Publications by authors named "Jeffrey R Scott"

43 Publications

Restoring HOmeostasis: is heme oxygenase-1 ready for the clinic?

Trends Pharmacol Sci 2007 May 9;28(5):200-5. Epub 2007 Apr 9.

Transplant Research Center, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.

Inflammation and immunity result in a wide range of disease processes, including atherosclerosis, vascular thrombosis and sepsis. Heme oxygenase-1 (HO-1) is a key enzyme that is integral to the temporal and spatial regulation of the host response and, together with its products carbon monoxide (CO) and bilirubin, is crucial for maintaining homeostasis and the preservation of function and life. An increasing number of reports demonstrates that HO-1, CO and bilirubin regulate the immune response. As CO and bilirubin enter clinical trials, there are obstacles to be addressed before their full therapeutic potential can be achieved. In this article, we delineate the challenges that lie ahead regarding toxicity, pharmacokinetics and mechanisms of action to be able to take full advantage of the powerful cytoprotective properties of these agents for clinical benefit.
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http://dx.doi.org/10.1016/j.tips.2007.03.006DOI Listing
May 2007

Arterial and venous complications of heparin-induced thrombocytopenia in burn patients.

J Burn Care Res 2007 Jan-Feb;28(1):71-5

University of Washington/Harborview Medical Center Burn Center, Department of Surgery, Seattle, Washington 98104, USA.

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated complication of heparin treatment that can result in a number of devastating thrombotic complications. Given the common use of heparin for deep venous thrombosis prophylaxis in patients with burns, we reviewed the incidence and complications of HIT in our burn center. We performed a retrospective review of all patients treated with heparin at our burn center who underwent testing for HIT from 2001 to 2005. Screening for HIT was performed by platelet factor 4 enzyme-linked immunoassay. Records were reviewed with particular attention to indications for HIT testing, duration of heparin therapy, type of heparin used (fractionated vs unfractionated), indication for heparin use (prophylactic vs therapeutic), treatment of HIT, and complications of HIT. During the 4-year study period, 625 patients received heparin therapy at some point during their hospital course. Of these patients, 43 (6.9%) underwent testing for HIT and 10 of the 43 screened patients (23%) were positive; the incidence among all heparinized burn patients was 1.6%. Thrombotic complications of HIT included arterial thrombosis requiring limb amputation (two patients), deep venous thrombosis (three patients), and pulmonary embolism (two patients). One patient died, presumably secondary to a pulmonary embolism. All patients were anticoagulated after HIT diagnosis, and four patients developed bleeding complications. HIT is a potentially devastating complication of heparin administration. Whereas our overall incidence of HIT was low, HIT+ patients developed significant complications, including arterial and venous thrombosis, pulmonary embolus, limb loss, and death. Treatment for such HIT-related thromboses usually resulted in bleeding complications requiring transfusions. The routine use of heparin for deep venous thrombosis prophylaxis needs to be carefully considered in light of these potential complications.
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http://dx.doi.org/10.1097/BCR.0b013E31802C8929DOI Listing
March 2007

Inhaled carbon monoxide prevents graft-induced intimal hyperplasia in swine.

J Surg Res 2007 Mar 29;138(1):121-7. Epub 2006 Dec 29.

Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA.

Background: Arteriovenous grafts often fail due to stenosis caused by venous anastomotic intimal hyperplasia (IH) and vascular smooth muscle cell (VSMC) proliferation. We examined the effects of inhaled carbon monoxide (CO), a product of heme-oxygenase-1 degradation of heme, on IH in a porcine arteriovenous graft model.

Materials And Methods: Eighteen Yorkshire pigs were divided into three groups (N = 6/group): (1) CO 100 ppm preoperatively for 1 h; (2) CO 250 ppm preoperatively for 1 h and intraoperatively; and (3) air-treated controls. Animals underwent end-to-side placement of polytetrafluoroethylene grafts connecting the common femoral artery and vein in both groins. Intimal thickness of the venous anastomosis at 30 days was measured blinded. The effect of CO on pig VSMC proliferation was studied in cell culture using [(3)H]thymidine incorporation.

