Postoperative urinary retention in patients undergoing anorectal surgery.
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Anal Canal↗
Biomedical subjects
G Goldman
Publications and source records attributed to G Goldman.
Thromboxane A2 induces leukotriene B4 synthesis that in turn mediates neutrophil diapedesis via CD 18 activation.
Previous studies have indicated that thromboxane (Tx) and leukotriene (LT) B4 act synergistically to induce neutrophil (PMN) adhesion in the microvasculature. This study explores the ability of Tx to induce LTB4 synthesis, which then leads to activation of PMN and endothelial adhesion receptors. Tx-mimic (U46619, 1 microgram/ml) was administered into abraded skin chambers placed on the backs of rabbits (n = 6). After 3 hr LTB4 was synthesized in the blister fluid at 385 pg/ml, a value higher than levels in saline-treated blisters, 10 pg/ml (P less than 0.05). The LTB4 generation following Tx-mimic was correlated (P less than 0.05, r = 0.70) with neutrophil diapedesis. These averaged 645 PMN/mm3, values higher than saline values of 20 PMN/mm3 (P less than 0.05). Intravenous (iv) treatment of other rabbits (n = 4) with the lipoxygenase inhibitor diethylcarbamazine at 60 mg/kg, followed by 40 mg/kg/hr, prevented Tx-mimic-induced LTB4 synthesis (10 pg/ml) and diapedesis (19 PMN/mm3) (both P less than 0.05). Intravenous treatment of yet other rabbits (n = 4) with the anti-CD 18 monoclonal antibody R 15.7 at 1 mg/kg abolished Tx-induced diapedesis (3 PMN/mm3) (P less than 0.05). In contrast, local administration of 3 ng of the protein synthesis inhibitor actinomycin D, to prevent expression of endothelial adhesion proteins, limited TNF- but not Tx-induced diapedesis. The data indicate that Tx-induced diapedesis is mediated by the generation of LTB4 and the activation of neutrophil CD 18 but not endothelial adhesion proteins.
Animals↗
Interleukin-2 induces early multisystem organ edema mediated by neutrophils.
Interleukin-2 (IL-2), an agent known to activate neutrophils (PMN) with thromboxane (Tx)B2 release, produces pulmonary edema within 6 hours of intravenous infusion. This study tests the role of PMN in mediating the edema. Anesthetized rats received 10(6)U recombinant human IL-2 (n = 15) or vehicle (n = 14) as a constant intravenous infusion during a period of 1 hour. At this time there was leukopenia 3.63 +/- 0.43 (x10(3)/mm3) relative to vehicle-infused control rats 6.12 +/- 0.86 and a decline in PMN, 2.19 +/- 0.14 relative to control value of 3.33 +/- 0.05 (both p less than 0.05). After 6 hours edema, as measured by increase in the wet to dry weight (W/d) ratio, was present in the lungs (4.93 +/- 0.20 relative to control 4.06 +/- 0.10), heart (4.09 +/- 0.11 versus 3.76 +/- 0.08), liver (3.50 +/- 0.10 versus 3.18 +/- 0.10), and kidney (4.25 +/- 0.07 versus 4.00 +/- 0.07) (all p less than 0.05). There was increased lung permeability demonstrated by bronchoalveolar lavage fluid protein concentration of 1970 +/- 210 micrograms/mL relative to control 460 +/- 90 micrograms/mL (p less than 0.05). Interleukin-2 resulted in lung PMN sequestration of 53 +/- 7 PMN/10 high-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05) and increased plasma TxB2 levels to 1290 +/- 245 pg/mL relative to control 481 +/- 93 pg/mL (p less than 0.05). Pretreatment of other rats (n = 8) with selective anti-rat neutrophil antiserum 18 hours before the experiment led to a peripheral PMN count 10% of baseline and prevented edema in the lungs (W/d ratio 4.20 +/- 0.16) and heart (3.67 +/- 0.07) (both p less than 0.05) but not liver or kidney. Protein in lung lavage was reduced to 760 +/- 220 micrograms/mL (p less than 0.05). The protection afforded by leukopenia was associated with lack of PMN sequestration and prevention of the increase in plasma Tx levels (484 +/- 120 pg/mL, p less than 0.05). These data indicate that the rapid induction of lung and heart edema with a 1-hour infusion of IL-2 in the rat is mediated, in large part, by activated PMNs.
