An FcγRIIa polymorphism with decreased C-reactive protein binding is associated with sepsis and decreased monocyte HLA-DR expression in trauma patients.

BACKGROUND: A dysregulated immune response leading to sepsis is the most frequent cause of late posttraumatic deaths. We have found a novel anti-inflammatory pathway that is initiated by the acute phase protein, C-reactive protein (CRP), interacting with Fcγ receptor (FcγR) on monocytes. This pathway is protective in animal models of endotoxin shock. We hypothesized that genetic polymorphisms in the FcγR might contribute to monocyte responses and susceptibility to infectious complications after severe trauma. METHODS: We conducted an observational study on a prospectively identified cohort of adult patients with convenience enrollment admitted after severe trauma. We enrolled 66 patients and collected blood samples at enrollment and again at 48 hours and 72 hours. Patients were followed through their hospital stay, and any septic events before 14 days were recorded. Cytokine and CRP levels were determined in the plasma from all three blood draws. In addition, DNA was extracted from blood and analyzed for the 131 H/R FcγRIIa polymorphism that strongly affects the binding of IgG and CRP to this receptor. RESULTS: Elevated levels of interleukin 8 (IL-8), IL-6, IL-10, monocyte chemotactic protein 1, and CRP were associated with reduced time to posttraumatic sepsis in Cox regression analysis. Expression of monocyte human leukocyte antigen DR less than 45% on patient monocytes was also associated with sepsis (hazard ratio, 3.15; 95% confidence interval, 1.45-6.93). Genetic analysis found that individuals with the polymorphism of the FcγRIIa receptor that binds CRP poorly were also more likely to have decreased monocyte human leukocyte antigen DR and posttraumatic sepsis. In vitro studies showed that CRP could attenuate monocyte deactivation in volunteers with the polymorphism of the FcγRIIa receptor that binds CRP. CONCLUSION: Our findings suggest that a common genetic variation in the FcγRIIa receptor may contribute to infectious susceptibility in trauma patients. In vitro experiments suggest that this association is related to the inability of CRP to bind to this FcγRIIa receptor variant. LEVEL OF EVIDENCE: Prognostic study, level III.

Complications of pelvic ring fixation in patients requiring laparotomy.

BACKGROUND: Pelvic ring disruptions in blunt trauma are rarely an isolated finding. Many individuals needing operative pelvic fixation also require laparotomy for other injuries. Pelvic fixation can be performed by open reduction and internal fixation (ORIF) or external fixation (Ex-fix). Often when a laparotomy incision is present, ORIF is performed by extending this incision. We hypothesized ORIF performed by extending the laparotomy incision would result in higher rates of ventral hernia and wound complications versus Ex-fix. METHODS: All patients admitted from 2004-June 2014 who underwent laparotomy and pelvic fixation either by ORIF through extension of a laparotomy incision (ORIF group) or definitive Ex-fix group were identified. Injury severity score, demographics, associated injuries, and complications were collected. RESULTS: A total of 35 patients were identified who underwent laparotomy and pelvic fixation, 21 underwent Ex-fix, whereas 14 underwent ORIF through an extended laparotomy incision. There were no differences in injury severity score, demographics, associated injuries, or rate of ventral hernia. The ORIF group had more laparotomy incision infections (50.0% versus 4.8%, P < 0.01) and pelvic abscesses (42.9% versus 9.5%, P < 0.05). They required more procedures to address their complications (13 versus 5, P < 0.05). CONCLUSIONS: Individuals who have undergone laparotomy and pelvic fixation are a complex group of patients with multiple injuries. These data suggest that when surgical repair of a pelvic ring disruption is indicated and the patient has undergone laparotomy, careful consideration to the method of fixation should be given.

Effects of ethnicity on deceased organ donation in a minority-majority state.