Results: Pigs in the group receiving CO 250 ppm showed significantly less IH compared to animals in the group receiving 100 ppm and the air-treated group (267.5 +/- 21.4, 824 +/- 145.8, and 914.8 +/- 133.7 pixels, respectively, P < 0.0001). This effect was not observed when comparing the 100 ppm group to the air-treated group. COHb levels were significantly elevated in the 100 ppm and 250 ppm compared to air-treated pigs (5.8 +/- 0.47, 13.2 +/- 1.0 versus 2.3 +/- 0.11%, respectively, P < 0.001). Oxygen saturation, respiratory rate, and hemodynamics were not significantly different between the groups. CO induced VSMC growth arrest compared to air in vitro (11.9 +/- 4 versus 20.3 +/- 5 10(3) counts/min/well, P < 0.01).

Conclusion: A single exposure to a low concentration of inhaled CO (250 ppm) confers protection against intimal proliferation of VSMCs when given perioperatively in a clinically relevant model of arteriovenous grafts. These data are the first to suggest, in a clinically relevant model, the potential role for CO in clinical applications.
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http://dx.doi.org/10.1016/j.jss.2006.08.031DOI Listing
March 2007

Incidence and characteristics of hospitalized patients with pressure ulcers: State of Washington, 1987 to 2000.

Plast Reconstr Surg 2006 Feb;117(2):630-4

Department of Surgery, University of Washington, Harborview Injury Prevention and Research Center, Seattle, Washington, USA.

Background: Pressure ulcers complicate the hospital course of critically injured or ill patients. Guidelines have been promulgated to prevent pressure ulcers in hospitalized patients. The purpose of this study was to determine whether these guidelines have, in fact, reduced the incidence of pressure sores.

Methods: The authors examined census data from the National Center for Health Statistics and the Washington State Department of Health for the 14-year period 1987 through 2000 and identified patients with a pressure ulcer listed as the primary diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 707.0) and patients admitted for other diagnoses with pressure ulcer as a secondary diagnosis. The authors reasoned that patients who were admitted for treatment of pressure ulcers would have the diagnosis listed as primary, whereas those who were admitted for other reasons and developed pressure ulcers during the admission would have pressure ulcer listed as a secondary diagnosis. Other available data included patient age, sex, procedures for pressure ulcers (International Classification of Diseases, Ninth Revision, Clinical Modification codes 15920 through 15999), length of stay, and hospital charges for care.

Results: The incidence of pressure ulcers as a primary diagnosis varied from 7.0 to 8.3 per 100,000 population but did not change over the 14-year study period. The rate of operation for these ulcers also did not change. The incidence of pressure ulcers as either a primary or secondary diagnosis doubled from 34.5 to 71.6 per 100,000 (p < 0.001), whereas the incidence of operative procedures for these ulcers did not change.

Conclusion: The authors found no evidence that the guidelines for the prevention of pressure ulcers have been effective in decreasing pressure ulcer formation, but it may be that pressure ulcers are now being reported in a more thorough manner.
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http://dx.doi.org/10.1097/01.prs.0000197210.94131.39DOI Listing
February 2006

Heme oxygenase modulates small intestine leukocyte adhesion following hindlimb ischemia/reperfusion by regulating the expression of intercellular adhesion molecule-1.

Crit Care Med 2005 Nov;33(11):2563-70

Medical Biophysics, University of Western Ontario, London, ON, USA.

Objective: Heme oxygenase is the rate-limiting enzyme in the degradation of heme into carbon monoxide, iron, and bilirubin. Recent evidence suggests that the induction of heme oxygenase-1 is associated with potent anti-inflammatory properties. The objectives of this study were to determine the temporal, regional, and cellular distribution of heme oxygenase-1 within the small intestine and its role in modulating remote intestinal leukocyte recruitment following trauma induced by hindlimb ischemia/reperfusion.

Design: Randomized, controlled, prospective animal study.

Setting: Hospital surgical research laboratory.

Subjects: Male C57BL/6 mice.

Interventions: Mice underwent 1 hr of bilateral hindlimb ischemia, followed by 3, 6, 12, or 24 hrs of reperfusion.

