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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclooxygenase inhibition has been proposed as treatment for sepsis-induced acute lung injury. However, the mechanism of protection offered by the cyclooxygenase inhibitor ibuprofen is not well understood. To elucidate this mechanism, the effects of ibuprofen on the neutrophil respiratory burst and alveolar-capillary membrane leak were studied. Anesthetized swine (15 to 25 kg) were intubated and mechanically ventilated (fraction of inspired oxygen, 0.5). Control animals (n = 5) received a sham infusion of 0.9% NaCl, animals with sepsis (n = 10) received a 1-hour infusion of live Pseudomonas aeruginosa (5 x 10(8) colony-forming units/ml at 0.3 ml/20 kg/hr), and treated animals (ibuprofen-treated control animals [n = 4] or ibuprofen-treated animals with sepsis [n = 9]) received ibuprofen (12.5 mg/kg at 0 and 120 minutes). All animals were studied for 300 minutes. Neutrophils were isolated at 0, 60, and 300 minutes. Neutrophil superoxide anion production (O2-) was assessed in a kinetic fashion (in nanomoles per minute) by superoxide dismutase-inhibitable cytochrome C reduction (phorbol myristate acetate stimulation). Bronchoalveolar lavage protein estimation (0 and 300 minutes) and extravascular lung water (double indicator dilution) were performed to assess alveolar-capillary membrane leak. Ibuprofen significantly attenuated sepsis-enhanced maximum neutrophil generation of O2- (6.0 +/- 0.5 nmol/min for animals with sepsis, 300 minutes, vs 4.1 +/- 0.5 nmol/min for ibuprofen-treated animals, with sepsis, 300 minutes; p less than 0.05), indicating an in vivo down-regulatory effect on neutrophil oxidant generation. Ibuprofen also prevented increased airspace bronchoalveolar lavage protein and extravascular lung water accumulation, suggesting a protective effect on the alveolar-capillary membrane. This protective effect of ibuprofen in acute lung injury may be through a decreased neutrophil respiratory burst.
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PMID:The neutrophil respiratory burst and tissue injury in septic acute lung injury: the effect of cyclooxygenase inhibition in swine. 132 Feb 99

Although hemorrhage depresses splenocyte (SPL) functions and increases susceptibility to sepsis, it is not known whether increased tumor necrosis factor (TNF) or prostaglandin (PG) production are responsible for it. To study this, mice (C3H/HeN) were bled to a mean blood pressure of 35 mm Hg, maintained at that pressure for 60 min, resuscitated, and treated with ibuprofen (1.0 mg/kg body weight) or vehicle (saline). Hemorrhage reduced (P less than 0.05) SPL proliferation by 60%, SPL release of interleukin-2 (IL-2) by 47%, interferon-gamma (IFN-gamma) by 67%, TNF by 54%, and interleukin-6 (IL-6) by 46% compared to sham. In addition, splenic macrophage (sM phi) release of interleukin-1 (IL-1) and TNF was decreased by 58 and 67% (P less than 0.05), respectively. However, ibuprofen treatment increased (P less than 0.05) SPL proliferation, lymphokine (IL-2, IFN-gamma, and IL-6) synthesis, and IL-1 release by sM phi compared to hemorrhage alone. Furthermore, ibuprofen enhanced the release of TNF by SPL (+175%, P less than 0.05) and sM phi (+68%) compared to the vehicle group. Ibuprofen also decreased (P = 0.011) the susceptibility to sepsis following hemorrhage. These results indicate that PGs are involved in hemorrhage-induced suppression of cellular immunity and in the increased mortality of such animals following a septic challenge.
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PMID:Ibuprofen restores cellular immunity and decreases susceptibility to sepsis following hemorrhage. 140 92

Ibuprofen pretreatment attenuates the enhanced neutrophil (PMN) respiratory burst and reduces increased plasma tumor necrosis factor (TNF) activity in porcine sepsis-induced acute lung injury (ALI). These septic responses have been linked to increased alveolar-capillary membrane (ACM) permeability. This study was designed to establish whether delayed ibuprofen treatment would have the same effect and to examine the relationship between PMN oxidant generation and TNF. Three groups of anesthetized, ventilated pigs (15-25 kg) were used. Group Ps received Pseudomonas aeruginosa (5 x 10(8) CFU/mL at 0.3 mL/20 kg/min) for one hour IV; The control group (Con) received 0.9% NaCl. Group D-Ibu received ibuprofen 12.5 mg/kg as a delayed bolus at 30 minutes and again at 120 minutes after Ps. Protein (BAL-P, microgram/mL) in harvested bronchoalveolar lavage fluid and extravascular lung water (EVLW, mL/kg) were used to estimate the integrity of the ACM. Superoxide anion (O2-) generation (ferricytochrome c reduction) from circulating PMNs and plasma TNF activity (L929 fibroblast bioassay) were measured. The EVLW increased significantly (p less than 0.05), as did BAL-P (p less than 0.01), in the P. aeruginosa-treated animals at 300 minutes. These increases were abolished in Group D-Ibu: EVLW, 6.6 +/- 1.0 baseline vs. 14.6 +/- 2.6 Ps 300 vs. 6.8 +/- 0.9 D-Ibu 300; BAL-P, 175 +/- 28 baseline vs. 984 +/- 186 Ps 300 vs. 284 +/- 42.8 D-Ibu 300. Both enhanced PMN oxidant activity and increased plasma TNF activity were significantly attenuated by delayed ibuprofen treatment. These data support the efficacy of the nonsteroidal anti-inflammatory drug, ibuprofen, when used after the onset of a septic stimulus.
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PMID:Delayed cyclo-oxygenase blockade reduces the neutrophil respiratory burst and plasma tumor necrosis factor levels in sepsis-induced acute lung injury. 164 64

