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Biomedical subjects

E R Goodman

Publications and source records attributed to E R Goodman.

18 recordsLinked to original sources
PubMed1999

Role of granulocyte-macrophage colony-stimulating factor and its receptor in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis.

HYPOTHESIS: That granulocyte-macrophage colony-stimulating factor (GM-CSF) and its receptor modulate the suppression of apoptosis (Ao) of normal neutrophils incubated in the plasma of patients with postraumatic acute respiratory distress syndrome (ARDS). DESIGN: Experimental study using cultured human neutrophils. SETTING: University hospital, level I trauma center. PARTICIPANTS: Plasma was obtained from 14 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 22). All samples were drawn within 24 hours after injury. Plasma was also taken from up to 21 healthy control subjects. These volunteers were also used as sources of polymorphonuclear leukocytes (PMNs). MAIN OUTCOME MEASURES: (1) Effect of early, fulminant ARDS and normal plasma on spontaneous Ao and GM-CSF receptor expression in PMNs in vitro. (2) Effect of ligation of either GM-CSF or its receptor with a neutralizing monoclonal antibody (mAb) on PMN Ao in ARDS and normal plasma. (3) Correlation of extracellular GM-CSF concentration with rate of PMN Ao. (4) Levels of GM-CSF in ARDS and normal plasma and in culture supernatant of normal PMNs incubated in early, fulminant ARDS and normal plasma. RESULTS: Plasma from patients with ARDS enhanced PMN viability at 24 hours (data are given as mean +/- SEM) 52% +/- 3% control vs 60% +/- 3% ARDS, P<.05). Binding of the GM-CSF receptor with a neutralizing mAb significantly reduced PMN viability in ARDS plasma, but not in normal plasma (60% +/- 3% ARDS vs 53% +/- 3% ARDS + mAb, P<.05). Ligation of GM-CSF with mAb had no significant effect on PMN viability in either plasma. Only 1% of PMNs expressed detectable levels of the GM-CSF receptor when incubated for 24 hours in either ARDS or normal plasma. The GM-CSF levels were undetectable (>7 pg/mL) in both ARDS and normal plasma and in culture supernatants taken after 24 hours of incubation in both plasma types. Levels of GM-CSF ranging from 0 to 50000 pg/mL had no effect on PMN Ao in plasma-free medium. CONCLUSIONS: The antiapoptotic effect of ARDS plasma appears to be mediated by the GM-CSF receptor. This effect occurs at both low levels of plasma GM-CSF and surface expression of its PMN receptor. Ligation of GM-CSF had no effect of PMN Ao, suggesting that Ao is triggered by Fc portion-mediated receptor cross-linking. These results provide the theoretical basis for alphaGM-CSF receptor mAb therapy as a novel modality of treatment for ARDS.

Acute Disease↗
PubMed1999

Prevention of multiple organ failure.

Physicians are still largely ignorant of the underlying biology of SIRS and multiple organ failure. Nonetheless, strategies to prevent multiple organ failure are possible. These include aggressive resuscitation of hemodynamically unstable patients, careful assessment to avoid missing clinically significant injuries, early operative treatment of all possible injuries with debridement of all nonviable tissue, early nutritional support, and the early diagnosis and prompt treatment of infectious complications. Treatment of patients with established multiple organ failure is still largely supportive and has made little impact on the patient mortality rate over the past 20 years. Future treatment strategies must focus on multimodality combination therapy aimed at specifically suppressing excessive activation of the inflammatory response while preserving immune competence and normal antimicrobial defenses. Only then are physicians likely to begin to see a reduction in the mortality rate of patients with this complex and challenging condition.

Combined Modality Therapy↗
PubMed1999

CXCR2 stimulation primes CXCR1 [Ca2+]i responses to IL-8 in human neutrophils.