Animals↗
Intravascular chemoattractants inhibit diapedesis by selective receptor occupancy.
An extravascular chemoattractant leads to migration of polymorphonuclear neutrophils (PMN) to that site, whereas intravascular administration leads to PMN oxidative activity and sequestration in microvessels but no diapedesis. This study examines the inhibitory role of intravascular chemoattractants. Rabbits (n = 37) were pretreated with zymosan-activated plasma (ZAP), leukotriene (LT) B4, or thromboxane (Tx) mimic. These agents were given intra-arterially, topically into plastic chambers taped atop sites of dermabrasion on the back, or into a lobar bronchus (n = 35). Intra-arterial injection of each chemoattractant resulted, 10 min later, in a 29-42% increase in intracellular PMN H2O2. In saline-infused animals, topical administration of the chemoattractants into dermabrasion chambers resulted in PMN accumulation per cubic millimeter after 3 h of 600 with ZAP, 536 with LTB4, and 643 with Tx mimic; all values higher than 46 with saline and 63 with normal plasma (all P less than 0.05). In other saline-infused animals, lobar lung aspiration of chemoattractants led to diapedesis as measured in bronchoalveolar lavage (BAL) fluid (PMN x 10(4)/ml) after 3 h: 19.0 with ZAP, 11.2 with LTB4 and 14.5 with Tx mimic, all greater than aspiration with saline or normal plasma 4.0 and 4.9, respectively (all P less than 0.05). Intra-arterial chemotactic administration inhibited subsequent PMN diapedesis in response to that same chemoattractant, both in dermabrasion chambers and in BAL fluid. When different intra- and extra-vascular chemoattractants were used diapedesis was promoted. Thus Tx infused intra-arterially and ZAP applied to a blister or lobar bronchus led to rapid cell migration and increased cell numbers.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neutrophil elastase and oxygen radicals: synergism in lung injury after hindlimb ischemia.
Hindlimb ischemia and reperfusion lead to lung injury dependent on activated polymorphonuclear neutrophils (PMN) adherence. This study tests whether elastase and oxygen radicals participate in PMN-induced injury once they have become sequestered in lungs. Anesthetized rats treated with saline (n = 9) or the specific elastase inhibitor methoxysuccinyl-L-Ala-L-Ala-L-Pro-L-Val-chloromethylketone (MAAPV, n = 6) underwent 4 h of bilateral hindlimb tourniquet ischemia followed by 4 h of reperfusion. At this time, in saline-treated rats, PMN were sequestered in lungs as assayed by myeloperoxidase activity [(MPO) 51 +/- 5 U/g tissue], higher than MPO in saline-treated sham rats (n = 9; 18 +/- 3 U/g MPO; P less than 0.01); bronchoalveolar lavage (BAL) fluid leukotriene (LT) B4 levels increased to 594 +/- 46 relative to 200 +/- 38 pg/ml in shams (P less than 0.01); increased permeability was documented by BAL fluid protein content of 599 +/- 91 compared with 214 +/- 35 micrograms/ml in sham animals (P less than 0.01); and edema was shown by increase in lung wet-to-dry weight ratio of 4.77 +/- 0.14 relative to 4.00 +/- 0.09 in sham rats (P less than 0.01). In MAAPV-treated animals, lung neutrophil sequestration (62 +/- 9 U/g MPO) and rise of LTB4 in BAL fluid (780 +/- 244 pg/ml) were not affected, but both BAL fluid protein (335 +/- 32 micrograms/ml) and lung wet-to-dry weight ratio (4.21 +/- 0.17) were reduced (both P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Attenuation of IL-2-induced multisystem organ edema by phalloidin and antamanide.
