Uric acid induces NADPH oxidase-independent neutrophil extracellular trap formation.

Neutrophil extracellular traps (NETs) are composed of extracellular DNA fibers with antimicrobial peptides that capture and kill microbes. NETs play a critical role in innate host defense and in autoimmune and inflammatory diseases. While the mechanism of NET formation remains unclear, reactive oxygen species (ROS) produced via activation of NADPH oxidase (Nox) are known to be an important requirement. In this study, we investigated the effect of uric acid (UA) on NET formation. UA, a well-known ROS scavenger, was found to suppress Nox-dependent ROS release in a dose-dependent manner. Low concentrations of UA significantly inhibited Nox-dependent NET formation. However, high concentrations of UA unexpectedly induced, rather than inhibited, NET formation. NETs were directly induced by UA alone in a Nox-independent manner, as revealed by experiments using control neutrophils treated with ROS inhibitors or neutrophils of patients with chronic granulomatous disease who have a congenital defect in ROS production. Furthermore, we found that UA-induced NET formation was partially mediated by NF-κB activation. Our study is the first to demonstrate the novel function of UA in NET formation and may provide insight into the management of patients with hyperuricemia.

Risk factors for incisional surgical site infections in elective surgery for colorectal cancer: focus on intraoperative meticulous wound management.

PURPOSE: An incisional surgical site infection (I-SSI) is a frequently observed complication following colorectal surgery. Intraoperative wound management is one of the most important factors that determine the incidence of postoperative I-SSI. The purpose of this study was to assess the impact of the methods used for intraoperative wound management on the incidence of I-SSI following elective surgery for colorectal cancer. METHODS: Between November 2009 and February 2011, the data of 1,980 consecutive patients who underwent elective colorectal resection for colorectal cancer were prospectively collected from 19 affiliated hospitals. The incidence of and risk factors for I-SSI were investigated. RESULTS: Overall, 233 I-SSIs were identified (11.7 %). Forty-two possible risk factors were analyzed. Using a multivariate analysis, the independent risk factors for I-SSI were identified to be a high body mass index, previous laparotomy, chronic liver disease, wound length, contaminated wound class, creation or closure of an ostomy, right hemicolectomy procedure, the suture material used for fascial closure and the incidence of organ/space SSI. CONCLUSION: To prevent I-SSI following elective colorectal surgery, it is crucial to avoid making large incisions and reduce fecal contamination whenever possible. A high quality randomized control trial is necessary to confirm the definitive intraoperative procedure(s) that can minimize the incidence of I-SSI.

Postoperative neuroleptic malignant syndrome-like symptoms improved with intravenous diazepam: a case report.

A 75-year-old man who had undergone left upper lobectomy of the lung exhibited fever and insomnia on postoperative day (POD) 1 and muscle rigidity, autonomic instability, and somnolence on POD2 after epidural administration of droperidol and withdrawal of oral etizolam. He had not been known to have any neuromuscular diseases or psychiatric diseases, with the exception of anxiety disorder. Brain computed tomography did not show cerebrovascular disorders. Consultation with a neurologist led to a suspicion of neuroleptic malignant syndrome (NMS). Epidural droperidol was stopped and administration of dantrolene was initiated. These measures, in addition to supportive care, only partially ameliorated the symptoms of the patient, and consciousness disturbance developed; the patient finally became comatose on POD3. However, intravenous diazepam (10 mg) improved his symptoms abruptly. Subsequently, oral administration of lorazepam (1 mg/day) was started, and his symptoms disappeared within 2 days (POD5). Although NMS-like symptoms are rarely seen in clinical practice, some factors may induce it during the perioperative period, such as the administration of dopamine antagonists and the cessation of benzodiazepines. Intravenous diazepam is an effective treatment in cases with suspected gamma-aminobutyric acid (GABA) hypoactivity at the GABA(A) receptor induced by the cessation of benzodiazepines.

Singlet oxygen is essential for neutrophil extracellular trap formation.