OBJECTIVE: To define how ethnicity affects donation rates in New Mexico when compared with the United States. We hypothesized that deceased donation rates in New Mexico would reflect the ethnic rates of the population. DESIGN: We performed a retrospective review of the Organ Procurement Database for New Mexico from 2009 to June 2012. METHODS: Rates for donors and transplant candidates were calculated relative to 2010 census population estimates by ethnicity for non-Hispanic Whites, Hispanics, and American Indians. Poisson regression analyses were used to test whether United States and New Mexico rates differed. Rates were scaled to 100,000 patient-years for reporting. SETTING: State of New Mexico population compared to United States population. SUBJECTS: Reported deaths to New Mexico Donor Services and United Network for Organ Sharing from 2009 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Non-Hispanic White age-adjusted donor rates per 100,000 patient-years were 2.58 in New Mexico versus 2.60 in the United States, Hispanic donor rates were 1.98 in New Mexico versus 2.03 nationwide, and American Indian donor rates in New Mexico were 0.26 versus 1.23 nationwide (rate ratio = 0.21; 95% CI, 0.05-0.86). American Indians have significantly lower donor rates in New Mexico compared to non-Hispanic Whites (rate ratio = 0.11) and Hispanics (rate ratio = 0.13) and nationally (non-Hispanic Whites: rate ratio = 0.32 and Hispanics: rate ratio = 0.43). Hispanics and non-Hispanic Whites had similar donor rates regardless of geographic strata (Hispanics vs non-Hispanic Whites, New Mexico: 0.83; United States: 0.75). In New Mexico, Hispanic patients were 1.43 times more likely to be listed as transplant candidates than non-Hispanic Whites and American Indians were 3.32 times more likely to be listed than non-Hispanic Whites. In the United States, Hispanic patients were 1.90 times more likely to be listed as transplant candidates than non-Hispanic Whites and American Indians were 1.55 times more likely to be listed than non-Hispanic Whites. CONCLUSIONS: Donor and transplant candidate rates did not show strong differences by geographic strata. These findings suggest that further work is needed to elucidate the causes for ethnic differences in rates of consent and donation, particularly in the American Indian population.

Family presence during brain death evaluation: a randomized controlled trial*.

OBJECTIVE: To evaluate if a family presence educational intervention during brain death evaluation improves understanding of brain death without affecting psychological distress. DESIGN: Randomized controlled trial. SETTING: Four ICUs at an academic tertiary care center. SUBJECTS: Immediate family members of patients suspected to have suffered brain death. INTERVENTIONS: Subjects were group randomized to presence or absence at bedside throughout the brain death evaluation with a trained chaperone. All randomized subjects were administered a validated "understanding brain death" survey before and after the intervention. Subjects were assessed for psychological well-being between 30 and 90 days after the intervention. MEASUREMENTS AND MAIN RESULTS: Follow-up assessment of psychological well-being was performed using the Impact of Event Scale and General Health Questionnaire. Brain death understanding, Impact of Event Scale, and General Health Questionnaire scores were analyzed using Wilcoxon nonparametric tests. Analyses were adjusted for within family correlation. Fifty-eight family members of 17 patients undergoing brain death evaluation were enrolled: 38 family members were present for 11 brain death evaluations and 20 family members were absent for six brain death evaluations. Baseline understanding scores were similar between groups (median 3.0 [presence group] vs 2.5 [control], p = 0.482). Scores increased by a median of 2 (interquartile range, 1-2) if present versus 0 (interquartile range, 0-0) if absent (p < 0.001). Sixty-six percent of those in the intervention group achieved perfect postintervention "understanding" scores, compared with 20% of subjects who were not present (p = 0.02). Median Impact of Event Scale and General Health Questionnaire scores were similar between groups at follow-up (Impact of Event Scale: present = 20.5, absent = 23.5, p = 0.211; General Health Questionnaire: present = 13.5, absent = 13.0, p = 0.250). CONCLUSIONS: Family presence during brain death evaluation improves understanding of brain death with no apparent adverse impact on psychological well-being. Family presence during brain death evaluation is feasible and safe.