Interleukin 2 (IL-2) is a potent cytokine with diverse effects, including the ability to stimulate lymphocyte differentiation into cells capable of lysing tumor. Its therapeutic efficacy is limited because of side effects such as breakdown of the microvascular barrier and edema. Control of the microvascular barrier is in part regulated by endothelial cell cytoskeletal contractile proteins. This study tests whether the cyclopeptides that maintain actin filament organization and distribution and reduce macromolecular flux across the endothelial cell junction in vitro would similarly maintain barrier tightness and prevent early edema produced by IL-2 in vivo. Anesthetized rats were treated at 30-min periods with intravenous saline (0.5 ml, n = 41), phalloidin (20 micrograms in 0.5 ml, n = 21), or antamanide, (20 micrograms in 0.5 ml, n = 21), starting 30 min before the 1-h infusion of 10(6) U of recombinant human IL-2 or saline. Six hours after the start of IL-2, there was edema in the saline/IL-2 group, as measured by increased wet-to-dry ratios (W/D) in the lungs, heart, and kidney. With saline/IL-2, bronchoalveolar lavage (BAL) fluid contained an elevated protein concentration and higher plasma thromboxane levels compared with controls. The number of neutrophils sequestered in the lungs was more than twice that of saline controls. Phalloidin significantly attenuated edema in lung and reduced BAL protein leak. Antamanide treatment was as effective in limiting lung and heart edema, but, in contrast to phalloidin, antamanide prevented kidney edema and did not lead to an alteration in the liver W/D. Antamanide also prevented BAL fluid protein leak.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Neutrophil accumulations due to pulmonary thromboxane synthesis mediate acid aspiration injury.
Acid aspiration leads to lung injury associated with high levels of plasma thromboxane (Tx). This study tests the role of Tx synthesis by the aspirated lung segment in mediating local and remote neutrophil (PMN) sequestration, alveolar diapedesis, and permeability edema. Anesthetized rats underwent tracheostomy and insertion of a fine-bore cannula into the anterior segment of the left lung. This was followed by the installation of either 0.1 ml saline (n = 18) or the Tx synthase inhibitor OKY 046 (0.1 mg/kg in 0.1 ml, n = 18). Twenty minutes later either 0.1 ml 0.1 N HCL or 0.1 ml saline was similarly introduced (n = 18). Three hours later, in the saline-HCl group, the rise in Tx concentration in both plasma (1,340 pg/ml) and bronchoalveolar lavage (BAL) fluid (2,100 pg/ml) was higher than that in the saline-saline aspirated control group (350 and 115 pg/ml, respectively; both P less than 0.05). In the acid-aspirated lung PMN sequestration [87 PMN/10 high-power fields (HPF)] and diapedesis (96 x 10(4) PMN/ml in BAL) were higher than control values of 7 PMN/10 HPF and 3 x 10(4) PMN/ml (both P less than 0.05). Acid aspiration induced local permeability edema with a high protein concentration in BAL of 3,350 micrograms/ml and an increase in lung wet-to-dry weight ratio (W/D) of 6.6, both higher than control values of 482 micrograms/ml and 3.4, respectively (P less than 0.05). Leukosequestration in the aspirated side started at 30 min and was progressive over a 3-h monitoring period.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Role for tumor necrosis factor as mediator of lung injury following lower torso ischemia.
Ischemia and reperfusion of the ischemic lower torso lead to a neutrophil- (PMN) dependent lung injury characterized by PMN sequestration and permeability edema. This mimics the injury seen after infusion of tumor necrosis factor alpha (TNF), a potent activator of PMN and endothelium. This study tests whether TNF is a mediator of the lung injury after lower torso ischemia. Anesthetized rats underwent 4 h of bilateral hindlimb tourniquet ischemia, followed by reperfusion for 10 min, 30 min, 1, 2, 3, and 4 h (n = 6 for each time point). Quantitative lung histology indicated progressive sequestration of PMN in the lungs, 25 +/- 3 (SE) PMN/10 high-power fields (HPF) 10 min after reperfusion vs. 20 +/- 2 PMN/10 HPF in sham animals (NS), increasing to 53 +/- 5 PMN/10 HPF after 4 h vs. 23 +/- 3 PMN/10 HPF in sham animals (P less than 0.01). There was lung permeability, shown by increasing protein accumulation in bronchoalveolar lavage (BAL) fluid, which 4 h after reperfusion was 599 +/- 91 vs. 214 +/- 35 micrograms/ml in sham animals (P less than 0.01). Similarly, there was edema, shown by the lung wet-to-dry weight ratio, which increased by 4 h to 4.70 +/- 0.12 vs. 4.02 +/- 0.17 in sham animals (P less than 0.01). There was generation of leukotriene B4 in BAL fluid (720 +/- 140 vs. 240 +/- 40 pg/ml, P less than 0.01), and in three of six rats tested at this time TNF was detected in plasma, with a mean value of 167 pg/ml. TNF was not detectable in any sham animal.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Thromboxane mediates diapedesis after ischemia by activation of neutrophil adhesion receptors interacting with basally expressed intercellular adhesion molecule-1.