Plasma tumor necrosis factor (TNF) activity, cardiac index, extravascular lung water, systemic and pulmonary arterial pressures, pulmonary vascular resistance index, and arterial PO2 were monitored for 300 min in four groups of anesthetized pigs: saline-infused animals (n = 5), saline-infused animals given ibuprofen (12.5 mg/kg iv) at 0 and 120 min (n = 4), animals infused for 60 min with live Pseudomonas aeruginosa (Ps, 5 x 10(8) organisms/ml at 0.3 ml.20 kg-1.min-1, n = 6), and animals infused for 60 min with Ps plus ibuprofen administered at 0 and 120 min (n = 4). Infusion of Ps induced significant elevations (greater than 4-fold increase in units/ml of TNF by 60 min, P less than 0.05) in plasma TNF activity (L929 cytolysis assay) and alterations (P less than 0.05) in all hemodynamic and pulmonary parameters within 30-60 min. Ibuprofen administration in sepsis significantly decreased peak TNF activity by 2 units/ml and attenuated many of the physiological alterations due to sepsis. These results show that ibuprofen attenuates sepsis-induced injury and that alterations of acute septic insult are correlated with reduced plasma TNF activity in septic animals given ibuprofen.
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PMID:Ibuprofen attenuates plasma tumor necrosis factor activity during sepsis-induced acute lung injury. 175 29

Current knowledge of alveolar pathophysiology during early sepsis-induced acute lung injury (ALI) and the role of resident alveolar macrophages (AM) in mediating alveolar inflammatory events during sepsis is limited. Further, the effects of ibuprofen pretreatment upon alveolar pathophysiology and AM function during early sepsis-induced ALI is unclear. Utilizing repetitive bronchoalveolar lavage (BAL) in a porcine model of sepsis-induced ALI, we studied changes in alveolar cellular constituents, BAL protein content and molecular composition, and AM superoxide anion (O2-.) generation during early sepsis. The neutrophil percentage of recovered alveolar cells (17 +/- 8%, t = 300 min versus 2 +/- 1%, t = 0; p = 0.06) and the bronchoalveolar lavage total protein content (493 +/- 110 micrograms/ml, t = 300 min versus 109 +/- 18 micrograms/ml, t = 0; p less than 0.05) increased in septic animals. Increases in BAL fluid total protein were primarily due to low-molecular-weight plasma protein, indicating relative preservation of alveolar-capillary membrane size selectivity. Alveolar macrophages harvested following 300 min of sepsis generated significantly less O2-. following phorbol myristate acetate (PMA) stimulation compared to AM harvested at baseline. Ibuprofen pretreatment of septic animals completely blocked leakage of plasma proteins into the alveoli and attenuated neutrophil migration but did not prevent downregulation of AM O2-. generation. Increased alveolar-capillary membrane permeability, neutrophil migration into the alveoli, and downregulation of AM oxidant generation occur within hours of the onset of sepsis. Ibuprofen pretreatment significantly attenuates early sepsis-induced ALI without altering sepsis-induced AM dysfunction.
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PMID:Sepsis-induced lung injury and the effects of ibuprofen pretreatment. Analysis of early alveolar events via repetitive bronchoalveolar lavage. 184 66

Ibuprofen is a potent cyclooxygenase inhibitor known to reduce the production of arachidonic acid metabolites. Prostacyclin and thromboxane are well-studied metabolites that play a prominent role in inflammation. Many of the effects of ibuprofen can be linked to its anti-inflammatory properties. Beneficial results from ibuprofen therapy have been documented, and more widespread use of the drug seems indicated. Conditions ranging from immunologic response to trauma and sepsis to postburn lung dysfunction to wound edema are improved by the use of ibuprofen. The fact that ibuprofen is effective in the various conditions detailed above, while other steroidal and nonsteroidal drugs are effective only in selective instances, increases the value of ibuprofen. Other properties of the drug, aside from its anti-inflammatory effects, are not as well studied and not as well known. Their importance, however, should not be overlooked. Superoxide radical tissue injury may be very important in acute injury and this phenomenon needs further study. In several studies ibuprofen has been shown to antagonize this type of injury. Similarly fibrinolysis inhibition is known to occur in burn wounds, but its role in other injuries is unknown. The antagonism of this inhibitor by ibuprofen maintains vascular patency. The clinical use of ibuprofen will increase as research further elucidates the mechanisms of tissue injury in acute situations and the many and varied mechanisms of action of ibuprofen.
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PMID:Ibuprofen in acute-care therapy. 240 73