Nosocomial infections after severe trauma are associated with lower apolipoproteins B and AII.

BACKGROUND: Infection after severe trauma is a significant cause of morbidity and mortality days to weeks after the initial injury. Apolipoproteins play important roles in host defense and circulating concentrations are altered by the acute inflammatory response. The purpose of this study was to determine if patients who acquire infection after severe trauma have significantly lower apolipoprotein levels than trauma patients who do not become infected. METHODS: We conducted a case-control study on a prospectively identified cohort of adult patients admitted to our intensive care unit after severe trauma (Injury Severity Score ≥ 16). We compared plasma apolipoprotein levels between patients who acquired an infection within 30 days after trauma (cases) and those that remained infection free (controls). RESULTS: Of 40 patients experiencing severe trauma, we identified 22 cases that developed an infection within 30 days after injury. Cases had significantly lower posttrauma plasma levels of apolipoprotein B (p = 0.02) and apolipoprotein AII (p = 0.02) compared with controls. Consistent with previous studies, cases also received greater volumes of crystalloid infusions (p < 0.01) and blood transfusions (p < 0.01). Cases also had a more profound inflammatory response as measured by interleukin 6 levels (p = 0.02). CONCLUSION: Infection after severe trauma is associated with decreased circulating apolipoproteins as compared with uninfected controls. Profoundly decreased plasma apolipoproteins B and AII could potentially contribute to the impaired immunity after severe trauma. Apolipoproteins are potential targets for identifying those patients at risk of infection after trauma and for interventions aimed at preventing nosocomial infections. LEVEL OF EVIDENCE: Prognostic study, level III.

Monocyte deactivation correlates with injury severity score, but not with heme oxygenase-1 levels in trauma patients.

Traumatic injury induces a local and systemic release of pro-inflammatory cytokines, acute phase proteins, hormones, and other inflammatory mediators. The excessive release of these mediators plays an important role in the pathogenesis of shock. In parallel to this pro-inflammatory response, there is a regulatory response characterized by the release of anti-inflammatory mediators, which is thought to represent the host's attempt to restore immunological equilibrium. Studies in septic patients have suggested the compensatory anti-inflammatory response may result in an "immunodeficient state" that leaves the host susceptible to further infectious insults. A key feature of the anti-inflammatory state in septic patients is a change in the responsiveness of monocytes that has been termed "monocyte deactivation." This is supported by data that link monocyte deactivation to increased mortality in septic patients. Monocytes with reduced HLA-DR expression have been described in trauma patients. We collected blood from 25 severely injured patients and evaluated peripheral blood mononuclear cells (PBMC) for HLA-DR expression and TNF-α response to LPS stimulation as markers of monocyte deactivation. Levels of intracellular HO-1 were determined in each patient, as HO-1 has been implicated in monocyte deactivation in patients with severe systemic inflammatory response syndrome (SIRS). HLA-DR expression correlated inversely with Injury Severity Scores and TNF-α response to LPS stimulation, but failed to correlate with HO-1 levels in these patients. HLA-DR expression was decreased in normal monocytes stimulated with patient plasma, but this treatment had no effect on HO-1 levels. These results suggest monocyte deactivation in trauma patients is unlikely to be mediated by HO-1.

Transforming growth factor-ß, macrophage colony-stimulating factor and C-reactive protein levels correlate with CD14(high)CD16+ monocyte induction and activation in trauma patients.

