The effect of three different miniaturized blood purification devices on plasma cytokine concentration in an ex vivo model of endotoxinemia.

PURPOSE: A novel type of adsorptive plasma filtering device (ETX-A) capable of removing endotoxin from blood in a single step has recently been developed using nanotechnology. METHODS: In a miniaturized, ex vivo model of extracorporeal circuits, we tested the capacity to reduce plasma cytokine concentration of ETX-A filters in comparison to standard high-flux (HF) filters, high cut-off (HCO) filters and a control. Blood from six healthy volunteers was spiked with endotoxin and then circulated through closed (ETX-A, control) or open (HF, HCO) circuits. Blood flow was set at 16 ml/min and filtration flow at 1 ml/min. Samples for measurement of IL-1ra and IL-6 were taken at baseline and at 4 hours. RESULTS: Compared to control (703.3 [850.6] pg/mL), in HCO (383.5 [1144.1] pg/mL) and ETX-A (490.1 [683.2] pg/mL) filters, plasma IL-1ra pooled pre- and postfilter concentrations were lower at the end of the experiment (P=0.002; P=0.050, respectively) whereas, in standard HF filters, IL-1ra concentration was higher than control. HCO showed a trend toward a reduced relative increase in IL-6 concentration from commencement to end of experiment compared to control (P=0.07). After pooling end-of-experiment plasma cytokine values of novel blood purification devices, we found HCO + ETX-A superior to H with regard to reduction of IL-1ra (-27.0 [-20.5]% vs. 8.1 [18.9]%; p<0.001) and IL-6 (-18.0 [38.3]% vs. -1.1 [24.3]%; P=0.050) compared to control. CONCLUSIONS: HCO and ETX-A appeared to significantly reduce plasma IL-1ra and, when combined, plasma IL-6 concentration as well. It appears desirable to manufacture full-size blood purification devices using this technology and to explore their effect on cytokine removal.

Beta2-microglobulin removal and plasma albumin levels with high cut-off hemodialysis.

PURPOSE: beta2-microglobulin (beta2MG) is pivotal to the pathogenesis of dialysis-related amyloidosis. We compared the effects of high cut-off hemodialysis (HCO-HD) with those of standard high-flux hemodialysis (HF-HD) regarding the concentration and clearance of beta2MG and albumin. DESIGN: We enrolled ten patients with acute renal failure in a double-blind, cross-over, randomized controlled trial. PROCEDURES: Each patient received four hours of HCO-HD (estimated in vivo cutoff 50-60 kDa) and four hours of HF-HD (estimated in vivo cutoff 15-20 kDa) in random order. Statistical methods and outcome measures: As data lacked normal distribution, we used nonparametric statistical analysis. Plasma and dialysate concentrations of beta2MG and albumin were measured at baseline and after four hours of each study treatment. MAIN FINDINGS: We found significantly greater diffusive beta2MG clearances for HCO-HD compared to HF-HD (at the start: 71.8 ml/min vs. 5.1 ml/min; P=0.008 and at the end: 68.8 ml/min vs. 5.7 ml/min; P=0.008). We found a reduction in plasma beta2MG concentrations of -31.6% during HCO-HD compared to an increase by 25.7% during HF-HD; P=0.008. At baseline (HCO-HD: 26.0 g/L vs. HF-HD: 26.5 g/L), and at the end of both treatments, plasma albumin concentrations were comparable (HCO-HD: 25.5 g/L vs. HF-HD: 26.5 g/L; P=0.25). During HCO-HD, albumin clearance was 1.9 ml/min at the start and decreased significantly to 0.8 ml/min at the end; P=0.008. HF-HD had an albumin clearance of 0.01 ml/min. CONCLUSIONS: HCO-HD was more effective in decreasing plasma beta2MG concentrations than standard HF-HD and did not reduce plasma albumin levels. Further studies of HCO-HD in the treatment of dialysis-related beta2MG accumulation appear warranted.

