Role of interleukin-1 and tumour necrosis factor in leukocyte recruitment to acute dermal inflammation

The cytokines IL-1 and TNF-α are involved in inflammation and their production is stimulated by various agents, especially endotoxin (LPS). Here, using the human IL-1 receptor antagonist (IL-1RA) and a new monoclonal antibody (mAb 7F11) to rabbit TNF, the role of endogenous IL-l and TNF production in acute (3h) leukocyte (PMNL) recruitment to dermal inflammation in rabbits has been studied. IL-1RA inhibited by 27% the PMNL accumulation in reactions induced by killed Escherichia coli (p < 0.05) but not by LPS. The monoclonal antibody to TNF inhibited by 27% and 38% (p < 0.002) the PMNL accumulation in LPS and E. coli reactions respectively, but a combination of the mAb with IL-1RA was not more effective. Treatment of human umbilical vein endothelium with LPS for 3 h activated endothelium to induce PMNL transendothelial migration in vitro, which was not inhibited by IL-1RA, antibody to TNF-α, IL-1 or to IL-8. In conclusion, TNF and IL-1 may partially mediate acute PMNL infiltration in vivo to LPS and Gram negative bacteria, but there is a major IL-1/TNF independent mechanism, at least in dermal inflammation, which may be due to direct LPS activation of the microvasculature or perhaps the generation of cytokines other than IL-1 and TNF

Metabolic effects of exercise in patients with type IV hyperlipoproteinemia

Metabolic responses to 30 minutes of submaximal exercise were investigated in 11 healthy control subjects and 6 patients with type IV hyperlipoproteinemia (endogenous or essential hypertriglyceridemia). All subjects were male and ranged in age from 35 to 55 years. Before exercise they fasted overnight for at least 12 hours.The relative work performed, judged by the levels in heart rate and cardiac output on exercise, was comparable in the two groups, and the effects of exercise were qualitatively similar. Plasma glucose and triglyceride levels showed little change. Plasma concentration of cholesterol increased at the end of exercise by approximately 13 percent above control values compared to a concomitant increase in hematocrit of 3 percent. Plasma free fatty acid levels fell as exercise started and then returned to normal valves at the end of the 30 minutes of exercise; they then increased markedly after exercise but returned subsequently to control levels after 45 minutes.In response to muscular exercise, therefore, both control subjects and patients with type IV hyperlipoproteinemia significantly increase plasma cholesterol concentration. Subjects with hyperlipoproteinemia appear to mobilize free fatty acids in a normal manner for energy purposes, and the excess release of free fatty acids during exercise is apparently not derived from the abundantly circulating triglycerides; the latter were not altered by submaximal exercise.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32754/1/0000123.pd

β1 Integrins Are Critically Involved in Neutrophil Locomotion in Extravascular Tissue In Vivo

Recruitment of leukocytes from blood to tissue in inflammation requires the function of specific cell surface adhesion molecules. The objective of this study was to identify adhesion molecules that are involved in polymorphonuclear leukocyte (PMN) locomotion in extravascular tissue in vivo. Extravasation and interstitial tissue migration of PMNs was induced in the rat mesentery by chemotactic stimulation with platelet-activating factor (PAF; 10−7 M). Intravital time-lapse videomicroscopy was used to analyze migration velocity of the activated PMNs, and the modulatory influence on locomotion of locally administered antibodies or peptides recognizing various integrin molecules was examined. Immunofluorescence flow cytometry revealed increased expression of α4, β1, and β2 integrins on extravasated PMNs compared with blood PMNs. Median migration velocity in response to PAF stimulation was 15.5 ± 4.5 μm/min (mean ± SD). Marked reduction (67 ± 7%) in motility was observed after treatment with mAb blocking β1 integrin function (VLA integrins), whereas there was little, although significant, reduction (22 ± 13%) with β2 integrin mAb. Antibodies or integrin-binding peptides recognizing α4β1, α5β1, or αvβ3 were ineffective in modulating migration velocity

Angiotensin II Induces Leukocyte–Endothelial Cell Interactions In Vivo Via AT1 and AT2 Receptor–Mediated P-Selectin Upregulation

Background—Angiotensin II (Ang II) plays a critical role in the development of vascular lesions in hypertension, atherosclerosis, and several renal diseases. Because Ang II may contribute to the leukocyte recruitment associated with these pathological states, the aim of the present study was to assess the role of Ang II in leukocyte–endothelial cell interactions in vivo. Methods and Results—Intravital microscopy of the rat mesenteric postcapillary venules was used. Sixty minutes of superfusion with 1 nmol/L Ang II induced a significant increase in leukocyte rolling flux (83.8±20.7 versus 16.4±3.1 cells/min), adhesion (11.4±1.0 versus 0.8±0.5 cells/100 µm), and emigration (4.0±0.7 versus 0.2±0.2 cells/field) without any vasoconstrictor activity. These effects were not mediated by mast cell activation. Intravenous pretreatment with AT1 (losartan) or AT2 (PD123,319) receptor antagonists significantly reduced Ang II–induced responses. A combination of both receptor antagonists inhibited the leukocyte rolling flux, adhesion, and extravasation elicited by Ang II at 60 minutes. Pretreatment of animals with fucoidin or an adhesion-blocking anti–rat P-selectin monoclonal antibody abolished Ang II–induced leukocyte responses. Furthermore, rat platelet P-selectin expression was not affected by Ang II stimulation. Conclusions—Ang II induces significant leukocyte rolling, adhesion, and emigration, which may contribute not only to hypertension but also to the onset and progression of the vascular damage associated with disease states in which plasma levels of this peptide are elevated.Piqueras Ruiz, Laura, [email protected] ; Alvarez Ribelles, Angeles, [email protected] ; Esplugues Mota, Juan Vicente, [email protected] ; Sanz Ferrando, Maria Jesus, [email protected]

Distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model of CHARGE syndrome

Mutations in the gene encoding the ATP dependent chromatin‐remodeling factor, CHD7 are the major cause of CHARGE (Coloboma, Heart defects, Atresia of the choanae, Retarded growth and development, Genital‐urinary anomalies, and Ear defects) syndrome. Neurodevelopmental defects and a range of neurological signs have been identified in individuals with CHARGE syndrome, including developmental delay, lack of coordination, intellectual disability, and autistic traits. We previously identified cerebellar vermis hypoplasia and abnormal cerebellar foliation in individuals with CHARGE syndrome. Here, we report mild cerebellar hypoplasia and distinct cerebellar foliation anomalies in a Chd7 haploinsufficient mouse model. We describe specific alterations in the precise spatio‐temporal sequence of fissure formation during perinatal cerebellar development responsible for these foliation anomalies. The altered cerebellar foliation pattern in Chd7 haploinsufficient mice show some similarities to those reported in mice with altered Engrailed, Fgf8 or Zic1 gene expression and we propose that mutations or polymorphisms in these genes may modify the cerebellar phenotype in CHARGE syndrome. Our findings in a mouse model of CHARGE syndrome indicate that a careful analysis of cerebellar foliation may be warranted in patients with CHARGE syndrome, particularly in patients with cerebellar hypoplasia and developmental delay