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Jeffrey S Upperman

Publications and source records attributed to Jeffrey S Upperman.

At least 19 recordsLinked to original sources
PubMed2006

Lipopolysaccharide induces cyclooxygenase-2 in intestinal epithelium via a noncanonical p38 MAPK pathway.

Necrotizing enterocolitis (NEC), a severe intestinal inflammation in neonates, occurs following bacterial colonization of the gut. LPS-induced production of inflammatory factors in immature enterocytes may be a factor in NEC. Previously, we described LPS-induced p38 MAPK-dependent expression of cyclooxygenase-2 (COX-2) in rat IEC-6 cells. In this study, we examine COX-2 expression in newborn rat intestinal epithelium and further characterize the mechanisms of COX-2 regulation in enterocytes. Induction of NEC by formula feeding/hypoxia increased phospho-p38 and COX-2 levels in the intestinal mucosa. Celecoxib, a selective COX-2 inhibitor, exacerbated the disease, suggesting a protective role for COX-2. COX-2 was induced in the intestinal epithelium by LPS in vivo and ex vivo. The latter response was attenuated by the p38 inhibitor SB202190, but not by inhibitors of ERK, JNK, or NF-kappaB. In IEC-6 enterocytes, COX-2 was induced by the expression of MAPK kinase 3 EE (MKK3EE), a constitutive activator of p38, but not of activators of ERK or JNK pathways. However, neither MKK3/6 nor MKK4, the known p38 upstream kinases, were activated by LPS. Dominant-negative MKK3 or MKK4 or SB202190 failed to prevent LPS-induced, p38-activating phosphorylation, ruling out important roles of these kinases or p38 autophosphorylation. LPS increased COX-2 and activating phosphorylation of p38 with similar dose-response. Blockade of LPS-induced expression of COX-2-luciferase reporter and destabilization of COX-2 message by SB202190 indicate that p38 regulates COX-2 at transcription and mRNA stability levels. Our data indicate that p38-mediated expression of COX-2 proceeds through a novel upstream pathway and support the role of the neonate's enterocytes as bacterial sensors.

Animals↗
PubMed2005

High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod.

High-mobility group box 1 (HMGB1) is a late mediator of endotoxemia known to stimulate the production of proinflammatory cytokines that are putative mediators of intestinal inflammation associated with necrotizing enterocolitis (NEC). We hypothesized that HMGB1 is also involved in the pathogenesis of NEC. We examined the expression of HMGB1 and the effect of the novel drug semapimod on intestinal inflammation in an experimental model of NEC in neonatal rats. Newborn rats were subjected to hypoxia and fed a conventional formula by gavage (FFH) or were breast fed (BF). Rats were killed on day 4, and the distal ileum was harvested for morphological studies and Western blot analysis. FFH newborn rats but not BF controls developed intestinal inflammation similar to the histological changes observed in human NEC. We found that the expression of HMGB1 and its receptor for advanced glycation end products (RAGE) as well as that of other apoptosis/inflammation-related proteins (Bad, Bax, inducible nitric oxide synthase, and cyclooxygenase 2) was upregulated in the ileal mucosa of FFH newborn rats compared with BF animals. Administration of the drug semapimod inhibited the upregulation of those proteins and partially protected the animals against the FFH-induced intestinal injury. Elevated levels of HMGB1 were also found in ileal samples from infants undergoing intestinal resection for acute NEC. Our results implicate HMGB1 and RAGE as important mediators of enterocyte cell death and hypoxia-induced injury in NEC and support the hypothesis that inhibitors such as semapimod might play a therapeutic role in chronic intestinal inflammation characterized by this animal model.

Animals↗
PubMed2005

The impact of hospitalwide computerized physician order entry on medical errors in a pediatric hospital.

PURPOSE: Medication errors contribute significantly to the morbidity and costs of pediatric health care. The authors hypothesized that hospitalwide computerized physician order entry (CPOE) in a pediatric hospital would lead to a decrease in medication errors. METHODS: The authors retrospectively evaluated and prospectively analyzed inpatient discharge and usage and adverse drug event (ADE) rate data pre- and postintroduction of a hospitalwide implementation of CPOE in a tertiary care pediatric hospital. They compared pre- and postintervention ADEs (Student's t test) and computed the number needed to treat (NNT) analog. RESULTS: Over the 9-month study period, there were 45,615 in patient days and 8619 discharges. Pre-CPOE verbal order regulatory compliance was 80%, whereas post-CPOE increased to 95%. Transcription errors were eliminated. All ADEs pre-CPOE were 0.3 +/- 0.04 per 1000 doses, whereas post-CPOE ADEs were 0.37 +/- 0.05 per 1000 doses (P = .3). Harmful ADEs pre-CPOE were 0.05 +/- 0.017 per 1000 doses, while post-CPOE ADEs were 0.03 +/- 0.003 per 1000 doses (P = .05). Our NNT data demonstrate that CPOE would prevent 1 ADE every 64 (95% CI 25-100) patient days. CONCLUSIONS: CPOE decreases harmful ADEs in a pediatric hospital, thus leading to increased patient safety. In addition, CPOE provides an automated system for monitoring and improving health care quality.