Neutrophil extracellular traps (NETs) that bind invading microbes are pivotal for innate host defense. There is a growing body of evidence for the significance of NETs in the pathogenesis of infectious and inflammatory diseases, but the mechanism of NET formation remains unclear. Previous observation in neutrophils of chronic granulomatous disease (CGD) patients, which defect NADPH oxidase (Nox) and fail to produce reactive oxygen species (ROS), revealed that ROS contributed to the formation of NETs. However, the active species were not identified. In this study, we discovered that singlet oxygen, one of the ROS, mediated Nox-dependent NET formation upon stimulation with phorbol myristate acetate. We also revealed that singlet oxygen itself could induce NET formation by a distinct system generating singlet oxygen with porfimer sodium (Photofrin) in CGD neutrophils, as well as healthy neutrophils. This was independent of Nox activation. These results show that singlet oxygen is essential for NET formation, and provide novel insights into the pathogenesis of infectious and inflammatory diseases.

Ozone production by amino acids contributes to killing of bacteria.

Reactive oxygen species produced by phagocytosing neutrophils are essential for innate host defense against invading microbes. Previous observations revealed that antibody-catalyzed ozone formation by human neutrophils contributed to the killing of bacteria. In this study, we discovered that 4 amino acids themselves were able to catalyze the production of an oxidant with the chemical signature of ozone from singlet oxygen in the water-oxidation pathway, at comparable level to antibodies. The resultant oxidant with the chemical signature of ozone exhibited significant bactericidal activity in our distinct cell-free system and in human neutrophils. The results also suggest that an oxidant with the chemical signature of ozone produced by neutrophils might potentiate a host defense system, when the host is challenged by high doses of infectious agents. Our findings provide biological insights into the killing of bacteria by neutrophils.

The role of endothelial interleukin-8/NADPH oxidase 1 axis in sepsis.

Sepsis is a generalized inflammatory disease, caused by the hyperinflammatory response of the host, rather than by invading organisms. Endothelial cells play a crucial role in the pathogenesis of sepsis. In this study, we investigated the effects of interleukin-8 (IL-8), a known neutrophil chemoattractant, on lipopolysaccharide (LPS) -induced reactive oxygen species (ROS) production by endothelial cells, and its significance in the pathogenesis of LPS-mediated sepsis. The results revealed that IL-8 directly induced ROS production in human umbilical vein endothelial cells (HUVECs), and also mediated LPS-induced ROS production by HUVECs. Stimulation of HUVECs by LPS strongly enhanced tissue factor expression, a hallmark of severe sepsis, which was suppressed by IL-8 knockdown. We further discovered that NADPH oxidase (Nox) 1 expression in LPS-stimulated HUVECs was markedly repressed by IL-8 knockdown, and Nox1 knockdown reduced tissue factor expression, suggesting that the LPS/IL-8 signalling in endothelial cells was predominantly mediated by Nox1. In conclusion, LPS stimulation of endothelial cells causes activation of the IL-8-Nox1 axis, enhances the production of ROS, and ultimately contributes to the progression of severe sepsis.

Substituent effects of pterin derivatives on singlet oxygen scavenging activity.

The relationship of chemical structures of 6-formylpterin (6FP) and its derivatives with scavenging activity of singlet oxygen ((1)O(2)) was examined. First, effects of pterin derivatives on (1)O(2) released from activated human neutrophils were examined. The neutrophils, stimulated with opsonized zymosan, released (1)O(2) that was detected by chemiluminescence using a (1)O(2) specific probe, trans-1-(2'-methoxyvinyl)pyrene. 6FP and its derivatives suppressed the (1)O(2) release. 6FP and other commercially available pterin derivatives, such as biopterin and neopterin, which have different substitutions at the 6-position, suppressed the (1)O(2) release with similar extent. On the other hand, newly synthesized pterin derivatives, which have different substitutions at the 2- and/or 3-position, such as 2-amino-6-formyl-3-methylpteridin-4-one, suppressed the (1)O(2) release in a dose-dependent manner and more potently than 6FP. Then, the (1)O(2) scavenging activity of pterin derivatives was examined photochemically by direct analysis of near-infrared luminescence at 1270 nm, the most sensitive method for the detection of (1)O(2). When rose Bengal, a photosensitizer, in D(2)O solution, was irradiated by 514 nm laser beam, the emission spectrum of (1)O(2) was observed. 6FP suppressed this emission spectrum of (1)O(2), and the newly synthesized pterin derivatives with different substituent at the 2- and/or 3-position suppressed the spectrum more potently than 6FP. The order of potency was similar to that obtained from biological assays. These findings indicate that the substitutions at the 2- and/or 3-position play an important role in (1)O(2) scavenging activity of pterin derivatives.