A pilot study of high-adsorption hemofiltration in human septic shock.

BACKGROUND: To compare the hemodynamic and biological effects of high-adsorption continuous veno-venous hemofiltration (CVVH) with standard CVVH in septic shock. METHODS: In a randomized cross-over clinical trial twelve patients with septic shock and multiple organ failure were enrolled at a tertiary intensive care unit. Patients were allocated to either 9 hours of high-adsorption hemofiltration (CVVH with 3 hourly filter change using AN69 hemofilters - 3FCVVH) or 9 hours of standard hemofiltration (CVVH without filter change - 1F-CVVH). RESULTS: Changes in hemodynamic variables, dose of noradrenaline required to maintain a mean arterial pressure greater than 75 mmHg and plasma concentrations of cytokines (IL-6, IL-8, IL-10 and IL-18) were measured. A 9-hour period of 3F-CVVH was associated with greater reduction in noradrenaline dose than a similar period of 1F-CVVH (median reduction: 16 vs. 3.5 microg/min, p=0.036; median percentage reduction: 48.1% vs. 17.5%, p=0.028). Unlike 1F-CVVH, 3F-CVVH was associated with a reduction in the plasma concentration of IL-6, IL-10 and IL-18 at 9 hours and a significant decrease 30 minutes after additional filter changes (IL-6: p<0.01, p<0.01; IL-10: p=0.03, p=0.016 and IL-18: p=0.016, p<0.01, respectively). Both, 3F-CVVH and 1F-CVVH were associated with decreased plasma concentrations of IL-8 at 9 hours (p<0.01, p<0.01, respectively). In a confirmatory ex-vivo experiment IL-6 concentrations substantially decreased during 3F-CVVH (at baseline 511 pg/mL and at end: 21 pg/mL) whereas IL-6 concentrations increased in control blood (at baseline 511 pg/mL and at end: 932 pg/mL). CONCLUSIONS: High-adsorption CVVH appears more effective than standard CVVH in decreasing noradrenaline requirements and plasma concentrations of cytokines in septic shock patients.

Non-CF bronchiectasis: clinical and HRCT evaluation.

Childhood bronchiectasis not related to underlying disease is still common in some populations in affluent countries. The aims of the study were to: 1) describe demographics, 2) evaluate the effectiveness of routine investigations, and 3) determine the relationship between spirometry and radiology scoring systems, in children with chronic suppurative lung disease (CSLD) living in Central Australia. Data of children living in Central Australia aged 70%) and early hospitalisation for pneumonia were common (median age, 0.5 years). Previous admissions for pneumonia were almost universally present and significantly more common than bronchiolitis (95% CI for proportional difference, 0.4-0.51). Although the majority did not have a treatable underlying cause, investigations had significant impact on management in 12.3% of children. None of the chest HRCT scores related to any spirometry data. In conclusion, CSLD is unacceptably common in indigenous children of this region, commences early in life, and is associated with significant comorbidities. Spirometry data do not reflect the severity of lung disease in HRCT scans. While improvement in the living standards is of utmost importance, the medical management that includes thorough investigations of these children should not be neglected.

Bronchoscopic findings in children with non-cystic fibrosis chronic suppurative lung disease.