Adverse Drug Reaction Reporting Systems↗
PubMed2005

Disordered enterocyte signaling and intestinal barrier dysfunction in the pathogenesis of necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in neonates, and is characterized by the development of diffuse intestinal necrosis in the stressed, pre-term infant. Systemic stress causes a breakdown in the intestinal mucosal barrier, which leads to translocation of bacteria and endotoxin and the initiation of a signaling response within the enterocyte. This review summarizes recent evidence defining a clear role that defective enterocyte signaling plays in the pathogenesis of NEC through the following mechanisms: 1) The localized production of nitric oxide by villus enterocytes results in an increase in enterocyte apoptosis and impaired proliferation; 2) The translocation of endotoxin results in a PI3K-dependent activation of RhoA-GTPase within the enterocyte leading to decreased enterocyte migration and impaired restitution; 3) Dysregulated sodium-proton exchange within the enterocyte by endotoxin renders the enterocyte monolayer more susceptible to damage in the face of the acidic microenvironment characteristic of systemic sepsis; and 4) Endotoxin causes a p38-dependent release of the pro-inflammatory molecule COX-2 by the enterocyte, which potentiates the systemic inflammatory response. An understanding of the mechanisms by which disordered enterocyte signaling contributes to the pathogenesis of barrier failure and NEC--through these and other mechanisms--may lead to the identification of novel therapeutic approaches for this devastating disease.

Bacterial Translocation↗
PubMed2005

Mechanisms of nitric oxide-mediated intestinal barrier failure in necrotizing enterocolitis.

Necrotizing enterocolitis (NEC) is the leading intestinal emergency in premature infants. The underlying etiology of NEC remains elusive, but hypoxic conditions and early enteral feeding are consistently implicated as the main risk factors in the pathogenesis of NEC. We postulate that nitric oxide (NO) plays a key role as a molecular signaling "hub" in the generation of gut barrier failure in NEC. Clinical studies suggest that inflammatory cytokines and excessive NO production may contribute to the pathogenesis of NEC. One of the major challenges in defining the critical signaling pathways that lead to the development of NEC is the lack of specific biochemical markers that consistently delineate the early stages of NEC. Intestinal pathology and molecular markers derived from late-stage NEC represent end-stage findings and thus provide little insight into the early events that led to intestinal inflammation. Such markers may not represent viable therapeutic targets for the treatment or prevention of NEC. Therefore, novel strategies are needed to identify the patients at risk for NEC and define the clinically relevant molecules that characterize the early stages of NEC. This review will examine the mechanisms of NO-mediated gut barrier failure and propose novel genetic-based approaches for elucidating the critical molecular pathways in NEC.

Enterocolitis, Necrotizing↗
PubMed2005

Pediatric trauma susceptibility to sepsis.

OBJECTIVE: The purpose of this review is to review how pediatric trauma may predispose children to sepsis. DESIGN: The information discussed in this report is derived from a recent literature review of pediatric trauma and related topics and discussion at an international consensus conference on pediatric sepsis. MEASUREMENTS AND MAIN RESULTS: There is a paucity of evidence on sepsis-related complications in pediatric trauma patients. Severe traumatic brain injury is a leading predisposing factor for sepsis complications. Excluding burn trauma, traumatically injured children without severe head injury rarely succumb to overwhelming sepsis. CONCLUSIONS: Patients with multiple traumatic injuries are frequently admitted to the intensive care unit, and because head injury is the most common ailment, unconscious patients with a combination of injuries that include head injury will regularly require mechanical ventilation and central venous access and are at risk for life-threatening nosocomial infections. Outside of pulmonary contusions, organ-specific causes of infection are infrequent.

Adolescent↗
PubMed2005

Pediatric surgical site and soft tissue infections.

OBJECTIVE: The purpose of this review is to provide background and a concise set of definitions for pediatric surgical site and wound infections. DESIGN: The information discussed in this report is derived from a literature review and discussion at an international consensus conference on pediatric sepsis. MEASUREMENTS AND MAIN RESULTS: There is a paucity of literature on pediatric surgical site and wound infection definitions. Excluding burn wounds, surgical site and wound infections rarely lead to overwhelming sepsis. Nevertheless, surgical site or wound infections including pressure ulcers can lead to significant morbidity in the pediatric critical care setting. CONCLUSIONS: Although surgical site and wound infections rarely lead to intensive care unit admissions, definitions are still valuable for stratifying potential candidates for sepsis trials.

