The static elastic properties of arterial tree (abdominal aorta and common carotid artery) were studied in 19 normal subjects and in 49 patients with myocardial infarction with an ultrasonic phase-locked echo-tracking system that allows continuous transcutaneous measurement of the arterial diameter. The stifTness index (, which represented the mechanical properties in the arterial wall, was calculated from the relation between systemic blood pressure and the diameter of the artery. Patients with myocardial infarction underwent coronary angiography in their convalescent period to determine involved vessels. In 11 patients, coronary artery was patent; 15 patients had one-vessel disease, 12 had two-vessel disease, and the remaining 11 patients had three-vessel disease. In normal subjects, increasing age was associated with an increase in arterial stiffness. An average value of the stiffiess index of the abdominal aorta was 8.58±3.02 (mean± SD) and that of common carotid artery was 9.17±2.22. In patients with three-vessel disease, these values were significantly higher (22.37± 4.29 in abdominal aorta and 13.17 ±4.56 in common carotid artery) than those in normal subjects. Stiffness index of patients with two-or one-vessel disease was also increased but lower than those in patients with three-vessel disease (p<0.05). Forty-four of 49 patients with infarction had an arterial stiffness index of abdominal aorta higher than the 95% confidence limits of the normal data (p<0.05).Twenty-eight patients were outside the nomogram of common carotid artery (p<0.05). The mechanical properties of these elastic arteries provided sufficiently reliable information on changes caused by atherosclerosis. (Circulation 1989;80:78-86) T he amount of severity of atherosclerosis in the coronary bed shows a positive correlation with the degree of atherosclerosis in the aorta or other major arterial branches.1-5 Atherosclerotic changes in arterial wall have been shown to include smooth muscle cell proliferation, deposition of lipid, and accumulation of collagen, elastin, and proteoglycans.6,7 Changes in the ratio of collagen to elastin have been known to structurally affect the elastic behavior of arterial walls. The former is much stiffer than the latter, the elastic modulus (Young's modulus) being about 1,000x 106 dynes/ cm' at 100% elongation in collagen and only 3 x 106 dynes/cm2 in elastin.8,9 However, conflicting results

The static mechanical properties of major branches of the human arteries (common carotid artery, abdominal aorta, femoral artery, and brachial artery) were studied in 39 subjects, aged 6-81 years, using an ultrasonic phase locked echo tracking system that allows continuous transcutaneous measurement of the diameter of the artery. The stiffness indices were calculated from the relation between systemic blood pressure and arterial diameter. With advancing age there was a significant increase in the diameter of all arteries with a reduction in percentage change in diameter. The stiffness index increased with age in all arteries; however, in the brachial and femoral arteries there was considerable variation in the individual values for a given age. The age associated increase in stiffness was statistically significant only in the common carotid artery and the abdominal aorta. Although the mechanical properties of the peripheral arteries were significantly influenced by the measuring environment, the calculated stiffness indices were less vulnerable to these stimuli in the central arteries. These results indicate that the stiffness indices of the peripheral muscular arteries are modified appreciably by vasoactive stimuli and that the mechanical properties of the deeper elastic arteries provide sufficiently reliable information about changes caused by aging and arteriosclerosis. The new ultrasonic method used appears to be suitable for this analysis.