A case of Kounis syndrome presenting as coronary artery spasm associated with cefazolin-induced anaphylaxis during general anesthesia.

BACKGROUND: Kounis syndrome (KS) is defined as the occurrence of acute coronary syndrome (ACS) associated with an anaphylactic reaction, and there have only been a few reports of its occurrence under general anesthesia. CASE PRESENTATION: A 69-year-old woman underwent transurethral resection of a bladder tumor under general anesthesia. Cefazolin was administered intravenously after induction of general anesthesia. During the operation, we suspected ACS from sudden ST segment depression on electrocardiogram. The delayed onset of an erythematous rash reminded us of the anaphylactic reaction of KS. Coronary artery spasm of type 1 KS was diagnosed based upon the findings of coronary computerized tomography. Eleven days after the first surgery, the patient underwent nephroureterectomy uneventfully by a change in antibiotics. Finally, cefazolin proved to be the trigger drug by the intradermal test. CONCLUSION: When electrocardiogram changes suggesting ACS occur during general anesthesia, it is necessary to take KS into consideration as a differential diagnosis.

The radical scavenger edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) reacts with a pterin derivative and produces a cytotoxic substance that induces intracellular reactive oxygen species generation and cell death.

Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 microM of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROS-sensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 microM of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 microM. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.

General anesthesia with propofol for ovarian teratoma excision associated with anti-N-methyl-D-aspartate receptor encephalitis.

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder caused by production of anti-NMDAR antibodies that is often associated with ovarian teratoma and exhibits various manifestations including psychiatric symptoms, seizures, hypoventilation, and autonomic nerve instability. Patients with this disorder who receive early surgical tumor resection along with immunotherapy have better outcome than the rest of the patients. To establish an anesthetic plan, it is important to understand the pharmacological interaction between the anesthetic agents and the disabled NMDAR, because NMDAR is one of the major sites of action for commonly-used anesthetic agents. Herein, we describe two young female patients with anti-NMDAR encephalitis who required surgical resection of ovarian teratoma under general anesthesia using propofol, remifentanil, and fentanyl. In both of these anesthetic courses, neither psychoneuronal modification nor autonomic instability by propofol was evident. Furthermore, propofol has been reported to suppress the effects of ketamine on the posterior cingulate cortices, which is the area of the brain concerned with psychotomimetic activity and neural damage of NMDAR antagonists. Our cases imply that propofol is safely used in patients with anti-NMDAR encephalitis, although it has some pharmacological effects on NMDAR.

Gene expression in enhanced apoptosis of human lymphoma U937 cells treated with the combination of different free radical generators and hyperthermia.

The effects of various free radicals derived from 6-formylpterin (6-FP), alpha-phenyl-tert-butyl nitrone (PBN) and 2,2'-azobis (2-amidinopropane) dihydrochloride (AAPH) combined with hyperthermia, on gene expression in similarly enhanced apoptosis of human lymphoma U937 cells were investigated using cDNA microarrays containing approximately 16,600 genes and computational gene expression analysis tools. When the cells were treated for 10 min at 44 degrees C (15% apoptosis level), 39 up-regulated and 3 down-regulated genes were identified. In the up-regulated genes, apoptosis- and unfolded protein response-associated genes were contained. The combined treatment with heat and either chemical enhanced apoptosis level (approximately 30%) and showed a chemical-specific gene expression pattern. Furthermore, the expression levels of selected genes were confirmed by a real-time quantitative PCR. The present results will provide a basis for further understanding the molecular mechanisms in enhancement of heat-induced apoptosis by different intracellular oxidative stress.