Ischemic injury is characterized by neutrophil (PMN)--endothelial cell adhesion and diapedesis associated with thromboxane (TX) generation. Neutrophil-endothelial cell interaction is regulated in part by the leukocyte adhesion receptor CD 18 glycoprotein complex and the endothelial intercellular adhesion molecule-1 (ICAM-1). This study tests the role of TX in ischemia-induced diapedesis and evaluates whether the diapedesis is regulated by neutrophil or endothelial adhesion receptors. Plasma derived from rabbit hind limbs made ischemic for 3 hours (n = 6) and reperfused for 10 minutes had increased levels of TXB2 3,450 pg/ml, which was higher than sham rabbit (n = 6) values of 653 pg/ml (p less than 0.05). When introduced into abraded skin chambers placed on the dorsum of other normal rabbits (n = 6), this ischemic plasma induced 1,000 pg/ml of new TX synthesis and diapedesis of 1,235 PMN/mm3. The total TX concentration and PMN accumulations in blister fluid were correlated (r = 0.88, p less than 0.05). In contrast, sham rabbit plasma induced no TX synthesis and diapedesis of only 77 PMN/mm3 (p less than 0.05). Administration of 50 ng/ml of authentic TXB2 into blisters induced an accumulation of 453 PMN/mm3, which was higher than that in saline controls (18 PMN/mm3) (p less than 0.05). Pretreatment of normal rabbits used for the diapedesis assay (n = 4) with the TX synthetase inhibitor OKY 046 (2 mg/kg/hr) limited ischemic plasma and authentic TXB2 induced diapedesis to 142 and 76 PMN/mm3, respectively (both p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Modulation of pulmonary permeability in vivo with agents that affect the cytoskeleton.
In vitro studies show that the cytoskeleton of the microvascular barrier moderates polymorphonuclear leukocyte (PMN) diapedesis and the transport of macromolecules. This in vivo study tests indirectly whether the cytoskeleton of the pulmonary microvasculature responds similarly to agents known to reorganize the cytoskeleton to alter diapedesis and permeability in vitro. One of four agents, saline solution, cytochalasin B (which promotes actin microfilament disassembly), leukotriene (LT) B4 (PMN chemoattractant), or phalloidin (which promotes and stabilizes F-actin polymerization) was introduced into the bronchus of the anterior segment of the left lung of anesthetized rats (n = 152) through a tracheostomy and fine-bore cannula. Twenty minutes later, saline solution, cytochalasin B, LTB4, or phalloidin was similarly introduced. PMN accumulations (x 10(4) cells/ml), protein concentration in bronchoalveolar lavage fluid, and lung wet/dry weight ratios were measured 3 hours later. When the initial and secondary treatments were saline solution, PMN accumulations were 3 +/- 1 cells/ml and the protein level was 274 +/- 48 micrograms/ml. Secondary treatment of the saline-treated group with cytochalasin B or LTB4 led to increases in PMN to 18 +/- 2 and 9 +/- 2 cells/ml and protein to 960 +/- 50 and 840 +/- 40 micrograms/ml (p less than 0.05); secondary treatment with phalloidin was similar to that with saline solution. With saline solution used for both treatments, the wet/dry ratio was 3.4 +/- 0.2. Primary saline solution and secondary treatments with either cytochalasin B or LTB4 led to a similar increase in wet/dry ratios to 3.9 +/- 0.1 (p less than 0.05), whereas phalloidin was without effect (3.5 +/- 0.3). Initial cytochalasin B treatment followed by LTB4 led to increased PMN diapedesis (43 +/- 6 cells/ml and wet/dry ratio 4.3 +/- 0.2) (p less than 0.05). Secondary phalloidin treatment attenuated the cytochalasin B effect with counts of 12 +/- 2 PMN/ml, protein levels of 460 +/- 30 micrograms/ml, and a lower wet/dry ratio of 3.7 +/- 0.1 (p less than 0.05). Even more striking, phalloidin as initial treatment further reduced the cytochalasin B effect to 7 +/- 1 PMN/ml, whereas protein level was 490 +/- 60 micrograms/ml and wet/dry ratio was 3.5 +/- 0.1 (p less than 0.05). Further, phalloidin, given initially, attenuated the effect of secondary treatment with LTB4, resulting in fewer cells (4 +/- 2 PMN/ml), a lower wet/dry ratio (3.4 +/- 0.1), and protein level of 650 +/- 20 micrograms/ml (p less than 0.05).(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Interleukin-2-induced lung injury is mediated by oxygen free radicals.