BACKGROUND: Published data on the frequency and types of flexible bronchoscopic airway appearances in children with non-cystic fibrosis bronchiectasis and chronic suppurative lung disease are unavailable. The aims of this study were to describe airway appearances and frequency of airway abnormalities and to relate these airway abnormalities to chest high resolution computed tomography (cHRCT) findings in a cohort of children with non-cystic fibrosis chronic suppurative lung disease (CSLD). METHODS: Indigenous children with non-cystic fibrosis CSLD (>4 months moist and/or productive cough) were prospectively identified and collected over a 2.5 year period at two paediatric centres. Their medical charts and bronchoscopic notes were retrospectively reviewed. RESULTS: In all but one child the aetiology of the bronchiectasis was presumed to be following a respiratory infection. Thirty three of the 65 children with CSLD underwent bronchoscopy and five major types of airway findings were identified (mucosal abnormality/inflammation only, bronchomalacia, obliterative-like lesion, malacia/obliterative-like combination, and no macroscopic abnormality). The obliterative-like lesion, previously undescribed, was present in 16.7% of bronchiectatic lobes. Structural airway lesions (bronchomalacia and/or obliterative-like lesion) were present in 39.7% of children. These lesions, when present, corresponded to the site of abnormality on the cHRCT scan. CONCLUSIONS: Structural airway abnormality is commonly found in children with post-infectious bronchiectasis and a new bronchoscopic finding has been described. Airway abnormalities, when present, related to the same lobe abnormality on the cHRCT scan. How these airway abnormalities relate to aetiology, management strategy, and prognosis is unknown.

Effect of premedication guidelines and leukoreduction on the rate of febrile nonhaemolytic platelet transfusion reactions.

Platelet transfusion reactions were prospectively studied in haematology/oncology patients at five university teaching hospitals over three consecutive summers. The initial summer study provided baseline information on the use of premedications and the rate of platelet transfusion reactions (fever, chills, rigors and hives). Most (73%) platelet recipients were premedicated and 30% (95% CI 28-33%) of transfusions were complicated by reactions. The second study followed implementation of guidelines for premedicating platelet transfusions. Despite a marked reduction in premedication (50%), there was little change in the platelet transfusion reaction rate, 26% (95% CI 24-29%), or the type of reactions. The third study followed implementation of prestorage platelet leukoreduction while maintaining the premedication guidelines. The reaction rate decreased to 19% (95% CI 17-22%). For nonleukoreduced platelets, there was a statistically significant association between the platelet age and reaction rate (P = 0.04). For leukoreduced platelets, there was no statistically significant association between platelet age and reaction rate (P = 0.5). Plasma reduction of nonleukoreduced platelet products also reduced the reaction rate. These prospective studies document a high rate of platelet transfusion reactions in haematology/oncology patients and indicate premedication use can be reduced without increasing the reaction rate. Prestorage leukoreduction and/or plasma reduction of platelet products reduces but does not eliminate febrile nonhemolytic platelet transfusion reactions.

The extraction of quality-of-care clinical indicators from State health department administrative databases.

OBJECTIVE: To assess whether three proposed quality-of-care indicators (unplanned readmissions, hospital-acquired bacteraemia, and postoperative wound infection) can be accurately identified from State health department databases. DESIGN: Algorithms were applied to State health department databases to maximise the identification of individuals potentially positive for each indicator. Records of these patients were then examined to determine the percentage of cases that met the precise indicator definitions. SETTING: 10 public, acute-care hospitals from Victoria, South Australia and New South Wales. Data from the 1994-95 and 1995-96 financial years were collected. PARTICIPANTS: Individuals 18 years of age or older who were identified from State health department administrative databases as potentially meeting the indicator criteria. MAIN OUTCOME MEASURES: The proportion of screened cases that met the precise indicator definitions, and the elements of the indicator definitions which could not be extracted from the administrative databases. RESULTS: The proportions of cases confirmed by medical record review to be positive for the indicator events were 76.3% for unplanned readmissions within 28 days, 20% for hospital-acquired bacteraemia, 43.5% for wound infections after clean surgery, and 34.8% for wound infections after contaminated surgery. The clinical elements of each indicator definition were not easily extracted from the administrative databases. CONCLUSIONS: The three proposed clinical indicators could not be extracted from current State health department databases without an extensive process of secondary medical record review. If administrative databases are to be used for assessing quality of care, more systematic recording of data is needed.

Detection of intracellular lipocortin 1 in human leukocyte subsets.

