Protegrin-1 increases bacterial clearance in sepsis but decreases survival.
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Analysis of Variance↗
Biomedical subjects
Grace L Su
Publications and source records attributed to Grace L Su.
Emotional distress in chronic hepatitis C patients not receiving antiviral therapy.
BACKGROUND/AIMS: The aim of our study was to determine the prevalence, type, and severity of emotional distress in a large group of consecutive chronic hepatitis C (CHC) patients not receiving anti-viral therapy. METHODS: The brief symptom inventory and a 67-item questionnaire with the SF-36 embedded within it were used to study 220 outpatients with compensated CHC. RESULTS: Seventy-seven (35%) participants reported significantly elevated global severity index (GSI) T-scores compared to an expected frequency of 10% in population controls. In addition, significantly elevated depression, anxiety, somatization, psychoticism, and obsessive-compulsive subscale T-scores were reported in 28-40% of subjects. Subjects with an active psychiatric co-morbidity had significantly higher GSI and subscale T-scores compared to subjects with active medical co-morbidities and subjects without medical or psychiatric co-morbidities (P<0.01). However, patients with CHC alone also had a higher frequency of elevated GSI T-scores compared to population controls (20 versus 10%). GSI and subscale T-scores were strongly associated with SF-36 summary scores (P<0.001). CONCLUSIONS: Clinically significant emotional distress was reported in 35% of CHC patients not receiving antiviral therapy. In addition to depression, a broad array of psychological symptoms were observed. Further investigation into the etiopathogenesis and treatment of emotional distress in CHC patients is warranted.
Adolescent↗
Thermal injury induces expression of CD14 in human skin.
BACKGROUND: Skin is equipped with an array of immune mediators aimed at fighting invading microbes. CD14 has been shown to play a key role in modulating the activation of cells by LPS. Since LPS levels within burn wounds are often found to be elevated, we sought to examine the expression of CD14 within human skin following thermal injury. METHODS: Patients who sustained partial thickness burns, were recruited into the study (n=57). Total RNA was isolated from both burn and normal (control) skin. Northern blot analysis and TaqMan RT-PCR were used to determine skin CD14 mRNA levels. Immunohistochemistry was used to localize CD14 expression in burned and normal skin. RESULTS: Quantitative PCR showed significantly increased CD14 expression levels in the immediate post-burn period (P<0.05 burn versus non-burn). Immunohistochemistry revealed more pronounced CD14 staining 24 h after the injury, reaching normal levels approximately 5-7 days post-burn. CONCLUSION: CD14 expression peaks within the first week post-burn before declining, reaching normal levels after 14 days. This loss of supranormal CD14 expression locally within the wound may contribute to a weakened host defense response 5-6 days after injury, when patients become especially vulnerable to infection.
Adolescent↗
NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States.
The incidence of hepatocellular carcinoma (HCC) in the United States is increasing, but the clinical characteristics of American patients with HCC have not been well described. The aims of this study were to determine the etiology of liver disease and short-term outcome among HCC patients presenting to a single center in the United States. One hundred five consecutive patients with HCC were studied; mean age was 59 years, 67% were men, and 76% were non-Hispanic white. The most common etiology of liver disease was hepatitis C (51%) and cryptogenic cirrhosis (29%). Half of the patients with cryptogenic cirrhosis had histologic or clinical features associated with nonalcoholic fatty liver disease (NAFLD). Fifty-three (50%) patients had HCC detected during surveillance (group I), whereas the remaining patients had symptomatic tumors (group II). Group I patients had smaller tumors (P =.01), were more likely to be eligible for surgical treatment (P =.005), and had a better median survival compared with patients in group II (P =.001). Patients with cryptogenic cirrhosis were less likely to have undergone HCC surveillance and had larger tumors at diagnosis. In conclusion, hepatitis C and cryptogenic liver disease are the most common etiologies of diseases in our patients with HCC. NAFLD accounted for at least 13% of the cases. Patients who underwent surveillance had smaller tumors and were more likely to be candidates for surgical or local ablative therapies. Because of the increasing incidence of NAFLD, further studies are needed to determine the risk of HCC in patients with NAFLD.
Adult↗
An essential role for lipopolysaccharide-binding protein in pulmonary innate immune responses.
Lipopolysaccharide (LPS)-binding protein (LBP) greatly facilitates LPS activation of monocytic cells through the CD14 receptor, triggering activation of innate immune responses. An acute phase protein, LBP is produced predominantly by the liver; however, we and others have shown that LBP is produced extrahepatically in multiple locations, including the lung. The importance of LBP in the lung has remained unclear. LBP may make the host more acutely sensitive to LPS and development of septic complications; alternatively, it may be protective, aiding in detection, opsonization, and killing of bacteria. Our objective was to determine the role LBP plays in local pulmonary immune defenses to bacterial challenge. LBP knockout mice and age-matched C57BL/6 wild-type controls were challenged with direct intratracheal inoculation of Klebsiella pneumoniae. We observed a significant increase in mortality, earlier onset of bacteremia, and greater pulmonary bacterial loads in LBP knockout mice compared with controls. Total lung myeloperoxidase (MPO) activity, neutrophil recruitment to the alveolar space, and levels of KC--a chemokine involved in neutrophil recruitment--in bronchoalveolar lavage (BAL) fluid and lung homogenates were found to be significantly diminished in knockout mice compared with controls. Together, our findings suggest that LBP is essential in local pulmonary innate immune responses against bacteria.
