels of human pancreatic polypeptide as a marker for islet cell tumors.

The measurement of plasma levels of human pancreatic polypeptide (hPP) has been reported to be clinically useful in predicting the existence of pancreatic islet cell neoplasms in patients with familial multiple endocrine neoplasia type 1 (FMEN-I) and the possible presence of metastatic disease in patients with islet cell tumors. However, these studies have not been prospective and involve small numbers of patients. In this study, fasting plasma samples from 36 patients with biopsy-proved islet cell tumors were analyzed for hPP by radioimmunoassay and compared with age-matched control subjects. Of 13 patients with FMEN-I who had islet cell tumors, 7 (54%) had elevated plasma hPP levels before surgery. After resection of all islet cell tumors, 4 of 12 patients evaluated after surgery still had elevated levels. Fifteen patients had islet cell tumors that were localized (seven insulinomas and eight gastrinomas), but none of these patients had elevated hPP levels, either before or after surgery. Nine patients, including one with FMEN-I, with metastatic islet cell tumors to the liver were studied; three with more advanced disease had elevated hPP levels before surgery. Each of the nine patients underwent resection of all gross disease and the three patients with elevated preoperative levels had normal postoperative hPP levels. Our results indicate that basal plasma levels of hPP were not clinically useful. The hPP levels did not reliably predict the presence of islet cell tumors in patients with FMEN-I, because 46% of patients with tumors did not have elevated plasma levels, and in those with elevated values hPP levels did not reliably predict the resection of all tumor. Plasma levels of hPP have no utility in patients with localized sporadically occurring islet cell tumors and limited utility (33%) in predicting the presence of metastatic islet cell tumors to the liver.

Adenoma, Islet Cell↗

PubMed1989

Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity.

Passive immunization against TNF allowed non-tumor-bearing C3H/HEN mice and tumor-bearing C57BL/6 mice to tolerate significantly more doses of IL-2 before death (p less than 0.005 and p less than 0.001, respectively). The antitumor effect of IL-2 against both 3-d and 10-d pulmonary metastases was maintained in mice treated concurrently with neutralizing antibodies to TNF. In one experiment with 10-d pulmonary metastases, increased administration of IL-2 made possible by passive immunization against TNF significantly improved the antitumor response compared to equitoxic doses of IL-2 and control antibody. The results indicate that TNF is a mediator of IL-2 toxicity but contributes minimally to the antitumor effects of IL-2. Strategies to inhibit TNF may improve the therapeutic index of IL-2 as a neoplastic agent.

Animals↗

PubMedDate not supplied

Reconstructive approaches in soft tissue sarcoma.

Plastic surgical techniques continue to evolve to deal with problem wounds following soft tissue sarcoma resection. Important advances in how tissue is transferred have allowed most wounds to be closed following extirpation; the emphasis is now placed on refining these transfers while minimizing donor site injury. Reconstructive microsurgery has emerged as a frequently preferred way to resurface wounds after sarcoma resection, particularly in patients who have received radiotherapy or previous surgery. Free flaps provide well-vascularized tissue to fill dead space, cover exposed vital structures, and provide structural support and contour. These procedures demonstrate a high success rate of over 90% and often can ensure a healed wound in a single-stage operation. Creative use of the versatile rectus abdominis or latissimus dorsi myocutaneous flaps can reconstruct the majority of breast, extremity, and head and neck soft tissue defects. Endoscopic harvest of muscle flaps has minimized donor morbidity and scarring. The use of "fillet flaps" is an important concept that spares a patient donor site. Composite free flaps, including bone, are routinely used to rebuild the mandible or other bony structures. The future holds great promise for sarcoma reconstruction because tissue engineering is rapidly closing in on techniques that can duplicate tissues in the laboratory for ultimate use in reconstruction, thus sparing the donor site from disease.

Humans↗