Interaction of CD44 and hyaluronan is the dominant mechanism for neutrophil sequestration in inflamed liver sinusoids.

Adhesion molecules known to be important for neutrophil recruitment in many other organs are not involved in recruitment of neutrophils into the sinusoids of the liver. The prevailing view is that neutrophils become physically trapped in inflamed liver sinusoids. In this study, we used a biopanning approach to identify hyaluronan (HA) as disproportionately expressed in the liver versus other organs under both basal and inflammatory conditions. Spinning disk intravital microscopy revealed that constitutive HA expression was restricted to liver sinusoids. Blocking CD44-HA interactions reduced neutrophil adhesion in the sinusoids of endotoxemic mice, with no effect on rolling or adhesion in postsinusoidal venules. Neutrophil but not endothelial CD44 was required for adhesion in sinusoids, yet neutrophil CD44 avidity for HA did not increase significantly in endotoxemia. Instead, activation of CD44-HA engagement via qualitative modification of HA was demonstrated by a dramatic induction of serum-derived HA-associated protein in sinusoids in response to lipopolysaccharide (LPS). LPS-induced hepatic injury was significantly reduced by blocking CD44-HA interactions. Administration of anti-CD44 antibody 4 hours after LPS rapidly detached adherent neutrophils in sinusoids and improved sinusoidal perfusion in endotoxemic mice, revealing CD44 as a potential therapeutic target in systemic inflammatory responses involving the liver.

A novel mechanism of erythrocyte capture from circulation in humans.

OBJECTIVE: The capture of blood cells from the circulation is mediated by highly specialized adhesion molecules. These molecules contribute to the specificity of recruitment for various subsets. Here, we used a simple substrate of hyaluronic acid to investigate the specificity of CD44-mediated recruitment from human whole blood under shear conditions. MATERIALS AND METHODS: Human whole blood was perfused through a parallel-plate flow chamber, which mimics intravascular conditions. Microscopy was used to directly observe blood-cell interactions with adhesion molecule substrates. RESULTS: Erythrocytes, but not leukocytes, efficiently tethered to and rolled on the hyaluronic acid substrate. These interactions were demonstrated to be mediated by CD44 and regulated by the sialic acid content of the cells. Inflammatory stimuli did not result in enhanced erythrocyte rolling. Rather, interactions were restricted to aged erythrocytes approaching senescence. This mechanism of erythrocyte capture from the blood flow was found to be restricted to primates and not conserved across mammalian species. CONCLUSION: This is the first report of erythrocyte tethering and rolling under shear conditions, a behavior, until now, thought to be exclusive to leukocytes. It may represent an important mechanism to identify, capture, and clear old erythrocytes during normal homeostasis or clot formation.

Simple clinical tests may predict severe oropharyngeal dysphagia in Parkinson's disease.

OBJECTIVE: To determine if simple screening tests can predict severe oropharyngeal dysphagia in subjects with Parkinson's disease. METHODOLOGY: Forty-five subjects (26 females) of average age 75 (range: 65-94) who were classified as Modified Hoehn and Yahr stages 2 to 5 were enrolled. The presence of oropharyngeal dysphagia was assessed by a symptom questionnaire, 50 ml water swallowing test and videofluroscopic swallowing study. RESULTS: Six of the subjects had severe oropharyngeal dysphagia in videofluroscopic swallowing study. Subsequent multivariate analysis showed that 3 factors could independently predict severe oropharyngeal dysphagia. These included higher Modified Hoehn and Yahr stage (P = 0.042), low Body mass index (P = 0.014), and increased difficulty in keeping food or drink in the mouth (P = 0.047). The regression model had a positive predictive power of 96% (sensitivity: 83.3%, specificity: 97.4%). CONCLUSION: A combination of 3 simple clinical parameters may be useful for screening for severe oropharyngeal dysphagia as shown radiologically in subjects with Parkinson's disease.