Measurements And Main Results: Heme oxygenase-1 messenger RNA, heme oxygenase-1 protein, and heme oxygenase activity were measured using reverse transcription polymerase chain reaction, Western blot, immunohistochemistry, and spectrophotometric assay, respectively. The jejunum was also exteriorized to quantify the flux of rolling and adherent leukocytes and R-Phycoerythrin conjugated intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity in submucosal postcapillary venules with the use of intravital microscopy. Ischemia/reperfusion led to a significant increase in heme oxygenase-1 messenger RNA in the jejunum and ileum 3 hrs following limb reperfusion, with a subsequent increase in heme oxygenase-1 protein and heme oxygenase activity at 6 hrs. Ischemia/reperfusion also led to a significant 1.4-fold increase in leukocyte rolling, whereas inhibition of heme oxygenase via injection of tin protoporphyrin IX (20 micromol/kg intraperitoneally) resulted in a three-fold increase in leukocyte adhesion, compared with ischemia/reperfusion alone. This increase in adhesion was significantly reduced to baseline in mice treated with intercellular adhesion molecule-1 monoclonal antibody before heme oxygenase inhibition (40 microg/mouse), whereas inhibition of heme oxygenase activity following ischemia/reperfusion also led to a significant increase in R-Phycoerythrin intercellular adhesion molecule-1 monoclonal antibody fluorescence intensity.

Conclusions: Our data suggest that remote trauma induced by hindlimb ischemia/reperfusion leads to an increase in heme oxygenase activity within the small intestine, which modulates intercellular adhesion molecule-1 dependent intestinal leukocyte adhesion.
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http://dx.doi.org/10.1097/01.ccm.0000186765.61268.fcDOI Listing
November 2005

Substance P levels and neutral endopeptidase activity in acute burn wounds and hypertrophic scar.

Plast Reconstr Surg 2005 Apr;115(4):1095-102

Department of Surgery and the Division of Plastic and Reconstructive Surgery, University of Washington, Seattle, Wash, USA.

Background: Substance P, a cutaneous neuroinflammatory mediator released from peripheral nerves, plays a role in responses to injury. Neutral endopeptidase is a cell membrane-bound metallopeptidase enzyme that regulates substance P activity. The question of substance P involvement in hypertrophic scar development has been based on observations that hypertrophic scars have increased numbers of nerves. The authors hypothesized that hypertrophic scar has greater substance P levels and decreased neutral endopeptidase activity compared with uninjured skin and acute partial-thickness burns, which may contribute to an exuberant response to injury.

Methods: The authors obtained small skin samples of deep partial-thickness burns (n = 7; postburn days 7 to 78) and uninjured skin (n = 14) from patients (eight male patients and six female patients; 2 to 71 years old) undergoing burn wound excision. Hypertrophic scar samples were obtained from six patients (three male patients and three female patients; 8 to 47 years old) undergoing surgical excision 13 to 64 months after burn injury. Protein concentrations were determined using a bicinchoninic acid assay. Substance P concentration was determined by means of indirect enzyme-linked immunosorbent assay. Neutral endopeptidase activity was measured using an enzymatic assay that quantifies a fluorescent degradation product, methoxy-2-naphthylamine (MNA). Substance P and neutral endopeptidase data were standardized to sample weight.

Results: Substance P levels were greater in hypertrophic scar (3506 pg/g) compared with uninjured skin (1698 pg/g; p < 0.03) and burned skin (958 pg/g; p < 0.01). Hypertrophic scar samples had decreased neutral endopeptidase enzyme activity (8.8 pM MNA/hour/microg) compared with normal skin (16.3 pM MNA/hour/microg; p < 0.05). Acute burn wounds (27.9 pM MNA/hour/microg) demonstrated increased neutral endopeptidase enzyme activity (p < 0.05).

Conclusions: Increased substance P concentration in hypertrophic scar correlates with histologic findings of increased nerve numbers in hypertrophic scar samples. Decreased neutral endopeptidase enzyme activity in hypertrophic scar may contribute to increased available substance P that may result in an exuberant neuroinflammatory response.
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http://dx.doi.org/10.1097/01.prs.0000156151.54042.daDOI Listing
April 2005

Chronic lower extremity ischemia: a human model of ischemic tolerance.

Can J Surg 2004 Oct;47(5):352-8

Department of Medical Biophysics, University of Western Ontario, Lawson Health Research Institute, London.