Lipocortin 1, a putative mediator of the anti-inflammatory actions of glucocorticoids, is present intracellularly in a variety of tissues including human peripheral blood leukocytes. We investigated the presence of lipocortin 1 in human leukocyte subsets using permeabilization flow cytometry. Constitutive lipocortin 1 was detected in U937 myelomonocytic leukemia cells, and lipocortin 1 was increased by treatment with PMA or PMA+IFN-gamma (P < 0.05) but not by dexamethasone. Lipocortin 1 was present in all leukocyte subsets except B lymphocytes (CD19/20+, P < 0.001). Lipocortin 1 content was maximal in monocytes and polymorphonuclear neutrophils and least in lymphocytes (P < 0.001). Monocyte lipocortin 1 was strongly associated with surface expression of CD14 and HLA-DR. Among non-B lymphocytes, a range of lipocortin 1 fluorescence was observed. Lipocortin 1 fluorescence was greatest in natural killer cells (CD56+, P < 0.001) and CD57+ cells, but T cell subset markers did not otherwise discriminate variations in lipocortin 1. Induction of lymphocyte proliferation by PHA, anti-CD3, Con A, superantigen, and SAC was not associated with significant shifts in lipocortin 1 content. Dexamethasone (10(-10)-10(-6) M) did not induce increases in PB leukocyte lipocortin 1. We conclude that lipocortin 1 content in human leukocytes varies significantly among phenotypic subsets. This has significance for the investigation of inflammatory disease where certain cell types predominate.

Interleukin-6 and interleukin-8 extraction during continuous venovenous hemodiafiltration in septic acute renal failure.

OBJECTIVES: To determine whether continuous venovenous hemodialfiltration (CVVHD) is associated with the extraction of interleukin-6 (IL-6) and interleukin-8 (IL-8) from the circulation of critically ill patients with septic acute renal failure. To quantitate their clearance and assess any possible effect of CVVHD on these cytokines' serum concentrations. DESIGN: Prospective controlled study of IL-6 and IL-8 removal by CVVHD in patients with septic acute renal failure. SETTING: Intensive care unit of a tertiary institution. PATIENTS: Ten critically ill patients with sepsis, acute renal failure, and multiorgan failure. A control group of five patients experiencing an acute illness while undergoing chronic hemodialysis. INTERVENTIONS: Collection of blood samples before CVVHD. Simultaneous collection of prefilter blood and ultradiafiltrate after 4 and 24 h of treatment. IL-8 concentrations were measured in blood and ultradiafiltrate. Their clearances and daily extractions were calculated. MEASUREMENTS AND MAIN RESULTS: IL-6 and IL-8 were detected in the blood of all patients with septic acute renal failure prior to CVVHD. The median IL-6 blood level was 103 pg/mL (range: 19 to 900) and the median IL-8 blood level was 200 (range: 32 to 2925). Both cytokines were cleared by the hemofilter during CVVHD. The median hemofilter clearance of IL-6 were 1.99 L/day (range: 0 to 8.5) and the median clearance of IL-8 was 3.95 L/day (range: 0.31 to 42.8). These blood levels and clearances resulted in median daily extraction rates of 194 ng of IL-6 (range: 0 to 9031) and of 915 ng of IL-8 (range 47.5 to 3562). Control patients had negligible amounts of either IL-6 or IL-8 in their ultrafiltrate. The rate of extraction for IL-6 correlated with its blood levels (p < 0.0001). This was not true for IL-8. A correlation between IL-6 levels and the patients' white cell counts was found after 24 h of hemofiltration. CONCLUSIONS: CVVHD is associated with the extraction of IL-6 and IL-8 from the circulation of patients with septic multiorgan and renal failure. The biological significance of such extraction is undetermined, but such cytokine removal highlights the complexity of the effect of continuous hemofiltration on the soluble mediators of inflammation activated during human sepsis.

A prospective study of continuous hemodiafiltration in the management of severe acute renal failure in critically ill surgical patients.