Interleukin-2 therapy leads to respiratory dysfunction caused by increased vascular permeability. This study examines the role of oxygen-derived free radicals (OFR). Sheep (n = 6) with chronic lung lymph fistulae were given interleukin-2, 10(5) units/kg, as an intravenous bolus. The mean pulmonary artery pressure rose from 13 to 23 mm Hg (p less than 0.05) at 1 hour and remained elevated for 4 hours, although the pulmonary artery wedge pressure was unchanged at 4 mm Hg. Arterial oxygen tension fell from 88 to 77 mm Hg (p less than 0.05). Lung lymph flow rose from 2.2 to 6.4 ml/30 min (p less than 0.05) at 3 hours. This rise coincided with an increase in the lymph/plasma protein ratio from 0.67 to 0.77 (p less than 0.05) and lymph protein clearance from 1.5 to 4.4 ml/30 min (p less than 0.05), indicating increased lung microvascular permeability. Interleukin-2 led to transient increases in plasma thromboxane B2 from 168 to 388 pg/ml (p less than 0.05) and lung lymph thromboxane B2 from 235 to 694 pg/ml (p less than 0.05). The leukocyte count fell from 8156 to 4375/mm3 (p less than 0.05) primarily caused by a 78% drop in lymphocyte count. Platelet count declined from 292 to 184 X 10(3)/mm3 (p less than 0.05). Pretreatment with the hydroxyl radical scavenger dimethylthiourea, 1 gm/kg, intravenously, (n = 6) prevented the interleukin-2-induced increase in mean pulmonary artery pressure, lung lymph flow, lymph/plasma protein ration, lymph protein clearance, and thromboxane B2 levels in plasma and lung lymph. The arterial oxygen tension decreased from 85 to 80 mm Hg (p less than 0.05). The leukocyte count declined from 7854 to 6229/mm3 (p less than 0.05), but this was not as low nor as prolonged as the interleukin-2 group. Further, the decrease in platelet count was prevented (p less than 0.05). Interleukin-2 incubated with sheep or human leukocytes led to a dose-dependent increase in intracellular hydrogen peroxide production by neutrophils as measured by flow cytometry of dichlorofluorescein oxidation. These data indicate that interleukin-2 stimulates OFR generation and that OFR moderate the interleukin-2-induced increased lung permeability.
Animals↗
Interleukin-2-induced lung permeability is mediated by leukotriene B4.