Acute-Phase Proteins↗
Activity of novispirin G10 against Pseudomonas aeruginosa in vitro and in infected burns.
The emergence of multidrug-resistant microbes has serious implications for managing infection and sepsis and has stimulated efforts to develop alternative treatments, such as antimicrobial peptides. The objective of this study was to test a designer peptide, novispirin G10, against multidrug-resistant microorganisms. By two-stage radial diffusion assays, its activity against such organisms compared favorably with that of standard antibiotics and other antimicrobial peptides. It killed bacteria very rapidly, was nonhemolytic, and was relatively noncytotoxic. The peptide induced an immediate, massive efflux of potassium from Pseudomonas aeruginosa, suggesting that it altered the permeability of its inner membrane. The presence of human serum reduced but did not eliminate its activity. We tested the in vivo activity of novispirin G10 in rats with an infected, partial-thickness burn that covered 20% of their total body surface area. The burned area was seeded with 10(6) CFU of a Silvadene-resistant P. aeruginosa strain, and 24 h later a single treatment with 0, 1, 3, or 6 mg of synthetic novispirin G10 (n = 16 at each concentration) per kg was given intradermally. Significant bacterial killing (P < 0.0001) was evident within 4 h in each peptide group compared to controls receiving vehicle. Antimicrobial peptides such as novispirin G10 may provide a useful alternative or adjunct to standard antibiotic agents in treating burns or other wound infections.
Amino Acid Sequence↗
Activation of human and mouse Kupffer cells by lipopolysaccharide is mediated by CD14.
Upregulation of CD14 in Kupffer cells has been implicated in the pathogenesis of several forms of liver injury, including alcoholic liver disease. However, it remains unclear whether CD14 mediates lipopolysaccharide (LPS) signaling in this specialized liver macrophage population. In this series of experiments, we determined the role of CD14 in LPS activation of Kupffer cells by using several complementary approaches. First, we isolated Kupffer cells from human livers and studied the effects of anti-CD14 antibodies on LPS activation of these cells. Kupffer cells were incubated with increasing concentrations of LPS in the presence and absence of recombinant human LPS binding protein (LBP). With increasing concentrations of LPS, human Kupffer cell tumor necrosis factor-alpha (TNF-alpha) production (a marker for Kupffer cell activation) increased in a dose-dependent manner in the presence and absence of LBP. In the presence of anti-human CD14 antibodies, the production of TNF-alpha was significantly diminished. Second, we compared LPS activation of Kupffer cells isolated from wild-type and CD14 knockout mice. Kupffer cells from CD14 knockout mice produced significantly less TNF-alpha in response to the same amount of LPS. Together, these data strongly support a critical role for CD14 in Kupffer cell responses to LPS.
Acute-Phase Proteins↗
Lipopolysaccharides in liver injury: molecular mechanisms of Kupffer cell activation.
Endogenous gut-derived bacterial lipopolysaccharides have been implicated as important cofactors in the pathogenesis of liver injury. However, the molecular mechanisms by which lipopolysaccharides exert their effect are not entirely clear. Recent studies have pointed to proinflammatory cytokines such as tumor necrosis factor-alpha as mediators of hepatocyte injury. Within the liver, Kupffer cells are major sources of proinflammatory cytokines that are produced in response to lipopolysaccharides. This review will focus on three important molecular components of the pathway by which lipopolysaccharides activate Kupffer cells: CD14, Toll-like receptor 4, and lipopolysaccharide binding protein. Within the liver, lipopolysaccharides bind to lipopolysaccharide binding protein, which then facilitates its transfer to membrane CD14 on the surface of Kupffer cells. Signaling of lipopolysaccharide through CD14 is mediated by the downstream receptor Toll-like receptor 4 and results in activation of Kupffer cells. The role played by these molecules in liver injury will be examined.
Acute-Phase Proteins↗
Pathogenesis of alcoholic liver disease--recent advances.
The article summarizes the proceedings of a symposium on recent advances in research on the pathogenesis of alcoholic liver disease at the 2001 RSA meeting in Montreal, Canada. The chairs were Amin A. Nanji and Samuel W. French. The presentations were (1) Role of inflammatory mediators in alcoholic liver injury by Amin A. Nanji, (2) Role of endotoxin, lipopolysaccharide binding protein, CD14 and Toll receptors in alcoholic liver injury by Grace Su, (3) Fatty acid ethyl esters: toxicity, metabolism and markers of ethanol intake by Michael Laposata, and (4) Cyclic changes in gene expression when rats are fed alcohol at a constant rate by Samuel W. French.
Acyltransferases↗