Background: Ischemic preconditioning (IPC) has been found in animals to have a protective effect against future ischemic injury to muscle tissue. Such injury is unavoidable during some surgical procedures. To determine whether chronic ischemia in the lower extremities would imitate IPC and reduce ischemic injury during vascular surgery, we designed a controlled clinical study.

Patients And Methods: Two groups of patients at a university-affiliated medical centre with chronic lower-extremity ischemia served as models of IPC: 6 patients awaiting femoral distal bypass (FDB) and 4 scheduled for aortobifemoral (ABF) bypass grafting for aortoiliac occlusive disease. Seven patients undergoing elective open repair of an infrarenal abdominal aortic aneurysm (AAA) were chosen as non-IPC controls. Three hematologic indicators of skeletal-muscle injury, lactate dehydrogenase (LDH), creatine kinase (CK) and myoglobin, were measured before placement of the proximal clamp, during surgical ischemia, immediately upon reperfusion, 15 minutes after and 1 hour after reperfusion, and during the first, second and third postoperative days.

Results: Baseline markers of skeletal-muscle injury were similar in all groups. In postreperfusion samples, concentrations of muscle-injury markers were significantly lower in the 2 PC groups than in the control group. For example, at day 2, LDH levels were increased by about 30% over baseline measures in the elective AAA (control) group, whereas levels in the FDB and ABF groups remained statistically unchanged from baseline. Myoglobin in controls had increased by 977%, but only by 160% in the FDB and 528% in the ABF groups. CK levels, in a similar trend, were 1432% higher in the control group and only 111% (FDB) and 1029% (ABF) in the study groups. Taken together, these data represent a significant level of protection.

Conclusions: Patients with chronic lower-extremity ischemia suffered less severe ischemic injury after a period of acute ischemia than those with acute ischemia alone. Ischemic preconditioning is one proposed mechanism to help explain this protective effect.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3211936PMC
October 2004

Inhalation of carbon monoxide prevents liver injury and inflammation following hind limb ischemia/reperfusion.

FASEB J 2005 Jan 28;19(1):106-8. Epub 2004 Oct 28.

Victoria Research Lab, 6th Floor, Rm. A6-105, 800 Commissioners Rd., London, ON, Canada N6A 4G4.

The induction of heme oxygenase (HO), the rate limiting enzyme in the conversion of heme into carbon monoxide (CO) and biliverdin, limits liver injury following remote trauma such as hind limb ischemia/reperfusion (I/R). Using intravital video microscopy, we tested the hypothesis that inhaled CO (250 ppm) would mimic HO-derived liver protection. Hind limb I/R significantly decreased sinusoidal diameter and volumetric flow, increased leukocyte accumulation within sinusoids, increased leukocyte rolling and adhesion within postsinusoidal venules, and significantly increased hepatocyte injury compared with naive animals. Inhalation of CO alone did not alter any microcirculatory or inflammatory parameters. Inhalation of CO following I/R restored volumetric flow, decreased stationary leukocytes within sinusoids, decreased leukocyte rolling and adhesion within postsinusoidal venules, and significantly reduced hepatocellular injury following hind limb I/R. HO inhibition did not alter microcirculatory parameters in naive mice, but did increase inflammation, as well as increase hepatocyte injury following hind limb I/R. Inhalation of CO during HO inhibition significantly reduced such microcirculatory deficits, hepatic inflammation, and injury in response to hind limb I/R. In conclusion, these results suggest that HO-derived hepatic protection is mediated by CO, and inhalation of low concentrations of CO may represent a novel therapeutic approach to prevent remote organ injury during systemic inflammatory response syndrome, or SIRS.
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http://dx.doi.org/10.1096/fj.04-2514fjeDOI Listing
January 2005

Remote liver injury is attenuated by adenovirus-mediated gene transfer of heme oxygenase-1 during the systemic inflammatory response syndrome.

Microcirculation 2004 Oct-Nov;11(7):587-95

Department of Medical Biophysics, University of Western Ontario, London, Ontario, Canada.