Interleukin (IL)-2 therapy leads to respiratory dysfunction due to increased vascular permeability. This study examines the role of the chemoattractant, immunomodulator, and permeability-promoting agent leukotriene (LT) B4 in this setting. Sheep with chronic lung lymph fistulae were given IL-2, 10(5) U/kg as an IV bolus (n = 6). Within 2 hours this led to a significant increase in LTB4 levels in both plasma and lung lymph. The mean pulmonary artery pressure (MPAP) rose while the pulmonary artery wedge pressure was unchanged. Arterial oxygen tension (PaO2) fell. Lung lymph flow (QL) was tripled (P less than 0.05) at 3 hours, coinciding with an increase in the lymph/plasma (L/P) protein ratio (P less than 0.05) resulting in an increase in the lymph protein clearance (P less than 0.05), data documenting increased microvascular permeability to protein. Mild leukopenia and thrombocytopenia (P less than 0.05) occurred. Body temperature rose and shaking chills were common. Pretreatment with the lipoxygenase inhibitor diethylcarbamazine (DEC; n = 6) reduced baseline plasma LTB4 levels and prevented the IL-2-induced increases in LTB4 in plasma and lung lymph (P less than 0.05). In contrast to IL-2 treatment alone, DEC blunted the increase in MPAP and prevented the rises in QL (P less than 0.05), L/P protein ratio (P less than 0.05), and lymph protein clearance (P less than 0.05). DEC also prevented the IL-2-induced leukopenia, the fall in platelet count, and the rise in body temperature (P less than 0.05, respectively). Infusion of IL-2 excipient control (n = 5) did not affect plasma or lymph LTB4 levels but there were mild increases in MPAP (P less than 0.05). The QL also rose but this occurred while the L/P protein ratio fell (P less than 0.05). Body temperature rose moderately. The PaO2, leukocyte, and platelet counts were unaffected. These data indicate that IL-2 administration leads to pulmonary dysfunction manifest by pulmonary hypertension and increased vascular permeability, events associated with LTB4 synthesis and prevented by DEC. Leukotriene B4 appears therefore to mediate the IL-2-induced lung injury.
Animals↗
Effects of patient, physician and hospital characteristics on the likelihood of vaginal birth after previous cesarean section in Quebec.
Repeat cesarean section is a major factor contributing to the rising cesarean section rate. Although vaginal birth after a previous cesarean section (VBAC) is advocated in most cases, it has not yet been adopted as widespread policy. In a case-control study we compared 400 women in Quebec who underwent VBAC with 1600 women who had a repeat cesarean section from 1985 to 1987 in an attempt to identify factors that favour vaginal delivery. Using both simple and multiple logistic regression analyses we examined the effect of independent variables linked to the patients (two variables), the attending physicians (seven) and the hospitals (two) on the dependent variable (type of birth) with the use of odds ratios. We found that the physician characteristics related to type of practice and the degree of hospital specialization were significant factors in predicting the type of delivery. Women who gave birth vaginally were more likely than those who had a repeat cesarean section to be attended by a physician with a specialized practice and to give birth in a hospital providing an intermediate or high level of care. This suggests that VBAC is still perceived as a high-risk option and is managed by only a minority of specialized obstetricians.
Adult↗
Neutrophil adherence receptors (CD 18) in ischemia. Dissociation between quantitative cell surface expression and diapedesis mediated by leukotriene B4.
Neutrophils and eicosanoid chemoattractants are centrally involved with ischemia-reperfusion (I/R) injury. The CD 18 complex of adhesive glycoproteins, readily up-regulated by chemoattractants in vitro, is required for polymorphonuclear leukocyte (PMN) adherence to endothelium. This study tests whether CD 18 is up-regulated by ischemia in vivo and its role in mediating PMN diapedesis. Anesthetized rabbits underwent 3 h of bilateral hindlimb tourniquet ischemia (n = 16). Ten min after tourniquet release, levels of plasma leukotriene (LT)B4 increased to 390 +/- 62 pg/ml (mean +/- SE), higher than 134 +/- 26 pg/ml in control rabbits (n = 13, p less than 0.01). Aliquots of plasma were added to whole blood from normal rabbits (n = 6) for flow cytometric analysis of neutrophils with the CD 18 mAb R 15.7. Addition of I/R plasma failed to demonstrate an increase in surface expression of CD 18. Similarly, no CD 18 up-regulation was observed in vivo upon reperfusion in ischemic animals pretreated with mAb R 15.7 (n = 3). However, I/R plasma when introduced into plastic chambers taped atop dermabrasion sites in normal rabbits (n = 12) resulted in diapedesis, measured by the accumulation after 3 h of 1130 +/- 125 PMN/mm3 in the chambers relative to 120 +/- 31 PMN/mm3 with control plasma (p less than 0.01). Diapedesis in response to I/R plasma was abolished by pretreatment with mAb R 15.7 (less than 5 PMN/mm3, n = 6), was reduced by U 75,302, an LTB4 receptor antagonist (253 +/- 101 PMN/mm3, n = 6) (both p less than 0.01) and was not protein synthesis dependent. These results demonstrate that PMN diapedesis in response to I/R plasma is exclusively dependent upon the CD 18 glycoprotein complex by an LTB4-dependent mechanism, despite the fact that CD 18 is not up-regulated on circulating PMN in ischemia. These data indirectly indicate the functional importance of conformational changes of CD 18 in determining PMN adhesion.