Neutrophil (PMN) priming and subsequent responses to the IL-8 presented on pulmonary endothelial surfaces may be crucial determinants of the development of adult respiratory distress syndrome after injury. Elevated plasma ELR+ C-X-C chemokine (CXC) levels might contribute to PMN priming after trauma, but the role of CXCs in priming circulating PMNs is unstudied. We evaluated the interactions of IL-8 and GRO-alpha in priming human PMN calcium fluxes [Ca2+]i within circulatory environments. At physiologic concentrations, GRO-alpha primes PMN for IL-8 mediated [Ca2+]i mobilization, whereas IL-8 abolishes GRO-alpha responses. Repeated GRO-alpha exposures further enhance IL-8 responses. PMN priming for IL-8 responses in normal plasma was CXCR2 dependent. CXCR2 was more responsive than CXCR1 to low levels of IL-8, together suggesting that CXCR2 is the important CXC receptor at circulating (i.e., low) agonist concentrations. CXCR1 stimulation down-regulated CXCR2 surface expression, whereas CXCR2 stimulation upregulated CXCR1 expression. GRO-alpha/ CXCR2 signaling enhanced post-receptor IL-8 initiated PMN [Ca2+]i influx as well as efflux. Sufficient stimulation of the CXCR1 terminated this cooperative relationship by downregulating surface expression of CXCR2. This study is the first to report that at physiologic concentrations, C-X-C chemokines can act on circulating human PMNs as an integrated system where CXCR2 agonists, rather than cross-desensitizing CXCR1, act to enhance signaling of IL-8 at CXCR1 both by receptor and post-receptor mechanisms. Such CXCR2 mediated priming of CXCR1/ IL-8 interaction may enhance PMN attack on the lung after injury.

Adult↗
PubMed1999

Integrated stimulation by CXC chemokines enhances PMN [Ca2+]i signaling in trauma and adult respiratory distress syndrome.

BACKGROUND: Trauma and adult respiratory distress syndrome (ARDS) are associated with increased CXC chemokine (CXC) activity. CXCs such as interleukin (IL)-8 activate polymorphonuclear neutrophils (PMNs) in the lung by means of calcium signals ([Ca2+]i). We studied CXC effects on PMN [Ca2+]i in ARDS and trauma. METHODS: Isolated PMNs were loaded with Fura-2 dye. Normal PMNs were incubated in ARDS plasma or volunteer plasma, with or without blocking antibodies to IL-8, growth-related oncogene alpha (GRO-alpha), or both (n = 6 pairs), and then stimulated with 1 to 10 nmol/L IL-8. PMNs from trauma patients or volunteers (n = 10 pairs) were stimulated with GRO-alpha, or with sequential GRO-alpha/IL-8. [Ca2+]i was measured with spectrofluorometry. RESULTS: [Ca2+]i responses to IL-8 were higher after being incubated in ARDS plasma than in volunteer plasma (251 +/- 33 vs 218 +/- 33 nmol/L, P = .03). Blockade of GRO-alpha or IL-8 reversed ARDS plasma effects. After GRO-alpha/IL-8, PMNs from trauma patients demonstrated more Ca2+ store release than did PMNs from volunteers (235 +/- 13 vs 170 +/- 10 nmol/L, P < .01). Conversely, PMNs from trauma patients lost receptor-operated Ca2+ influex to GRO-alpha. CONCLUSIONS: In traumatic ARDS, plasma CXCs prime PMNs for higher [Ca2+]i flux, making PMN activation more likely. IL-8 and GRO-alpha interact to modulate these PMN [Ca2+]i responses.

Adult↗
PubMed1998

Role of interleukin 8 in the genesis of acute respiratory distress syndrome through an effect on neutrophil apoptosis.

OBJECTIVE: To evaluate the role of interleukin 8 (IL-8) in the regulation of neutrophil (PMN) apoptosis in normal plasma and plasma from patients with early, fulminant acute respiratory distress syndrome (ARDS). DESIGN: Experimental study using cultured human PMNs. SETTING: University hospital, level I trauma center. PARTICIPANTS: Plasma was obtained from 6 patients with early, fulminant posttraumatic ARDS (mean Injury Severity Score, 26). All samples were drawn within 24 hours after injury. Plasma was also taken from 13 healthy control subjects. These controls were also used as sources of PMNs. MAIN OUTCOME MEASURES: Effect of early, fulminant ARDS and normal plasma on spontaneous apoptosis, CD16, and CD11-b expression in PMNs in vitro; levels of IL-8 in plasma; correlation of extracellular IL-8 concentration with rate of PMN apoptosis; and effect of IL-8 blockade on PMN apoptosis, CD16, and CD11-b expression in ARDS and normal plasma. RESULTS: Plasma from patients with early, fulminant ARDS inhibited spontaneous PMN apoptosis at 24 hours (35%+/-5% vs 54%+/-5%; P=.01). Neither CD16 nor CD1l-b differed significantly between the 2 groups. The mean plasma level of IL-8 in patients with early, fulminant ARDS was 359+/-161 pg/mL vs 3.0+/-0.4 pg/mL in healthy controls (P<.05). Interleukin 8 inhibited apoptosis in plasma-free medium at low doses (1-50 pg/mL) but had no significant effect at higher doses (100-5000 pg/mL) (P<.05). Interleukin 8 blockade with monoclonal antibody suppressed apoptosis in normal plasma (28%+/-5% with monoclonal antibody vs 51%+/-5% without monoclonal antibody; P=.008) but not in plasma from patients with early, fulminant ARDS (29%+/-5% with monoclonal antibody vs 34%+/-6% without monoclonal antibody; P=.67). It had no effect on CD16 or CD11-b expression in either plasma. CONCLUSIONS: Plasma from patients with early, fulminant ARDS contains soluble factors that inhibit PMN apoptosis in vitro. Low levels of IL-8 inhibit PMN apoptosis in normal plasma. Although plasma levels of IL-8 are markedly elevated in early, fulminant ARDS, IL-8 is not directly responsible for the antiapoptotic effect of plasma from patients with early, fulminant ARDS.