Severe injury remains a leading cause of death and morbidity in patients under 40, with the number of annual trauma-related deaths approaching 160,000 in the United States. Patients who survive the initial trauma and post-traumatic resuscitation are at risk for immune dysregulation, which contributes to late mortality and accounts for approximately 20% of deaths after traumatic injury. This post-traumatic immunosuppressed state has been attributed to over-expression of anti-inflammatory mediators in an effort to restore host homeostasis. We measured a panel of monocyte markers and cytokines in 50 severely injured trauma patients for 3 days following admission. We made the novel observation that the subpopulation of monocytes expressing high levels of CD14 and CD16 was expanded in the majority of patients. These cells also expressed CD163 consistent with differentiation into alternatively activated macrophages with potential regulatory or wound-healing activity. We examined factors in trauma plasma that may contribute to the generation and activation of these cells. The percentage of CD14(high)CD16(+) monocytes after trauma correlated strongly with plasma C-reactive protein (CRP) transforming growth factor-ß (TGF-ß), and macrophage colony-stimulating factor (M-CSF) levels. We demonstrate a role for TGF-ß and M-CSF, but not CRP in generating these cells using monocytes from healthy volunteers incubated with plasma from trauma patients. CD16 is a receptor for CRP and IgG, and we showed that monocytes differentiated to the CD14(high)CD16(+) phenotype produced anti-inflammatory cytokines in response to acute phase concentrations of CRP. The role of these cells in immunosuppression following trauma is an area of ongoing investigation.

Cyclooxygenase-1 suppresses lipopolysaccharide-induced changes in rat gastric inducible nitric oxide synthase.

OBJECTIVE: Both nitric oxide synthase (NOS) and cyclooxygenase (COX) have inducible isoforms that are up-regulated during inflammatory states. However, the interaction between these enzymes is not clearly understood. The objective was to clarify the interactions between NOS and COX in the rat gastric mucosa in the presence and absence of lipopolysaccharide. DESIGN: Laboratory study. SETTING: Medical school laboratory. SUBJECTS: Female Sprague-Dawley rats. INTERVENTIONS: We used nonselective and selective COX inhibitors to determine the role of COX on inducible NOS (iNOS) expression in the gastric mucosa. MEASUREMENTS AND MAIN RESULTS: The nonselective COX inhibitors salicylate and indomethacin enhanced the expression of iNOS in the rat gastric mucosa and exacerbated gastric injury in the presence of lipopolysaccharide, effects reversed by exogenous prostaglandin E2. Selective COX-1 inhibition with SC560 similarly increased gastric iNOS expression and exacerbated gastric injury, while the selective COX-2 inhibitor NS398 had no effect on iNOS expression or gastric injury in the presence of lipopolysaccharide. CONCLUSIONS: These data suggest that COX-1 derived prostaglandins exert an inhibitory effect on gastric iNOS during endotoxemia, and this may represent a potential cytoprotective mechanism not previously recognized for this enzyme, since up-regulation of iNOS is deleterious in some tissues.

Rat gastric gelatinase induction during endotoxemia.

Despite continued investigation, the pathogenesis of tissue injury secondary to sepsis remains elusive. Further evaluation of the mechanisms by which endotoxemia and sepsis induce tissue injury is necessary to formulate rational and effective treatment strategies. The purpose of these studies was to evaluate the role of the matrix metalloproteinases MMP-2 and MMP-9 in gastric injury during lipopolysaccharide induced endotoxemia. Lipopolysaccharide increased gastric gelatinase activity as determined by in situ and gelatin zymography. Specifically, lipopolysaccharide induced MMP-2, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) transcription, with subsequent increases in MMP-2 and TIMP-1 protein expression. Furthermore, selective metalloproteinase inhibition ameliorated gastric injury in this model. These data suggest that lipopolysaccharide-induced gastric injury is mediated, at least in part, by increased MMP-2 production.

Effects of lipopolysaccharide on gastric stasis: role of cyclooxygenase.