Effects of intravenous anesthesia with propofol on regional cortical blood flow and intracranial pressure in surgery for moyamoya disease.

BACKGROUND: The aim of this study was to compare the effects of inhalation anesthesia with sevoflurane and intravenous anesthesia with propofol on ICP and rCoBF during revascularization surgery for patients with MMD. METHODS: Between 1999 and 2004, a total of 90 revascularization surgeries were performed on 58 patients. Among them, in 20 consecutive operations on 14 patients, continuous monitoring of ICP was performed with an ICP monitoring probe. Subsequently, in 14 consecutive operations on 9 patients (CoBF group), intraoperative monitoring of rCoBF was carried out with a laser Doppler flowmeter probe. The monitoring of ICP and rCoBF was performed for more than 20 minutes after the administration of anesthetic was changed from 1.5% to 2.5% sevoflurane to 6 mg/kg per hour of propofol. In all cases, the Paco(2) of these patients was strictly maintained between 38 and 40 mm Hg throughout the operations. RESULTS: In both the ICP and the CoBF groups, the values of physiologic parameters obtained under inhalation anesthesia did not differ statistically from those obtained under intravenous anesthesia. The value for ICP under anesthesia with propofol was significantly lower than that under anesthesia with sevoflurane (P < .0001). The value for rCoBF in the frontal lobe under anesthesia with propofol was significantly higher than that under anesthesia with sevoflurane. CONCLUSIONS: Intravenous anesthesia with propofol has potential to provide brain protection and preservation of rCBF in the frontal lobes in surgery for MMD. Whether choice of anesthetic agents might be important in surgery for MMD should be investigated further.

Long-term survival of a patient with advanced gastric cancer with paraaortic lymph node metastasis who attained pathological complete response after S-1/CDDP chemotherapy: A case report.

INTRODUCTION: Gastric cancer with paraaortic lymph node (PAN) metastasis have unfavorable prognosis. There are no evidence-based preoperative chemotherapy regimens available. CASE PRESENTATION: A 62-year-old female was diagnosed with advanced gastric cancer and PAN metastasis. We attempted S-1/CDDP chemotherapy in six coursed and total gastrectomy as well as systematic dissection of regional lymph nodes and PAN. Histologically, no cancerous cells were detected in specimens. The patient has been disease-free for 5 years since the surgery. DISCUSSION: Long-term survival case of gastric cancer with PAN metastasis attaining pathologically complete response is extremely rare. It is possible that preoperative S1/CDDP with surgery might be a standard treatment strategy for gastric cancer with PANs. CONCLUSION: We report herein a rare case of gastric cancer with PAN metastases who achieved a 5-year survival after S-1/CDDP chemotherapy and surgery.

Poorly differentiated adenocarcinoma with signet-ring cells in duodenal papilla: a case report.

An 82-year-old woman with common bile duct (CBD) dilatation observed during routine ultrasonography was referred to our hospital. Preliminary blood tests revealed elevated levels of hepatobiliary enzymes. Computed tomography (CT) scan showed lower bile duct wall thickening and enhancement. Esophagogastroduodenoscopy revealed mildly swollen papilla of Vater, without ulceration. Endoscopic retrograde cholangiography demonstrated that the CBD was grossly dilated with a constriction in the lower part. The final diagnosis indicated poorly differentiated adenocarcinoma of duodenal papilla with signet-ring cells; pT3N0M0, stage IIA (Unio Internationalis Contra Cancrum, 7th edition), for which subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) was performed. This case is quite rare, and the surgery resulted in a desirable outcome. The patient has been disease-free for 5 years since the surgery.

LPS-induced ROS generation and changes in glutathione level and their relation to the maturation of human monocyte-derived dendritic cells.

Lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) generation and the concomitant decline in the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) were demonstrated in human monocyte-derived dendritic cells (DC). Further, their relation to the maturation of DC, characterized by the production of cytokines, up-regulation of cell surface molecules and allo-stimulatory capacity, was examined. The LPS-induced ROS generation was demonstrated using electron paramagnetic resonance spectroscopy in intact cells, and was also confirmed using laser scanning confocal microscopy. The GSH/GSSG was assesed using a glutathione assay kit. When the DC were treated with alpha-phenyl-tert-butylnitrone, the ROS generation was attenuated, but the declined GSH/GSSG was not attenuated, and only cytokine production was suppressed among the above-mentioned maturation characteristics. When the DC were treated with glutathione monoethyl ester, both the ROS generation and the declined GSH/GSSG were attenuated, and the maturation characteristics were all suppressed. These findings suggest that the LPS-induced ROS generation and the concomitant decline in GSH/GSSG occur in human monocyte-derived DC and that the former is involved in cytokine production, while the latter is involved in the up-regulation of cell surface molecules and allo-stimulatory capacity. Since the cytokine production and the allo-stimulatory capacity of DC play an important role in inflammatory and immune responses, differential regulation of the ROS generation and the declined GSH/GSSG may be useful as therapeutic tools in diseases where both responses become entangled, such as sepsis and graft-versus-host disease.

One hundred consecutive hepatobiliary resections for biliary hilar malignancy: preoperative blood donation, blood loss, transfusion, and outcome.

BACKGROUND: Many reports on blood loss and transfusion requirements during hepatectomy for metastatic liver cancer or hepatocellular carcinoma have been published; however, there are no reports on these issues in hepatectomy for biliary hilar malignancy. The aim of this study was to review our experience with blood loss and perioperative blood requirements in 100 consecutive hepatectomies for biliary hilar malignancy. METHODS: One hundred consecutive hepatectomies with en bloc resection of the caudate lobe and extrahepatic bile duct for hilar malignancies were performed, including 81 perihilar cholangiocarcinomas and 19 advanced gallbladder carcinomas involving the hepatic hilus. Fifty-eight hilar resections were combined with other organ and/or vascular resection. Data on preoperative blood donation, intraoperative blood loss, and perioperative transfusion were collected and analyzed. RESULTS: Preoperative autologous blood donation was possible in 73 patients (3.4 +/- 1.2 U). Intraoperative blood loss was 1850 +/- 1000 mL (range, 677-5900 mL), and it was < 2000 mL in 62 patients. Intraoperatively, only 7 of the 73 patients (10%) who donated blood received transfusion of unheated, homologous blood products (packed red blood cells or fresh frozen plasma), whereas 18 the 23 patients (67%) without donation received homologous transfusions. Only 16 patients received transfusion postoperatively, and overall, 35 patients received unheated homologous blood products. Total serum bilirubin concentrations after hepatectomy in patients receiving autologous blood transfusion only was similar to those in patients who did not receive transfusion. The incidence of postoperative complications was higher in the 35 patients who received perioperative homologous transfusion than in 65 patients who did not (94% vs 52%; P <.0001). The mortality rate (including all deaths) was 3% (myocardial infarction, intra-abdominal bleeding, and liver failure, 1 patient each). CONCLUSIONS: Despite the technical difficulties arising from hepatectomy for biliary hilar malignancy, approximately two thirds of hepatectomies can be performed in an experienced center without perioperative homologous blood transfusion using preoperative blood donation.

Protective effects of intracellular reactive oxygen species generated by 6-formylpterin on tumor necrosis factor-alpha-induced apoptotic cell injury in cultured rat hepatocytes.