Objectives: Adenovirus-mediated gene therapy is being investigated with increasing success for future treatment of autoimmune diseases. However, the use of adenoviruses is still limited by inflammatory and immune responses in the target organ. Previous work by the authors' laboratory established that the adenovirus encoding inducible heme oxygenase (Ad-HO-1) does not elicit the acute hepatic inflammation normally caused by adenoviruses, inviting further investigation in models of severe inflammation. Concurrently, there is increasing evidence for an endogenous protective role for heme oxygenase (HO) in the liver during the systemic inflammatory response syndrome (SIRS). Building on our previous results, this study investigated the effect of Ad-HO-1 pretreatment on remote liver injury during normotensive SIRS, induced by bilateral hind limb ischemia and reperfusion.

Methods: Microvascular perfusion and hepatocyte death were quantified using established intravital videomicroscopy techniques. Hepatocellular injury and liver function were assessed using blood-borne indicators.

Results: Microvascular perfusion deficits and increased hepatocyte death occurred following limb ischemia and 3 h of reperfusion in vehicle-pretreated animals; however, Ad-HO-1 pretreatment prevented these deficits. In contrast, the increase in serum alanine transaminase levels was unaffected by Ad-HO-1 pretreatment. Serum bilirubin levels were increased during systemic inflammation, predominantly in the conjugated form; and, this increase was prevented by administration of Ad-HO-1.

Conclusions: These data indicate that gene transfer of inducible HO is an effective method to protect the liver during SIRS, providing incentive for further investigation into gene therapy strategies exploiting this anti-inflammatory enzyme.
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http://dx.doi.org/10.1080/10739680490503384DOI Listing
March 2005

Endogenous heme oxygenase induction is a critical mechanism attenuating apoptosis and restoring microvascular perfusion following limb ischemia/reperfusion.

Surgery 2004 Jul;136(1):67-75

Department of Medical Biophysics, University of Western Ontario, and the London Health Science Centre and Lawson Health Research Institute, London, Ontario, Canada.

Background: A protective role for endogenous heme oxygenase (HO) in the initiation of remote liver injury after limb ischemia/reperfusion has been established. This study expands on our previous work by investigating the role of endogenous HO on hepatocellular injury, hepatocyte death (necrotic and apoptotic), and microvascular perfusion at protracted post-reperfusion times.

Methods: Remote liver injury was studied after 1 hour of bilateral hind limb ischemia and 3, 6, or 24 hours of reperfusion in male C57BL6 mice. Inhibition of HO was achieved with the use of chromium mesoporphrin (CrMP). Established intravital videomicroscopy techniques were used to evaluate microvascular perfusion and hepatocyte death. Hepatocellular injury was quantified by serum alanine transaminase. Apoptosis was measured by using DNA laddering, Cell Death ELISA, and caspase-3 activity.

Results: Although significant perfusion deficits and hepatocellular injury/death occurred after 3 hours, progression of hepatocellular death beyond 6 hours was not observed. A transient increase in apoptosis was observed at 6 hours. By 24 hours, microvascular perfusion was completely restored. This lack of progression correlated with increased HO activity, observed throughout the protocol. Administration of CrMP reduced HO activity to sham nonstressed levels, and caused increased microvascular perfusion deficits, hepatocellular injury, and hepatocyte death over 24 hours. The transient increase in apoptosis was increased in duration and magnitude in CrMP-treated animals.

Conclusions: These results suggest that endogenous HO activity prevents the progression of remote liver injury after limb ischemia/reperfusion.
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http://dx.doi.org/10.1016/j.surg.2003.11.002DOI Listing
July 2004

Heme oxygenase modulates hepatic leukocyte sequestration via changes in sinusoidal tone in systemic inflammation in mice.

Microvasc Res 2004 Jul;68(1):20-9

Klinik und Poliklinik für Anästhesiologie, Julius-Maximilians-Universität, Würzburg, Germany.