Patients suffering severe trauma, including thermal injuries, demonstrate both a hypermetabolic response and an immunosuppressed state following the injury. Biochemically, these patients produce extremely large amounts of cyclooxygenase products, including prostaglandin E. We have investigated the effect of a drug, ibuprofen, which blocks the synthesis of prostaglandins in a burned rat model. Ibuprofen at high doses was found to significantly diminish the hypermetabolic response to burn injury and sepsis. The same dosage of ibuprofen increased the mortality rate in the same burn sepsis model. Prostaglandin E may therefore exert some beneficial effects in traumatized patients by altering their metabolism.
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PMID:The effect of ibuprofen on postburn metabolic and immunologic function. 278 85

Ibuprofen is a cyclo-oxygenase inhibitor that is alleged to have additional direct effects on leukocyte function. These properties suggest that Ibuprofen may be of potential therapeutic value for neutrophil (PMN)-mediated acute lung injury in humans such as that resulting from septicemia by gram-negative organisms. This study quantitated the effect of pretreatment with Ibuprofen on the intensity of acute neutrophilic alveolitis following endotoxemia. The effect of Ibuprofen on neutrophilic alveolitis was biphasic: There was suppression of inflammation at a high dose (30 mg/kg), enhancement at a low dose (3 mg/kg), and intermediate doses (10-20 mg/kg) had no effect. In contrast, both 10 and 30 mg/kg of Ibuprofen prevented early hypoxemia following endotoxemia, suggesting that early hypoxemia and inflammation by neutrophils were not causally related. The dose of Ibuprofen required to suppress neutrophil alveolitis exceeds that required to inhibit cyclooxygenase in the model. Therefore, suppression of alveolitis by 30 mg/kg of Ibuprofen may depend on other pharmacologic properties of Ibuprofen such as its direct effect on neutrophil migration.
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PMID:Effects of ibuprofen on endotoxin-induced alveolitis: biphasic dose response and dissociation between inflammation and hypoxemia. 293 83

Blockade of the arachidonic acid cascade has been shown to improve survival and hemodynamic alterations in animal models of sepsis and acute respiratory failure (ARF). The effects of intravenous ibuprofen, a cyclooxygenase inhibitor, were observed in 20-30 kg pigs with ARF induced by a continuous LD100 infusion of live Pseudomonas aeruginosa (2 X 10(8)/20 kg/min). Cardiopulmonary parameters were monitored in animals intubated, paralyzed, and ventilated at a 250-ml tidal volume and 0.5 FiO2. Pigs were randomly assigned to three groups: Group I received 2 bolus infusions of ibuprofen (12.5 mg/kg) at 20 and 210 min after baseline; Group II had Ps. aeruginosa (2 X 10(8) CFU/20 kg/min) only; Group III received Ps. aeruginosa and 12.5 mg/kg of ibuprofen at 20 and 210 min of ARF. Ibuprofen alone caused no significant changes in cardiorespiratory parameters. With Ps. aeruginosa infusion, significant pulmonary hypertension, hypoxemia, increased intrapulmonary shunt fraction, and systemic hypotension occurred. In the septic animals treated with ibuprofen, oxygenation was improved by a significant decrease in shunt, pulmonary edema, and pulmonary hypertension.
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PMID:Effects of ibuprofen on a porcine model of acute respiratory failure. 670 94

Prostaglandins released during inflammatory reactions cause increases in microvascular hydrostatic pressure, a primary cause of edema. Ibuprofen, a nonsteroidal, anti-inflammatory agent that reduces prostaglandin synthesis via inhibition of cyclooxygenase, was used to investigate the possible role of prostaglandins in the cardiopulmonary responses during sepsis. Sheep, surgically prepared for cardiopulmonary studies and collection of lung lymph, were given 0.75 micrograms/kg per 30 min of E. coli endotoxin iv. Ibuprofen (14 mg/kg) was given 15 min before and 1 h 45 min after the administration of endotoxin. We had previously noted a triphasic character to the hypovolemia encountered in endotoxin sepsis. The initial phase occurs during the first hour after endotoxin administration; it is characterized by decreases in PaO2, neutrophil count, and lymph-to-plasma (L/P) protein concentration ratios and by increases in mean arterial pressure, body temperature, hematocrit, lymph flow, and total plasma protein concentration. In the second phase these variables return toward their baseline values. In Phase 3 the same changes are observed an in Phase 1 except for a decrease in total plasma protein concentration and an increase in L/P ratios. Ibuprofen administration results in a statistically significant reduction in magnitude of Phase 1 changes, without notable effect on Phase 2 or Phase 3 values. These observations support the hypothesis that prostaglandins released during inflammatory reactions contribute to the extravascular fluid movement. Ibuprofen appears to lessen the severity of microvascular hydrostatic pressure-induced edema and the hypovolemia that occurs in the early stages of endotoxin.
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PMID:The effects of a prostaglandin synthetase inhibitor, ibuprofen, on the cardiopulmonary response to endotoxin in sheep. 675 68


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