The effects of 6-formylpterin on tumor necrosis factor (TNF)-alpha-induced apoptotic cell injury were studied in cultured rat hepatocytes. The incubation of the hepatocytes with TNF-alpha and actinomycin D (ActD) induced the apoptotic cell injury. The level of aspartate transaminase (AST) in the culture supernatant increased, and the cell viability, estimated by mitochondrial respiration (MTT assay), decreased. The DNA fragmentation and the caspase 3-like activity, which are characterized to apoptosis, increased. When the hepatocytes were incubated with 100-500 microM 6-formylpterin, the intracellular formation of reactive oxygen species (ROS) was observed, and the ratio of reduced and oxidized glutathione (GSH/GSSG) of whole cell lysate decreased. The co-incubation of the TNF-alpha/ActD-treated hepatocytes with 100-500 microM 6-formylpterin attenuated the TNF-alpha/ActD-induced apoptotic cell injury. The level of AST decreased and the cell viability increased. Both the DNA fragmentation and the caspase 3-like activity decreased. The caspases, executors of apoptosis, are known to require a reduced cystein in their active site to function, and the intact intracellular GSH/GSSG is essential for the caspase activation. Therefore, our findings suggest that intracellular ROS generated by 6-formylpterin decline the intracellular redox state to an oxidant state, which suppresses the caspase activity and prevents the apoptotic cell injury of hepatocytes.

Effects of intracellular reactive oxygen species generated by 6-formylpterin on T cell functions.

The intracellular generation of reactive oxygen species (ROS) by 6-formylpterin and its effects on the human T cell functions were examined in vitro. When T cells isolated from fresh blood were incubated with 6-formylpterin for 1hr, the oxygen consumption and concomitant ROS generation were observed. The incubation of T cells with 50-500microM 6-formylpterin for 24hr brought about the elevation of intracellular ROS without inducing cell death. In contrast, the incubation of T cells with exogenously administered hydrogen peroxide (H(2)O(2)) or other pterin derivatives (6-hydroxymethylpterin, pterin-6-carboxylic acid, pterin, neopterin, biopterin and folic acid) for 24hr did not cause the intracellular ROS elevation. In the T cells stimulated with mitogenic lectin phytohemagglutinin (PHA) in conjunction with phorbol myristate acetate (PMA), 6-formylpterin suppressed the NF-kappaB-dependent transcription, the production of cytokines (IFN-gamma and IL-2) and the cell proliferation. These suppressive effects of 6-formylpterin were all reversed by N-acetyl-l-cystein (NAC). However, 6-formylpterin did not inhibit the NF-kappaB-DNA binding of the nuclear extracts obtained from the PHA/PMA-stimulated T cells. Since the NF-kappaB-DNA binding assay performed in vitro merely shows the presence or absence of NF-kappaB subunit in the nuclear extracts but not guarantees the actual binding of NF-kappaB with DNA in the nucleus, these findings suggest that intracellular ROS generated by 6-formylpterin does not affect the translocation of NF-kappaB to the nucleus but that it inhibits the NF-kappaB-dependent transcription in the nucleus, resulting in the suppression of cytokine production and cell proliferation in the activated T cells.

Hepatic killing but not clearance of systemically circulating bacteria is dependent upon peripheral leukocytes via Mac-1 (CD11b/CD18).

The hepatic reticuloendothelial system (RES) is the primary mechanism for removing circulating bacteria from the systemic circulation. While Kupffer cells are important for this process, leukocytes appear to play a significant role as well. Hepatic leukocyte accumulation following ischemia/reperfusion or cytokine stimulation is well documented, but its contribution to phagocytic killing by the hepatic RES is not fully understood. We evaluated the role of leukocytes in general, and leukocyte-endothelial adhesion in particular, in hepatic RES function. This was done by inducing confirmed leukopenia with cyclophosphamide or by blocking leukocyte-endothelial adhesion molecules with specific blocking antibodies. Hepatic phagocytic clearance (HPC) and hepatic phagocytic killing (HKE) of systemically intravenously injected E. coli were assayed and quantitated by a validated dual isotope label technique. HPC among the various experimental groups and respective controls varied only slightly, with no statistically significant differences observed. Leukopenia or CD11b blockade each significantly decreased the HKE relative to the controls. Antibody blockade of certain other adhesion molecules had no significant effect on HKE (or HPC). The role of leukocytes in killing systemically circulating bacteria is an integral component of hepatic RES function. This capability of the leukocyte appears to be dependent, in part, on the adhesion molecule, Mac-1.