Burns↗
PubMed2005

The introduction of computerized physician order entry and change management in a tertiary pediatric hospital.

OBJECTIVES: The objectives of this review were to document the introduction of computerized physician order entry (CPOE)-centered changes in an academic tertiary care center and to review the CPOE-focused literature. DESIGN: We performed a systematic literature review of CPOE-related articles indexed on Medline, with particular emphasis on pediatric applications. We focused our commentary around the concepts involved in the implementation process at a tertiary pediatric hospital. RESULTS: In 2001, the Children's Hospital of Pittsburgh (CHP) embarked on the process of CPOE design and implementation. We determined that CPOE is a tool for improving pediatric care. The CPOE implementation process is more than a technologic change; it involves an organizational cultural transformation. Although the complete transition to CPOE was little more than 1 year ago, CHP has overcome the typical obstacles of CPOE implementation to begin to realize its many benefits. The early success of CHP was achieved by creating a realistic, positive, work environment, which fostered hospital-wide participation and integration. CONCLUSION: CPOE is an invaluable resource for supporting patient safety in health care settings. The successful implementation of CPOE requires a paradigm shift in hospital policies and processes.

Efficiency, Organizational↗
PubMed2005

Dominance of high-producing interleukin 6 and low-producing interleukin 10 and interferon gamma alleles in glucose-6-phosphate dehydrogenase-deficient trauma patients.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a condition associated with malaria resistance, is a common genetic polymorphism. Decreased interleukin (IL)-10 production was demonstrated in vivo and in vitro in the African and Mediterranean forms of G6PD deficiencies. We hypothesized that low-producing IL-10 alleles are more abundant in the G6PD-deficient than nondeficient population. One hundred eleven men with African American ancestry were tested for G6PD deficiency (Type A-202/376) and for the cytokine gene promoter polymorphisms of IL-10 (-1082 G/A, -819 T/C, and -592 A/C), tumor necrosis factor (TNF)-alpha (-308 G/A), transforming growth factor (TGF)-beta1 (C/T codon 10 and C/G codon 25), IL-6 (-174 G/C), and interferon (IFN)-gamma (+874 A/T). There were no differences in the allele frequencies for TNF-alpha, IL-6, or TGF-beta1 between the G6PD-deficient and nondeficient population. In contrast, the low-producing IL-10 alleles (-592A) and low-producing IFN-gamma (+874A) allele frequencies were greater in G6PD-deficient than nondeficient samples (P = 0.035 and 0.009). Seventy-one percent of G6PD-deficient and 50% of nondeficient samples carried the high-producing IL-6(G) allele with low-producing IL-10(A) allele (P = 0.03). Furthermore, 95% of deficient and 81% of nondeficient samples carried the IL-6(G) allele together with low-producing IFN-gamma(A) allele (P = 0.017). These investigations indicate a predominant presence of high-producing IL-6 alleles together with low-producing IL-10 and IFN-gamma alleles in individuals with ancestry from malaria-endemic regions. The frequency of low-producing IL-10 genotypes is greater in the G6PD-deficient compared with nondeficient patients. The fact that these genetic differences are preserved in the current African American G6PD-deficient population indicates their potential role in pathophysiological processes in the absence of the selective pressure caused by tropical diseases.

Black or African American↗
PubMed2004

The role of the glutathione antioxidant system in gut barrier failure in a rodent model of experimental necrotizing enterocolitis.

BACKGROUND: Evidence suggests that intestinal barrier failure in necrotizing enterocolitis results in part from overproduction of nitric oxide and other toxic oxidant species that result in enterocyte death and intestinal barrier failure. We hypothesize that the glutathione detoxifying system is important in maintaining intestinal barrier integrity by protecting against nitrosative stress. METHODS: Newborn rats were subjected to hypoxia (5% O2, tid) and fed formula by gavage (NEC), or were breast-fed without hypoxia (BF). Rats were killed and the distal ilea were harvested for RNA, protein, and morphologic studies. RNA underwent cDNA microarray analysis. To assess glutathione in protecting against nitrosative stress, IEC-6 cells were exposed to SIN-1 and/or L-buthionine-(S,R)-sulfoximine (BSO), a glutathione inhibitor. Cells were analyzed for glutathione-S-transferase activity, apoptosis and mitochondrial function. RESULTS: BF controls developed normal intestinal architecture, whereas NEC animals sustained damage to the intestinal epithelium. Microarray analysis demonstrated that 93 genes were overexpressed in NEC compared with controls. In the array, glutathione-S-transferase pi and alpha 2, GSH-dependent detoxifying enzymes, RNA were upregulated compared with BF controls. IEC-6 cells exposed to SIN-1/BSO produced an increase in apoptosis. Poly ADP-ribosylpolymerase cleavage and apoptosis-inducing factor (AIF) nuclear localization, markers of apoptosis, were seen in IEC-6 cells exposed to SIN-1/BSO as opposed to media controls. CONCLUSION: These data support the hypothesis that GSH antioxidant system plays a crucial role in gut barrier protection by attenuating enterocyte death.