This study was done to examine the role of cyclooxygenase (COX) in lipopolysaccharide (LPS)-induced gastroprotection and gastric stasis. In conscious rats, LPS dose and time dependently increased gastric luminal fluid accumulation. LPS decreased blood flow (laser Doppler) and prevented gastric injury from acidified ethanol at time points before significant fluid accumulation occurred. LPS increased COX-2 but not COX-1 expression. In contrast, LPS decreased gastric mucosal prostaglandin synthesis. LPS-induced gastric luminal fluid accumulation was negated by both nonselective COX inhibition with salicylate and selective COX-2 inhibition with NS-398 but not by selective COX-1 inhibition with SC-560. Neither salicylate nor NS-398 blocked LPS-induced gastroprotection. LPS-induced gastroprotection does not depend entirely on accumulation of luminal fluid and is independent of COX-1 and COX-2. However, the ability of LPS to cause gastric stasis and increase gastric luminal fluid accumulation involves COX-2.

Outcome after surgical resection of recurrent rhabdomyosarcoma.

BACKGROUND/PURPOSE: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Patients with localized disease have a cure rate of 50% to 90%; however, there has been little evidence that aggressive surgical resection for recurrent disease is of benefit. We reviewed our experience with aggressive surgical resection for recurrent RMS. METHODS: A retrospective review of the records for patients with RMS was performed. Data extracted included tumor site, histology, initial therapy, time to recurrence, treatment, and outcomes. RESULTS: From 1991 to 2002, 122 patients with RMS (3 months-18 years) were treated at the MD Anderson Cancer Center. Of 32 patients with recurrent RMS, 19 had surgical resection and 13 had biopsy only or no resection. The common primary sites included extremity (12), genitourinary nonbladder/prostate (7), and retroperitoneal/trunk (7). In the resection group, 33 operations were performed with 5 (15%) major complications and no deaths. Seventeen (52%) of these procedures (7 pelvic, 5 thoracic, 3 amputations, and 2 cranial) were classified as aggressive. After a mean follow-up period of 4.9 years, 7 patients (37%) had no evidence of disease, 8 (42%) died, and 4 were lost to follow-up. There was no correlation between survival and the type of resection. In the no-resection group only, 1 (8%) of 13 patients survived. CONCLUSIONS: Despite morbidity, aggressive surgical resection is warranted to improve survival in patients with recurrent RMS.

Salicylate enhances rat gastric gelatinase activity.

BACKGROUND: Increased matrix metalloproteinase (MMP) activity is associated with tissue injury in some organs. Their role in gut injury remains to be fully elucidated. We recently demonstrated that increased MMP-2 activity participated in lipopolysaccharide (LPS)-induced gastric injury. Thus we hypothesized that MMPs may play a role in other models of gastric injury. MATERIALS AND METHODS: The effect of L-NAME (10 mg/kg IP) or salicylate (100 mg/kg IP) on gastric injury from 20% ethanol was evaluated in an anesthetized model of gastric injury. In a separate experiment, gastric metalloproteinase activity was assessed after salicylate or L-NAME administration. Rats were given either L-NAME (10 mg/kg), salicylate (100 mg/kg), or saline IP and sacrificed after 6 hours. Gastric mucosa was harvested and portions of the glandular stomach snap frozen for gelatin and in situ zymography as indices of MMP activity. Subsequently the effect of MMP inhibition on macroscopic gastric injury from salicylate and a dilute luminal irritant was determined. RESULTS: Both L-NAME and salicylate significantly increased gastric injury from 20% ethanol versus saline controls. Salicylate treatment significantly increased gelatinase activity as determined by in situ zymography and gelatin zymography while L-NAME did not. MMP inhibition ameliorated macroscopic gastric injury secondary to salicylate and a dilute luminal irritant. CONCLUSIONS: This is the first study to report that MMP activity increases in the stomach following salicylate treatment. These data suggest that MMPs may play a role in the ability of salicylate to exacerbate gastric injury from irritants, but likely do not play a role in mediating the deleterious effects of L-NAME.

Follow up of infants with congenital diaphragmatic hernia.