Severe acute renal failure associated with surgical disease and a highly catabolic state poses a major therapeutic challenge. Treatment by conventional dialysis or arteriovenous hemofiltration suffers from serious shortcomings. The current study assesses the clinical and biochemical impact of a newer approach (continuous hemodiafiltration) in a cohort of 60 critically ill surgical patients with severe renal failure. All patients were studied prospectively and assessed for illness severity. Their biochemical response to therapy was analyzed and their clinical course to either death or hospital discharge documented. The use of continuous hemodiafiltration (CHD) permitted full control of azotemia in all patients (mean steady-state urea concentration: 19.8 mmol/L) and was associated with rapid control of acidemia (mean pretreatment pH: 7.27; mean ph after 24-h treatment: 7.35; p < .001). During the 15,696 h of therapy, there were no treatment-induced episodes of hypotension and/or hypoxemia. All patients were able to receive full-dose enteral (9) or parenteral (51) nutritional support with 1.5 to 2.5 g/kg/day of protein as tolerated. Despite their illness severity (mean APACHE II score: 28.9) and the need for vasopressor support and ventilation in 90% of cases, 21 patients (35%) survived to hospital discharge. We conclude that continuous hemodiafiltration is safe and effective in surgical critically ill patients with acute renal failure, and that it is associated with a low morbidity and an encouraging survival rate.

Continuous veno-venous hemofiltration with dialysis removes cytokines from the circulation of septic patients.

OBJECTIVE: To determine whether continuous veno-venous hemofiltration with dialysis leads to extraction of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta) from the circulation of critically ill patients with sepsis and acute renal failure and to quantitate the clearance and removal rates of these cytokines and their effect on serum cytokine concentrations. DESIGN: Prospective, controlled study of TNF-alpha IL-1 beta extraction by continuous veno-venous hemofiltration with dialysis in patients with septic acute renal failure. SETTING: Intensive care unit of a tertiary institution. PATIENTS: Eighteen critically ill patients with sepsis and acute renal failure. Control group of six patients experiencing an acute illness while undergoing chronic hemodialysis. INTERVENTIONS: Collection of blood samples before continuous veno-venous hemofiltration with hemodialysis. Simultaneous collection of prefilter blood and ultradiafiltrate after 4 and 24 hrs of treatment. MEASUREMENTS AND MAIN RESULTS: TNF-alpha and IL-1 beta concentrations were measured in blood and ultradiafiltrate. Their clearances and daily extraction were calculated and compared with a control group. TNF-alpha was detected in 66.6% of serum samples of patients with septic acute renal failure; IL-1 beta was detected in 55% of patients' sera samples. Both TNF-alpha and IL-1 beta were cleared by the hemofilter during continuous veno-venous hemofiltration with dialysis. The mean clearance for TNF-alpha was 30.7 L/day (95% confidence interval 22.4 to 39) with a daily mean excretion of 14.1 micrograms (95% confidence interval 1.7 to 26.5). Mean IL-1 beta clearance was 36.1 L/day (95% confidence interval 25.4 to 46.8) equivalent to a mean daily IL-1 beta excretion of 1 microgram (95% confidence interval 0.9 to 1.1). No measurable concentrations of TNF-alpha or IL-1 beta were found in the serum or ultrafiltrate specimens of control patients. CONCLUSIONS: These findings demonstrate that continuous veno-venous hemofiltration with dialysis can remove both TNF-alpha and IL-1 beta from the circulation of septic, critically ill patients. This cytokine extraction may prove to be of benefit in attenuating the progression of multiple organ dysfunction in patients with sepsis-associated renal failure, who are receiving continuous veno-venous hemofiltration with dialysis. This potential benefit of existing hemofiltration therapies supports their preferential implementation in patients with renal failure associated with severe sepsis. These observations may stimulate the modification of filtration membrane design seeking to specifically augment the clearance from the circulation of a variety of such cytokines.

Tumor necrosis factor clearances during veno-venous hemodiafiltration in the critically ill.