Apoptosis↗
PubMed1996

Fludarabine phosphate: A DNA synthesis inhibitor with potent immunosuppressive activity and minimal clinical toxicity.

Fludarabine phosphate selectively eliminates normal and malignant mononuclear cells in large animals and man through the inhibition of DNA synthesis. The drug depletes mononuclear cells from culture within 24 hours of initial exposure, CD4 and CD8 T cells being more sensitive than either CD20 B cells or CD34 bone marrow precursors. Mitogenic activation of lymphocytes enhances cellular elimination from culture. Fludarabine inhibits PHA-induced T-cell proliferation by >90 per cent and mixed lymphocyte reactions (allogeneic and xenogeneic) by >95 per cent. Fludarabine exerts its cytolytic effects through the induction of endonuclease-independent apoptosis. A 5-day course of fludarabine (50 mg/m2 intravenously once daily) induces both T- and B-cell lymphopenia in Cynomolgus monkeys and Papio baboons. Transient neutropenia was the only side-effect seen in experimental animals. Pretreatment of Cynomolgus monkeys with this regimen of fludarabine causes a prolongation of ABO-compatible skin allograft survival from 8 days (control) to 16 days (drug treated group). Secondary allotransplantation into presensitized recipients showed a similar prolongation of graft survival with fludarabine pretreatment (8 days vs 5 days control). Fludarabine promises to be a potent immunosuppressive agent with low clinical toxicity.

Animals↗
PubMed1996

The effect of clinical and biochemical donor parameters on pancreatic islet isolation yield from cadaveric organ donors.

The recovery of pancreatic islet cells from cadaveric donors for allotransplantation may depend on the functional condition of the pancreas of the donor prior to organ harvesting. We examined donor hemodynamic and biochemical parameters and their effects on the subsequent yield of islet cells after harvesting. All pancreata were flushed and preserved in University of Wisconsin (UW) solution and digested using automated method within 8 hours. In the first analysis, digestions were divided into high-yield (> 2000 IEQ/g pancreas), and low-yield (< 2000 IEQ/g) groups and donor variables were averaged for each group. Donors whose pancreata yielded > 2000 IEQ/g received significantly greater amounts of Dopamine (14.43 micrograms/kg/min vs 9.35 mg/kg/min, p = 0.05). The daily urine output between groups was also significantly different. Maximum systolic blood pressure (SBP), minimum systolic blood pressure, use of vasopressin, length of hospitalization, and maximum base deficit were compared between the two groups. Less severe hypoglycemia (lowest blood glucose 143 mg/dL vs 107 mg/dL, p = 0.02) and lower amylase levels (36.2 U vs 80.7, p = 0.07 were noted in the high-yield group. A trend towards higher islet yields was associated with lowest hourly urine output > 60 (2040 IEQ/g vs 1649 IEQ/g p = 0.09), maximum SBP > 200 (2097 vs 1673, p = 0.07, and surprisingly, lowest SBP below 80 (2013 vs 1742, p < 0.1). Amount of fluids administered prior to procurement had no influence on islet yield. In conclusion, hemodynamic variables such as urine output, systolic blood pressure, and degree of pressor support were modestly associated with successful islet isolation. The preliminary data suggest that better multifactor donor analysis is imperative for standardization and monitoring of multiorgan donors. The association of higher blood glucose levels with successful isolation may also be related to resuscitation with dextrose-containing fluids.

Adenosine↗
PubMed1994

Transplantation.

Parent-to-child transplantation is associated with a higher than expected risk of acute rejection. Much interest has been shown in newer immunosuppressive agents that inhibit both T- and B-lymphocyte function.

Humans↗
PubMed1993

Transplantation.

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Humans↗