Heme oxygenase (HO) modulates the accumulation of leukocytes within the liver during the early stages of a systemic inflammatory response syndrome (SIRS), but the anti-inflammatory mechanism(s) remain to be tested. The influence of HO on the adhesion molecule expression within the liver and on circulating leukocytes was assessed. In addition, the effect of HO and nitric oxide synthase (NOS) on the liver microcirculation was tested. Mice were subjected to 1 h bilateral hindlimb ischemia followed by 3 h of reperfusion, at which time blood samples and the liver were harvested and adhesion molecule expression determined (ICAM-1, CD49d and CD11b). Direct measures of sinusoidal diameter and estimates of volumetric blood flow were obtained using intravital microscopy. HO was specifically induced and inhibited by hemin and chromium mesoporphyrin (CrMP), respectively, whereas NOS was inhibited by N-nitro-L-arginine methyl ester (L-NAME). ICAM-1 expression was increased following hindlimb ischemia-reperfusion. Hemin caused only a modest, but significant decrease in ICAM-1 expression, whereas inhibition of HO had no effect. However, HO inhibition significantly reduced sinusoidal diameters and volumetric flow and such vessels were correlated with significantly increased numbers of stationary leukocytes. Inhibition of NOS had no effect on sinusoidal diameter or volumetric flow. In conclusion, the anti-inflammatory benefits afforded by HO activity within the liver appear to involve the control of sinusoidal diameter and volumetric blood flow rather than altered adhesion molecule expression during the early stages of SIRS.
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http://dx.doi.org/10.1016/j.mvr.2004.03.003DOI Listing
July 2004

Protective mechanisms during ischemic tolerance in skeletal muscle.

Free Radic Biol Med 2004 Feb;36(3):371-9

Department of Medical Biophysics, The University of Western Ontario, and The Lawson Health Research Institute, London, Ontario, Canada.

The purpose of this study was to test specific mechanisms of protection afforded the rat extensor digitorum longus (EDL) muscle during ischemic tolerance. Two days following five cycles of 10 min ischemia and 10 min reperfusion, heme oxygenase (HO) and calcium-dependent nitric oxide synthase (cNOS) activities were increased 2- and 2.5-fold (p <.05), respectively. Interestingly, calcium-independent NOS (iNOS) activity was completely downregulated (p <.05). The levels of superoxide dismutase (SOD) and catalase were increased 2-fold (p <.05), while glutathione peroxidase activity remained unchanged from non-preconditioned controls. Using intravital microscopy combined with chromium mesoporphyrin (CrMP), a selective HO inhibitor, and l-NAME, a NOS inhibitor, the roles of HO and cNOS were evaluated. Ischemic tolerance in the EDL muscle, 48 h after the preconditioning stimulus, was characterized by complete protection from both microvascular perfusion deficits and tissue injury after a 2-h period of ischemia. Removal of NOS activity completely removed the benefit afforded microvascular perfusion, while inhibition of HO activity prevented the parenchymal protection. These data suggest that ischemic tolerance within skeletal muscle is associated with the upregulation of specific cytoprotective proteins and that the benefits afforded by cNOS and HO activity are spatially discrete to the microvasculature and parenchyma, respectively.
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http://dx.doi.org/10.1016/j.freeradbiomed.2003.11.015DOI Listing
February 2004

Hepatic leukocyte recruitment in a model of acute colitis.

Am J Physiol Gastrointest Liver Physiol 2002 Sep;283(3):G561-6

Intestinal Disease Research Programme, Department of Medicine, McMaster University, Hamilton, Ontario, Canada L8N 3Z5.

There is a close relationship between inflammatory bowel disease (IBD) and various hepatobiliary disorders. The objective of this study was to determine whether hepatic leukocyte recruitment occurs in experimental colitis. We used the murine model of colitis induced by 2,4-dinitrobenezenesulfonic acid (DNBS). Male C57Bl/6 mice received an intrarectal injection of 4 mg DNBS in 100 microl 50% ethanol. Controls received 100 microl 50% ethanol. The hepatic microcirculation was examined at 3 and 14 days post-DNBS by intravital video microscopy. Three days post-DNBS, when mice had developed acute colitis, there was associated hepatic leukocyte recruitment. Within the postsinusoidal venules there was a fourfold increase in the flux of rolling leukocytes that was P-selectin dependent but not alpha(4)-integrin dependent. There was also an increase in stationary leukocytes within the sinusoids, although this was not associated with an increase in serum alanine transaminase. By 14 days post-DNBS when macroscopic evidence of colonic inflammation was resolved, rolling within the postsinusoidal venules had returned to control levels. In this murine model of colitis, we describe a link between acute colonic inflammation and remote hepatic leukocyte recruitment that is P-selectin dependent. Active IBD may lead to remote hepatic inflammation.
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http://dx.doi.org/10.1152/ajpgi.00462.2001DOI Listing
September 2002