Nostratola D. Vaziri

Leukocyte Toll-Like Receptor Expression in End-Stage Kidney Disease

Background: End-stage renal disease (ESRD) is simultaneously associated with inflammation, impaired immunity and increased susceptibility to microbial infections. Innate immune cells, monocytes and polymorphonuclear leukocytes (PMN) recognize pathogens via toll-like receptors (TLR) triggering phagocytosis, cellular activation and secretion of inflammatory cytokines. Data on expression and function of TLRs in ESRD are limited. Methods: Blood samples from 21 stable ESRD patients and 21 normal controls were processed for TLR2, TLR4, TLR7 and TLR 9 expression on monocytes and PMN by flow cytometry. TLR activity was examined by determining the response to TLR4 and TLR2 ligands. Results: The ESRD group exhibited significant upregulation of TLR2 and TLR4 (but not TLR7 or TLR 9) expressions on monocytes and of TLR4 on PMN. This was coupled with heightened cytokine production in response to TLR4 activation with lipopolysaccharide. However, the response to TLR2 stimulation with peptidoglycan was unchanged in the ESRD group. Conclusions: Monocyte TLR2 and TLR4 and neutrophil TLR4 expressions and TLR4 activity are increased hemodialysis patients, representing another dimension of ESRD-associated inflammation.

Effects of Chronic Spinal Cord Injury and Pressure Ulcer on 25(OH)-Vitamin D Levels

We studied 92 spinal cord injured (SCI) men (50 paraplegics and 42 quadriplegics) with normal renal function, 38 of whom had single or multiple pressure ulcers. The results were compared with those of 28 able-bodied normal controls. Serum concentrations of calcium and magnesium were measured by atomic absorption spectrometry, and 25(OH)-vitamin D was quantitated by a specific competitive binding assay using a sensitive vitamin D binding protein and tritiated 25(OH)-vitamin D. The SCI group exhibited significant reductions in serum 25(OH)-vitamin D and total calcium concentrations as compared to the normal control group. Although the mean serum concentration of 25(OH)-vitamin D in the quadriplegic patients as a whole was lower than that found in the entire paraplegic group, the difference did not attain statistical significance. Similar observations were made when the ulcer-free subgroups of paraplegics and quadriplegics were compared. The SCI subgroup which was least physically active, i.e., those with pressure ulcers, showed the greatest depression of serum 25(OH)-vitamin D, calcium, and magnesium concentrations. The observed reduction in serum 25(OH)-vitamin D in SCI patients appears to be partly related to reduced cutaneous vitamin D biosynthesis from sunlight deprivation occasioned by physical disability and hospitalization. In addition, nutritional deficiency and altered intestinal transport may be involved. The reduction in serum calcium concentration may be related to abnormal vitamin D metabolism and hypoalbuminemia (reduced protein-bound calcium).

Dimethyl fumarate ameliorates acute pancreatitis in rodent.

Objectives Pancreatitis is a complex inflammatory disorder, ranging from a mild attack, to severe and potentially fatal condition. Dimethyl fumarate (DMF), a potent antioxidant and anti-inflammatory, has been used medicinally for decades. The purpose of this study was to test the hypothesis that treatment with DMF may ameliorate acute pancreatitis (AP) in a rodent model. Methods Rats were treated with DMF (25 mg/kg) 24 hours prior to AP induction with l-arginine (3 g/kg). At 72 hours, the pancreas was processed for histology. Serum amylase, lactate dehydrogenase, pancreatic trypsin, and lipid peroxidation product (malondialdehyde) were evaluated. Key cytokines and chemokines in the supernatant of lipopolysaccharide-stimulated splenocytes were also determined. Results Pancreata from DMF-treated rats showed reductions in the severity of inflammatory cell infiltration, acinar damage, perilobar edema, and cell necrosis. This was associated with significantly lower amylase and malondialdehyde but not lactate dehydrogenase or trypsin levels. The apoptotic pancreatic cells (cleaved caspase 3 positive) were significantly lower in the DMF-treated rats. Lipopolysaccharide-stimulated splenocytes treated with DMF produced a significantly lower amount of key inflammatory mediators. Conclusion Administration of DMF attenuates AP in rats.

Salutary effect of pre-treatment with an Nrf2 inducer on ischemia reperfusion injury in the rat liver.

BACKGROUND Ischemia-reperfusion injury (IRI) is a common phenomenon occurring during liver surgery, transplantation, and trauma. IRI causes oxidative stress which plays a critical role in causing organ damage. The Nrf2 is the master regulator of numerous genes, encoding antioxidant, detoxifying, and cytoprotective molecules. Nrf2 dysfunction has been implicated in the pathogenesis of several inflammatory disorders, cancer, and aging. This study was undertaken to investigate the effect of Nrf2 pathway activator (dh404) on warm liver IRI in a rodent model. METHODS Ten Sprague-Dawley rats were treated with dh404 or vehicle. Dh404 was dissolved in sesame oil and was given orally (1.5mg/kg) the night before and 5 hours before procedures. Rat livers were subjected to 60 minutes of 70% ischemia followed by 3 hours of reperfusion. Serum ALT and Malondialdehyde (MDA) were determined and liver tissue was processed for histological examination, and determination of apoptosis, myeloperoxidase (MPO) activity, ADP/ATP ratio, and expressions of Nrf2, eNOS, anti-oxidant enzymes, and inflammatory mediators. RESULTS Serum ALT and MDA levels and tissue MPO activity were significantly lower, expression of the anti-oxidant enzyme, glutamate cysteine ligase were significantly higher, whereas expression of NFkB and COX-2 was unchanged in the dh404-treated group. Although the total Suzuki histology score did not differ significantly, the extent of sinusoidal congestion, vacuolization, and apoptosis was significantly reduced in the dh404 treated compared to the untreated group (P<0.01). CONCLUSIONS Pre-treatment with dh404 resulted in partial attenuation of hepatic ischemia reperfusion injury in rats.

Coagulation profile in persons with long-standing spinal cord injury.

Acute spinal cord injury (SCI) is associated with a marked propensity to thromboembolism and a variety of coagulation abnormalities. However, data on blood coagulation profiles in patients with uncomplicated long-standing SCI are limited. These data were studied here. Eight men with uncomplicated chronic SCI and nine able-bodied normal men were studied. Plasma activities and/or antigen concentrations of high molecular weight kininogen (HMWK) and of factors XII, XI, IX, VIII, VII, X, V, II and XIII as well as von Willebrand factor (vWF), fibrinogen and fibronectin were measured by appropriate functional and or immunological assays. The SCI group exhibited normal values for factors XII, IX, VIII, vWF, VII, X and V as well as HMWK, vWF and fibronectin concentration. However, they showed slight reductions in plasma factor XI activity, factor XIII antigen concentration and modest increases in fibrinogen and factor II concentrations. No correlation was found between the parameters studied and either the duration or the level of injury. In conclusion, in contrast to acute SCI, the coagulation profile in uncomplicated chronic SCI is noted to be largely normal with only a few minor alterations of questionable clinical significance.