Animals↗
PubMed2003

Peroxynitrite inhibits enterocyte proliferation and modulates Src kinase activity in vitro.

Overproduction of nitric oxide (NO) or its toxic metabolite, peroxynitrite (ONOO-), after endotoxemia promotes gut barrier failure, in part, by inducing enterocyte apoptosis. We hypothesized that ONOO- may also inhibit enterocyte proliferation by disrupting the Src tyrosine kinase signaling pathway, thereby blunting repair of the damaged mucosa. We examined the effect of ONOO- on enterocyte proliferation and Src kinase activity. Sprague-Dawley rats were challenged with LPS or saline, whereas intestinal epithelial cell line cells were treated with ONOO- or decomposed ONOO- in vitro. Enterocyte proliferation in vivo and in vitro was measured by 5-bromo-2'-deoxyuridine (BrdU) or [3H]thymidine incorporation. Src kinase activity in cell lysates was determined at various times. LPS challenge in vivo and ONOO- treatment in vitro inhibited enterocyte proliferation. ONOO- treatment blunted the activity of Src and its downstream target, focal adhesion kinase, in a time-dependent manner. ONOO- blocked mitogen (FBS, EGF)-induced enterocyte proliferation and Src phosphorylation while increasing Src nitration. Thus ONOO- may promote gut barrier failure not only by inducing enterocyte apoptosis but also by disrupting signaling pathways involved in enterocyte proliferation.

Animals↗
PubMed2003

Mechanism of intestinal-derived fungal sepsis by gliotoxin, a fungal metabolite.

BACKGROUND/PURPOSE: Gut barrier dysfunction resulting from fungal overgrowth may be caused by the interaction of gliotoxin (GT), a fungal metabolite, with enterocytes. The goal of this study was to determine the mechanisms by which gliotoxin (GT), a fungal metabolite, causes enterocyte apoptosis. METHODS: The authors measured enterocyte apoptosis, caspase-3 activity, pro-caspase-3, and poly (ADP-ribose) polymerase (PARP) cleavage in GT-exposed IEC-6 cells, a rat intestinal cell line. RESULTS: GT induced apoptosis in IEC-6 cells. The pan-caspase inhibitor ZVAD suppressed this GT-mediated apoptosis. GT induced a 15-fold increase in caspase-3 activity over media control. The authors detected PARP cleavage by after GT exposure. DTT pretreatment decreased apoptosis compared with GT alone. CONCLUSIONS: This study supports the concept that fungal overgrowth may lead to gut barrier dysfunction by the local release of gliotoxin and the induction enterocyte apoptosis.

Animals↗
PubMed2003

All-terrain vehicle rules and regulations: impact on pediatric mortality.

BACKGROUND/PURPOSE: All-terrain vehicles (ATV) use by children leads to severe injury and death. Since the US Consumer Product Safety Commission consent decree expired in 1998, there has been little movement in regulating ATV use for children (<16 yr). The authors hypothesized that states with laws and regulations restricting pediatric ATV use may abrogate excess death compared with states without such restrictions. METHODS: Pediatric mortality data reported to the consumer product safety commission from 1982 to 1998 were analyzed as well as state all-terrain vehicle requirements compiled by the Specialty Vehicle Institute of America in August 2001. The authors calculated ATV mortality rate by dividing ATV mortality frequency by 1980-2000 pediatric census results. They compared the top 26 states with the highest ATV mortality rates (TOP) with those of all other states (OTH) in terms of age, ATV type, ATV occupancy, and ATV laws. Chi-square analysis was performed. RESULTS: There were 1,342 ATV pediatric deaths during the 16-year period. The TOP states averaged approximately a 2-fold increase in adjusted ATV mortality rate compared with the national ATV pediatric mortality rate. Ninety-two percent of TOP states have no licensing laws compared with 73% of the OTH states (P <.07). There is no difference between groups with regard to minimum age requirements and safety certification. CONCLUSIONS: Current legal and regulatory standards have low probability of decreasing ATV-related pediatric mortality. States should adopt laws that restrict the use of ATV's for children less than 16 years of age and potentially prevent excess ATV-related pediatric mortality.

Accident Prevention↗