Survival of patients with congenital diaphragmatic hernia has improved with the introduction of more sophisticated treatments. Long-term follow up has led to the recognition of pulmonary morbidity not previously recognized. In addition, extrapulmonary problems associated with the survival of these high-risk infants are now being identified. This review describes associated morbidities in congenital diaphragmatic hernia survivors and their predictors.

Bombesin-induced gastroprotection.

Bombesin is an endogenous gut peptide that is prominent in the stomach. In addition to its effects on modulating acid and gut peptide secretion, recent evidence indicates that bombesin is a potent gastroprotective agent. This review article examines the ability of bombesin to prevent gastric injury. Its protective actions appear to be mediated primarily via the release of endogenous gastrin, as gastroprotection is negated by blockade of gastrin receptors. Bombesin-induced gastroprotection and gastrin release are modified by somatostatin. Immunoneutralization of endogenous somatostatin increases the ability of bombesin to prevent gastric injury by increasing gastrin release. In mechanistic studies, ablation of capsaicin-sensitive afferent neurons abolishes bombesin-induced gastroprotection while cyclo-oxygenase inhibition partially reverses this effect. Nitric oxide synthase inhibition also negates bombesin-induced gastroprotection as well as the ability of bombesin to increase gastric mucosal blood flow. Taken together, the available evidence indicates that bombesin causes release of endogenous gastrin that activates sensory neurons located in the gastric mucosa. Activation of sensory neurons causes increased production of nitric oxide through activation of constitutive nitric oxide synthase, which leads to a resultant increase in gastric mucosal blood flow and renders the stomach less susceptible to damage from luminal irritants.

Cholecystokinin-induced gastroprotection: a review of current protective mechanisms.

Cholecystokinin (CCK) is a member of a family of gastrointestinal peptides known to physiologically regulate pancreatic protein secretion, gallbladder contractility, and gut motility. In addition, CCK has been found to play important roles in endocrine and neural systems in the periphery as well as in the central nervous system. CCK has been proposed to play a role in satiety, anxiety, and intestinal transit in addition to its well-described effects in coordinating digestion of a meal. We and others have shown that exogenous and endogenous CCK prevent gastric injury from luminal irritants. These data suggest that the release of CCK may represent an important component of the intrinsic gastric mucosal defense system. This review focuses on the ability of CCK to render the stomach more resistant to injury from luminal insults and will summarize recent studies that examine the possible mechanisms involved.

Lipopolysaccharide-induced changes in rat gastric H/K-ATPase expression.

OBJECTIVE: To evaluate lipopolysaccharide (LPS)-induced inhibition of gastric acid secretion. SUMMARY BACKGROUND DATA: Endotoxemia from LPS inhibits gastric acid secretion by an unknown mechanism. Bacterial overgrowth in the stomach caused by decreased acid secretion could be responsible for nosocomial pneumonia developing in critically ill intensive care unit patients. Because acid secretion is via the H/K-ATPase and the effects of LPS on this enzyme are unknown, we hypothesized that LPS causes inhibition of gastric acid secretion by down-regulating the H/K-ATPase. METHODS: A rat model to study gastric acid secretion was created. Saline or LPS (0.05-20 mg/kg IP) was given for 1 hour, after which basal acid secretion was determined for 1 hour. Pentagastrin (PG; 10 microg/kg IV) or saline was then given and gastric acid output collected for another 2 hours. RESULTS: LPS dose dependently inhibited basal and PG stimulated acid secretion. LPS increased alpha- and beta-H/K-ATPase subunit mRNA expression (Northern blot) in the absence of PG compared with saline. In the presence of PG, LPS did not have this effect. Western blot analysis did not show any difference in alpha- or beta-subunit immunoreactivity. Immunofluorescence analysis demonstrated that PG increased staining in the secretory membranes for H/K-ATPase subunits whereas in all LPS-treated rats, it appeared that H/K-ATPase subunits remained within the tubulovesicles. Furthermore, changes in H/K-ATPase mRNA expression may not be related to changes in NF-kappaB activity. CONCLUSIONS: These data suggest that inhibition of gastric acid secretion by LPS is due to inhibition of H/K-ATPase enzymatic function or changes in cytoskeletal rearrangements in H/K-ATPase subunits rather than by down-regulation of transcriptional or translational events.