Animals↗
Ischemia activates neutrophils but inhibits their local and remote diapedesis.
Hindlimb ischemia and reperfusion results in local limb and distant lung injury. This study tests whether the mechanism of injury is by ischemia mediated polymorphonuclear leukocyte (PMN) activation and diapedesis. Anesthetized rabbits were subjected to three hours of hindlimb ischemia (n = 8) or sham ischemia (n = 4). PMN derived solely from the reperfused ischemic limb and assayed flow cytometrically displayed an oxidative burst of 135 /- 8 fentamoles dichlorofluorescein (fmDCF)/cell compared to preischemc levels of 74 +/- 14 fmDCF/cell (p less than 0.05). Additional aliquots of isolated neutrophils were treated with phorbol myristate acetate (PMA) 10(-7) M. In contrast to a 162% increase in oxidative burst before ischemia, neutrophils at ten minutes of reperfusion had an enhanced response to PMA of 336% (p less than 0.05). Plasma collected from the ischemic hindlimb at ten minutes of reperfusion when introduced into an abraded skin chamber or intratracheally induced diapedesis in nonischemic animals. PMN accumulations in the skin chamber were 1636 +/- 258 PMN/mm3 after three hours (n = 8) compared to 63 +/- 18 PMN/mm3 induced by sham plasma (n = 4, p less than 0.05). Introduction of ischemic plasma intratracheally into a lobar bronchus (n = 4) induced PMN accumulations after three hours, measured by bronchoalveolar lavage fluid of 19 +/- 2 X 10(4) PMN/mm3 compared to 5 +/- 1 X 10(4) PMN/mm3 with sham plasma (n = 4, p less than 0.05). Diapedesis was completely prevented (0-3 PMN/mm3, p less than 0.05) by introducing ischemic plasma into skin chambers in animals whose hindlimbs had been made ischemic (n = 6) or into chambers located on skin regions that had been previously made ischemic (n = 6). Similarly after hindlimb ischemia, lavage of the lung with ischemic plasma yielded few PMN 0-3/mm3 (p less than 0.05). These data indicate that ischemia and reperfusion lead to generation of a circulating component in plasma that causes an oxidative burst in PMN and inhibits their diapedesis but promotes diapedesis when applied extravascularly to a naive animal.
Animals↗
Tumor necrosis factor-alpha mediates acid aspiration-induced systemic organ injury.
