High and Low Molecular Weight Hyaluronic Acid Differentially Regulate Human Fibrocyte Differentiation

Following tissue injury, monocytes can enter the tissue and differentiate into fibroblast-like cells called fibrocytes, but little is known about what regulates this differentiation. Extracellular matrix contains high molecular weight hyaluronic acid (HMWHA; ∼2×10(6) Da). During injury, HMWHA breaks down to low molecular weight hyaluronic acid (LMWHA; ∼0.8-8×10(5) Da).In this report, we show that HMWHA potentiates the differentiation of human monocytes into fibrocytes, while LMWHA inhibits fibrocyte differentiation. Digestion of HMWHA with hyaluronidase produces small hyaluronic acid fragments, and these fragments inhibit fibrocyte differentiation. Monocytes internalize HMWHA and LMWHA equally well, suggesting that the opposing effects on fibrocyte differentiation are not due to differential internalization of HMWHA or LMWHA. Adding HMWHA to PBMC does not appear to affect the levels of the hyaluronic acid receptor CD44, whereas adding LMWHA decreases CD44 levels. The addition of anti-CD44 antibodies potentiates fibrocyte differentiation, suggesting that CD44 mediates at least some of the effect of hyaluronic acid on fibrocyte differentiation. The fibrocyte differentiation-inhibiting factor serum amyloid P (SAP) inhibits HMWHA-induced fibrocyte differentiation and potentiates LMWHA-induced inhibition. Conversely, LMWHA inhibits the ability of HMWHA, interleukin-4 (IL-4), or interleukin-13 (IL-13) to promote fibrocyte differentiation.We hypothesize that hyaluronic acid signals at least in part through CD44 to regulate fibrocyte differentiation, with a dominance hierarchy of SAP>LMWHA≥HMWHA>IL-4 or IL-13

Apnea of prematurity: from cause to treatment

Apnea of prematurity (AOP) is a common problem affecting premature infants, likely secondary to a “physiologic” immaturity of respiratory control that may be exacerbated by neonatal disease. These include altered ventilatory responses to hypoxia, hypercapnia, and altered sleep states, while the roles of gastroesophageal reflux and anemia remain controversial. Standard clinical management of the obstructive subtype of AOP includes prone positioning and continuous positive or nasal intermittent positive pressure ventilation to prevent pharyngeal collapse and alveolar atelectasis, while methylxanthine therapy is a mainstay of treatment of central apnea by stimulating the central nervous system and respiratory muscle function. Other therapies, including kangaroo care, red blood cell transfusions, and CO2 inhalation, require further study. The physiology and pathophysiology behind AOP are discussed, including the laryngeal chemoreflex and sensitivity to inhibitory neurotransmitters, as are the mechanisms by which different therapies may work and the potential long-term neurodevelopmental consequences of AOP and its treatment

Identification of Markers that Distinguish Monocyte-Derived Fibrocytes from Monocytes, Macrophages, and Fibroblasts

The processes that drive fibrotic diseases are complex and include an influx of peripheral blood monocytes that can differentiate into fibroblast-like cells called fibrocytes. Monocytes can also differentiate into other cell types, such as tissue macrophages. The ability to discriminate between monocytes, macrophages, fibrocytes, and fibroblasts in fibrotic lesions could be beneficial in identifying therapies that target either stromal fibroblasts or fibrocytes. and in sections from human lung. We found that markers such as CD34, CD68, and collagen do not effectively discriminate between the four cell types. In addition, IL-4, IL-12, IL-13, IFN-γ, and SAP differentially regulate the expression of CD32, CD163, CD172a, and CD206 on both macrophages and fibrocytes. Finally, CD49c (α3 integrin) expression identifies a subset of fibrocytes, and this subset increases with time in culture.These results suggest that discrimination of monocytes, macrophages, fibrocytes, and fibroblasts in fibrotic lesions is possible, and this may allow for an assessment of fibrocytes in fibrotic diseases

Biophysical parameters during radiofrequency catheter ablation of scar-mediated ventricular tachycardia: Epicardial and endocardial applications via manual and magnetic navigation

Ablation Effectiveness and Biophysical Parameters Background There is a paucity of data on biophysical parameters during radiofrequency ablation of scar-mediated ventricular tachycardia (VT)

Biophysical parameters during radiofrequency catheter ablation of scar-mediated ventricular tachycardia: Epicardial and endocardial applications via manual and magnetic navigation

© 2014 Wiley Periodicals, Inc. Ablation Effectiveness and Biophysical Parameters Background There is a paucity of data on biophysical parameters during radiofrequency ablation of scar-mediated ventricular tachycardia (VT).Methods and Results Data were collected from consecutive patients undergoing VT ablation with open-irrigation. Complete data were available for 372 lesions in 21 patients. The frequency of biophysical parameter changes were: >10Ω reduction (80%), bipolar EGM reduction (69%), while loss of capture was uncommon (32%). Unipolar injury current was seen in 72% of radiofrequency applications. Both EGM reduction and impedance drop were seen in 57% and a change in all 3 parameters was seen in only 20% of lesions. Late potentials were eliminated in 33%, reduced/modified in 56%, and remained after ablation in 11%. Epicardial lesions exhibited an impedance drop (90% vs. 76%, P = 0.002) and loss of capture (46% vs. 27%, P < 0.001) more frequently than endocardial lesions. Lesions delivered manually exhibited a >10Ω impedance drop (83% vs. 71%, P = 0.02) and an EGM reduction (71% vs. 40%, P < 0.001) more frequently than lesions applied using magnetic navigation, although loss of capture, elimination of LPs, and a change in all 3 parameters were similarly observed.Conclusions VT ablation is inefficient as the majority of radiofrequency lesions do not achieve more than one targeted biophysical parameter. Only one-third of RF applications targeted at LPs result in complete elimination. Epicardial ablation within scar may be more effective than endocardial lesions, and lesions applied manually may be more effective than lesions applied using magnetic navigation. New technologies directed at identifying and optimizing ablation effectiveness in scar are clinically warranted