Diverticulitis in the younger patient.

BACKGROUND: The purpose of this study was to examine the presentation of diverticulitis at an urban county hospital serving predominantly indigent patients and to analyze the differences, if any, in presentation and treatment in younger patients. METHODS: A retrospective review of medical records from 1995 to 2001 was performed at a single institution to identify patients admitted to the surgical service with the diagnosis of diverticular disease. Inclusion criteria were either diverticulitis confirmed at operation or radiographic findings consistent with the disease. Patient demographics, history, pertinent physical findings, and treatment were recorded. The data were analyzed after dividing the patients into two populations: a younger population 50 years of age or less, and a second population of patients older than 50. RESULTS: During the interval, a total of 64 patients were admitted to the surgical service with the diagnosis of diverticulitis. The mean age of this population was 45.5 years (range 21 to 86). Forty-six patients were under 50 years of age (72%). Analysis of sex differences, type and timing of surgical procedure, and complication rate with respect to age showed no significant difference between the two age groups. CONCLUSIONS: We are clearly treating a younger patient population than previous reports on patients with diverticulitis. Although there was a trend toward increased surgical intervention in the younger population, this number did not reach statistical significance. Diverticulitis in young patients at our institution does not appear to take a more aggressive course than the same disease in older patients.

Cholecystokinin secretagogue-induced gastroprotection: role of nitric oxide and blood flow.

This study was done to examine the role of CCK in gastric mucosal defense and to assess the gastroprotective roles of nitric oxide and blood flow. In rats, the CCK secretagogues oleate and soybean trypsin inhibitor augmented gastric mucosal blood flow and prevented gastric injury from luminal irritants. Type A CCK receptor blockade negated CCK secretagogue-induced gastroprotection and exacerbated gastric injury from bile and ethanol but did not block adaptive cytoprotection. CCK secretagogue-induced gastroprotection and hyperemia were negated by nonselective nitric oxide synthase (NOS) inhibition (N(G)-nitro-L-arginine methyl ester) but not by selective inducible NOS inhibition (aminoguanidine). Gastric mucosal calcium-dependent NOS activity, but not calcium-independent NOS activity, was increased following CCK and CCK secretagogues. The release of endogenous CCK plays a role in the intrinsic gastric mucosal defense system against injury from luminal irritants. The protective mechanism appears to involve increased production of nitric oxide from primarily the constitutive isoforms of NOS and a resultant increase in blood flow.

Does upregulation of inducible nitric oxide synthase play a role in hepatic injury?

Lipopolysaccharide (LPS) and gut ischemia/reperfusion (I/R) injury cause reversible liver injury. Because nitric oxide (NO) can have both beneficial and deleterious effects in the gastrointestinal tract, and because the role of NO in gut I/R-induced hepatic injury is unknown, this study examined its role in LPS and gut I/R-induced hepatic injury in the rat. Both LPS and gut I/R caused a similar increase in serum hepatocellular enzymes. LPS but not gut I/R caused a significant increase in upregulation of hepatic inducible NO synthase (iNOS) according to quantitative real-time RT-PCR and Western immunoblot analysis. Aminoguanidine, a selective iNOS inhibitor, attenuated LPS-induced hepatic injury and hypotension, but did not prevent gut I/R-induced hepatic injury. In contrast, the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester aggravated liver damage from both LPS and gut I/R. These data indicate that iNOS plays a role in mediating LPS-induced hepatic injury, but not gut I/R-induced hepatic injury. The data also suggest that the constitutive isoforms of NOS play a hepatoprotective role in both models of hepatic injury.