Acid aspiration-induced systemic organ injury is mediated by the sequestration of activated neutrophils (PMN). In other settings cytokines have been shown to increase neutrophil-endothelial adhesion, a requisite for injury. This study tests whether the systemic leukosequestration and permeability following localized aspiration is mediated by tumor necrosis factor (TNF)-alpha-induced synthesis of an adhesion protein. Anesthetized rats underwent tracheostomy and insertion of a fine-bore cannula into the anterior segment of the left lung. This was followed by the instillation of either 0.1 mL 0.1 N HCI (n = 18) or 0.1 mL saline in control rats (n = 18). Localized aspiration induced generalized pulmonary leukosequestration with 95 PMN/10 high-power fields (HPF) in the aspirated lung and 46 PMN/10 HPF in the nonaspirated lung, higher than control values of 7 PMN/10 HPF and 5 PMN/10 HPF in saline- and nonsaline-aspirated sides, respectively (p less than 0.05). The leukosequestration was associated with permeability edema shown by increased protein concentrations in bronchoalveolar lavage (BAL) of 3900 micrograms/mL in the aspirated and 2680 micrograms/mL in the nonaspirated side, higher than saline with 482 micrograms/mL and 411 micrograms/mL, respectively (p less than 0.05). There was generalized pulmonary edema following aspiration measured by increase in wet-to-dry weight ratios (w/d) of 6.6 in the aspirated and 5.1 in the nonaspirated lung, higher than control values of 3.5 and 3.4, respectively (p less than 0.05). Localized aspiration led to systemic leukosequestration documented by increases in myeloperoxidase activity (units/g tissue) of 2.2 and 1.7 in heart and kidney, higher than control values of 0.3 and 0.4, respectively (p less than 0.05). This event was associated with edema of these organs with w/d ratios of 4.6 and 4.3, relative to control values of 3.0 and 3.4 (p less than 0.05). Treatment of animals (n = 18) 20 minutes after aspiration with anti-TNF-alpha antiserum (rabbit anti-murine) but not normal rabbit serum (n = 18) reduced lung leukosequestration in the aspirated and nonaspirated segments (61 and 32 PMN/10HPF), BAL protein concentration (1490 and 840 micrograms/mL), and w/d ratio (4.3 and 3.7) (all p less than 0.05). In the heart and kidney there were reductions in myeloperoxidase activity (0.7 and 0.6) and w/d ratio (3.5 and 3.6) (both p less than 0.05). Treatment of rabbits (n = 18) with the protein synthesis inhibitor cycloheximide, 0.2 mg/kg/hr was as effective as TNF-alpha antiserum in modifying aspiration injury.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Involvement of thromboxane and neutrophils in multiple-system organ edema with interleukin-2.
Interleukin-2 (IL-2) produces toxicity characterized by generalized edema within 24 hours. This study tests whether the rate of IL-2 administration modulates the onset of edema and examines thromboxane (Tx) and neutrophils as possible mediators of this event. Recombinant human IL-2, 10(5) U (n = 7), 10(6) U (n = 9), or vehicle (n = 8) were given to anesthetized rats intravenously during a period of 1 hour. At 6 hours edema, as measured by increase in wet to dry weight (w/d) ratio, was present in the heart, liver, and kidney, with 10(5) U IL-2 and in the lung, heart, liver and kidney, with 10(6) U IL-2, relative to values with vehicle-infused controls (all p less than 0.05). With a 1-hour infusion of 10(6) U IL-2, there was an increase in plasma thromboxane (Tx)B2 level to 1290 +/- 245 pg/mL, higher than 481 +/- 93 pg/mL in control rats (p less than 0.05); lung polymorphonuclear leukocyte (PMN) sequestration of 53 +/- 7 PMN/10 higher-power fields (HPF) relative to 23 +/- 2 PMN/10 HPF in controls (p less than 0.05); and increased bronchoalveolar lavage (BAL) fluid protein concentration of 1970 +/- 210 micrograms/mL relative to 460 micrograms/mL in controls (p less than 0.05). When 10(6) U IL-2 was given as a 1-minute intravenous bolus (n = 9), edema was not demonstrated, plasma TxB2 levels were similar to controls, there was no leukosequestration, and BAL protein levels were normal. These data indicate that a constant infusion but not the rapid bolus administration of IL-2 produces in rats multiple-system organ edema, increased plasma TxB2, sequestration of PMNs, and microvascular permeability. These findings may explain the early toxicity seen in patients given high-dose IL-2 in cancer treatment.
6-Ketoprostaglandin F1 alpha↗
Polyamines--potential nucleating factors in bile.
Lithogenicity of human bile is dependent not only on cholesterol saturation, but also on the presence of nucleating and antinucleating factors. Most of the research in this field is directed toward biliary proteins, particularly glycoproteins. In the present study we have shown that spermine, spermidine, cadaverine and putrescine have a nucleating effect in model bile as well as in native human bile. These findings are based on 183 mixing experiments using biles from 10 patients and model biles. The effect seems to be dose dependent at concentrations up to 10 mmol/l. It is not accompanied by a shift in cholesterol distribution between its vesicular and micellar carriers. It is at present uncertain whether these effects are pharmacologic or physiologic. These findings emphasize, however, the potential importance of non-protein compounds in the cholesterol nucleation process in bile.
Bile↗