Tumor necrosis factor alpha (TNF) is a mediator of injury in the critically ill. Its small molecular size (17 kd) should allow its clearance during continuous hemodiafiltration (CHD). The authors studied TNF extraction in 12 critically ill patients (APACHE II score 26.3 mean; range, 19-34) receiving CHD. Tumor necrosis factor levels were measured in prefiltered and filtered blood and ultradiafiltrate at 0.4 and 24 hours of therapy. Before CHD, mean plasma TNF levels were 261 pg/ml (95% confidence interval [CI]: 184-578) and 291 pg/ml (95% CI: 0-589) after 24 hours. There were no statistically significant differences between prefilter and postfilter TNF levels. Most ultradiafiltrate samples (74%) contained demonstrable TNF (mean, 314 pg/ml; 95% CI: 67-561). Daily TNF excretion was a mean of 15.9 micrograms (+5.6 standard error [SE]), with a mean daily clearance of 27.5 L (95% CI: 2.5-52.5). The authors conclude that significant amounts of TNF are excreted in the ultradiafiltrate during CHD. This observation may provide a rationale for use of similar therapies in critically ill patients in the absence of conventional indications for dialytic support.

Macrophage-Fc-receptor affinity: role in cellular mediation of antibody initiated glomerulonephritis.

The role of immunoglobulin (Ig) Fc-macrophage cell surface receptor affinity (macrophage Fc-affinity) in determining the mediation systems responsible for immune glomerular injury has been studied. Glomerular injury was initiated in rabbits by the passive administration of immunoglobulin preparations directed against a "planted" glomerular antigen. The mediation systems inducing injury initiated by antibody pools of high and low macrophage Fc-affinity were compared. In this model of glomerulonephritis macrophage Fc-affinity was the only variable. IgFc-macrophage affinity was quantitated in fluid-phase and solid-phase assay systems (high affinity pool KA = 7.05 +/- 1.11 x 10(5) L/M; low affinity pool KA = 0.79 +/- 0.13 x 10(5) L/M). Comparative antibody binding studies demonstrated that renal injury occurred with high affinity antibody at kidney-fixed-antibody (KFA) binding levels significantly below the KFA levels required for glomerular injury with administration of low affinity antibody [KFA's: 25.1 +/- 2.1 micrograms antibody globulin/g kidney cortex (micrograms/g) and 60.5 +/- 2.4 micrograms/g, respectively, P less than 0.01]. Furthermore, antibody with high macrophage Fc-receptor affinity induced a macrophage-mediated, complement-independent glomerular injury while antibody with low macrophage Fc-receptor affinity induced renal injury via complement and neutrophil dependent mechanisms. IgFc-receptor affinity determined the degree of macrophage recruitment into glomeruli via immune adherence mechanisms, and therefore is an important determinant of which inflammatory mediator system is ultimately responsible for antibody-initiated glomerular injury.

Glomerular macrophages produce reactive oxygen species in experimental glomerulonephritis.

The production of reactive oxygen species by intraglomerular macrophages was assessed in a macrophage dependent model of diffuse proliferative glomerulonephritis in rabbits. Glomerular macrophages were obtained from isolated nephritic glomeruli by short term (60 min) culture. Control macrophage populations were simultaneously obtained from peripheral blood (blood monocytes) and lung lavage fluid (alveolar macrophages). Superoxide anion (O2-), hydrogen peroxide (H2O2) and hydroxyl radical (OH.) production was assessed. Glomerular macrophage production of O2- (48.9 +/- 5.5 nmol/hr/10(6) cells), H2O2 (4.4 +/- 2.5 nmol/hr/10(6) cells) and OH. (57.8 +/- 4.7 U/hr/10(6) cells) was significantly greater than the production of reactive oxygen species seen with control monocyte populations: alveolar macrophages, O2- 9.8 +/- 2.0 nmol/hr/10(6) cells; H2O2 0.6 +/- 0.3 nmol/hr/10(6) cells; OH. 11.0 +/- 1.8 U/hr/10(6) cells; blood monocytes, O2- 8.6 +/- 1.4 nmol/hr/10(6) cells; OH. 9.9 +/- 1.2 U/hr/10(6) cells, (all P less than 0.05 cf. glom macs). Hydrogen peroxide production by blood monocytes (1.6 +/- 0.9 nmol/hr/10(6) cells) was less than glomerular macrophages, however this difference was not statistically significant. The enhanced production of reactive oxygen species by glomerular macrophages in this macrophage dependent model of glomerulonephritis suggests that these mononuclear cells are locally activated within the glomerulus following recruitment from the circulation. Reactive oxygen species production by glomerular macrophages may contribute to their ability to induce glomerular basement membrane injury in this disease.