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Acute respiratory distress syndrome (ARDS) is a severe clinical condition marked by acute respiratory failure and dysregulated inflammation. Pulmonary vascular endothelial cells (PVEC) function as an important pro-inflammatory source in ARDS, suggesting that modulation of inflammatory events at the endothelial level may have therapeutic benefit. Dipeptidyl peptidase-4 (DPP4) inhibitors, widely used for the treatment of diabetes mellitus, have been reported to have possible anti-inflammatory effects. However, the potential anti-inflammatory effects of DPP4 inhibition on PVEC function and ARDS pathophysiology are unknown. Therefore, we evaluated the effects of sitagliptin, a DPP4 inhibitor in wide clinical use, on LPS-induced lung injury in mice and in human lung endothelial cells (EC) in vitro. In vivo, sitagliptin reduced serum DPP4 activity, BAL protein concentration, cell number and pro-inflammatory cytokine levels, after LPS, and alleviated histological findings of lung injury. LPS decreased the expression levels of CD26/DPP4 on pulmonary epithelial cells and PVEC isolated from mouse lungs, and the effect was partially reversed by sitagliptin. In vitro, human lung microvascular EC (HLMVEC) expressed higher levels of CD26/DPP4 than human pulmonary arterial EC. LPS induced release of TNFα, IL-6, and IL-8 by HLMVEC that was inhibited by sitagliptin. LPS promoted proliferation of HLMVEC, and sitagliptin suppressed this response. However, sitagliptin failed to reverse LPS-induced permeability in cultured EC or lung epithelial cells in vitro. In summary, sitagliptin attenuates LPS-induced lung injury in mice and exerts anti-inflammatory effects on HLMVEC. These novel observations indicate DPP4 inhibitors may have potential as therapeutic drugs for ARDS.

No abstract

Vascular disruption is one of the pathological hallmarks in acute respiratory distress syndrome. Bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) and lung tissue-resident EPCs have been considered to play a pivotal role in pulmonary vascular repair; however, which population is predominant in local pulmonary vasculogenesis remains to be clarified. We therefore examined the origin of EPCs participating in the regenerative process of pulmonary vascular endothelial cells (PVECs) in experimental acute respiratory distress syndrome. Lung samples from mice administered LPS intratracheally were investigated for cell dynamics and EPC functions. Quantitative flow cytometric analysis demonstrated that the number of PVECs decreased by roughly 20% on Day 1 and then recovered on Day 7 of LPS challenge. Bromodeoxyuridine-incorporation assays and immunofluorescence microscopy demonstrated that proliferating PVECs preferentially located in the capillary vessels. Experiments using BM chimera mice revealed that most of the regenerating PVECs were tissue-resident cells, and BM-derived cells hardly engrafted as PVECs. The population of circulating putative phenotypical EPCs decreased during the first week after LPS challenge. The regenerating PVECs were characterized by high colony-forming and vasculogenic capacities, intracellular reactive oxygen species scavenging and aldehyde dehydrogenase activites, and enhanced gene expression of Abcb1b (a drug-resistant gene), suggesting that the population of PVECs included tissue-resident EPCs activated during regenerative process of PVECs. The proliferating PVECs expressed CD34, Flk-1/KDR, and c-kit more strongly and Prom1/CD133 less strongly on the surface than nonproliferating PVECs. Our findings indicated that lung tissue-resident EPCs predominantly contribute to pulmonary vascular repair after endotoxin-induced injury.

Recently, we have proposed a new concept for cross-linking agents with inducible reactivity, in which the highly reactive cross-linking agent, the 2-amino-6-vinylpurine nucleoside analogue (1), can be regenerated in situ from its stable precursors, the phenylsulfide (4) and the phenylsulfoxide (3) derivatives, by a hybridization-promoted activation process with selectivity to cytidine. The phenylsulfide precursor (4) exhibited cross-linking ability despite its high stability toward strong nucleophiles such as amines and thiols. In this study, we investigated the substituent effects of the phenylsulfide group on the cross-linking reaction, and determined the 2-carboxy substituent of the phenylsulfide derivative (11k) as an efficient cross-linking agent with inducible reactivity. Detailed investigations have shown that the phenylsulfoxide (3) and phenylsulfide (4) precursors produce the 2-amino-6-vinylpurine nucleoside (1) as the common reactive species. It has been concluded that the nature of the inducible reactivity of the precursors (3 and 4) is acceleration of their elimination to the 2-amino-6-vinylpurine nucleoside (1) through the selective process in the duplex with the ODN having cytidine at the target site.

Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.