Heterologous cross-linking of Lyt-2 (CD8) to the alpha beta-T cell receptor is more effective in T cell activation than homologous alpha beta-T cell receptor cross-linking.

Ag recognition of Lyt-2 (CD8)-positive T lymphocytes requires the presentation by APC of a suitably processed Ag in association with MHC class I molecules. In previous studies we have obtained evidence that, for optimal activation, both the alpha beta-TCR and Lyt-2 have to participate in this recognition process. In the current study we investigate the functional consequences of limited cross-linking of these cell surface molecules by using soluble, dimeric hetero- and homoconjugates of mAb to Lyt-2 and to the TCR beta-chain (F23.1). Heterologous cross-linking of Lyt-2 to the TCR induced a vigorous, selective Lyt-2+ T cell proliferative response. Functionally active cytotoxic cells were generated, and a high frequency of responding cells was observed in limiting dilution analyses. In contrast, homologous TCR cross-linking initiated a less pronounced proliferation with a relatively low frequency of response, whereas Lyt-2 cross-linking resulted in no cellular proliferation. Significant T cell activation occurred with exposure to anti-Lyt-2: F23.1 mAb dimers at concentrations an order of magnitude lower than those required for stimulation by F23.1:F23.1 mAb dimers. The induction of proliferation by mAb dimers occurred in the absence of Fc components and in rigorously APC depleted, purified T cell preparations. Effective stimulation of resting T cells could be induced also by heterodimers of monovalent Fab fragments. Heterologous cross-linking of Lyt-2 to the TCR was superior to homologous TCR cross-linking primarily with respect to proliferation in IL-2 containing media and to IL-2R expression, whereas proliferation in response to other lymphokines and the production of IL-2 itself were similar under both cross-linking regimens. Thus, when linked to the TCR, Lyt-2 contributed a strong, positive signal toward IL-2-dependent growth of resting T cells. We assume that in the case of Ag-driven T cell activation, the class I MHC molecule acts as the physiologic cross-linking ligand for Lyt-2 and the TCR.

Alveolar macrophage procoagulant activity is increased in acute hyperoxic lung injury.

Alveolar macrophage accumulation and interstitial fibrin deposition are prominent in adult respiratory distress syndrome and chronic interstitial lung diseases. The role of alveolar macrophages in the initiation of fibrin deposition and lung injury in these diseases is uncertain. Expression of procoagulant activity by these cells may provide evidence of macrophage activation and involvement in the initiation of lung fibrin deposition. An experimental model of hyperoxia-induced lung injury in rats was studied for assessment of the relationship of lung injury, fibrin deposition, and alveolar macrophage procoagulant activity. Lung injury was assessed histologically and functionally, and the accumulation of inflammatory cells was quantified by bronchoalveolar lavage. Pulmonary injury, manifested by increased capillary permeability, developed progressively during exposure to hyperoxia and was associated with significant augmentation of the procoagulant activity of alveolar macrophages early in the disease. This increase preceded the accumulation of polymorphonuclear leukocytes. Alveolar macrophage procoagulant activity had functional characteristics consistent with tissue factor. These studies provide evidence of early alveolar macrophage activation in acute hyperoxic lung injury in rats and suggest a role for procoagulant activity in the development of interstitial fibrin deposition.