BACKGROUND: Neutrophil adhesion is initiated by the interaction of rapidly expressed endothelial selectins with oligosaccharide structures (sialyl Lewis(x) on polymorphonuclear neutrophils (PMN). The carbohydrate sialyl Lewis X analogue CY-1503 blocks selectin receptors, thereby inhibiting PMN rolling and subsequent firm adhesion and migration. METHODS: We evaluated the inhibitory effect of CY-1503 on PMN migration and reperfusion injury in canine left lung allografts. Donor lungs were flushed with modified Euro-Collins solution (1500 ml, 4 degrees C) and preserved for 21 hours at 1 degree C. Left lung allotransplantation was subsequently performed in 14 mongrel dogs. Immediately after transplantation and allograft reperfusion, the recipient contralateral right pulmonary artery and bronchus were ligated to permit assessment of isolated allograft function during a 6-hour postreperfusion period (FIO2 = 1.0). Allograft gas exchange (q 15 minutes) and hemodynamics (q 60 minutes) were assessed. After sacrifice, allograft bronchoalveolar lavage fluid (BALF) PMN count and allograft tissue myeloperoxidase (MPO) activity were measured. Two groups were studied: In group I (n = 7) CY-1503 was added to the donor lung flush (20 mg/L) and given to the recipient (35 mg/kg intravenous bolus) before reperfusion, followed by a continuous infusion (5.25 mg/kg/h intravenously) during the 6-hour assessment period. Group II animals (n = 7) received no CY-1503. RESULTS: Gas exchange in group I was superior throughout the assessment period (p < 0.01 at 6 hours after reperfusion). BALF PMN count in group I was reduced to 0.57 +/- 0.3 x 10(6) PMN/ml compared with 3.9 +/- 1.3 x 10(6) PMN/ml in group II (p < 0.05). Group I allograft MPO activity was 0.21 +/- 0.06 compared with 0.40 +/- 0.02 delta OD/mg/ min in controls (p < 0.02). Two animals in each group died early after reperfusion as a result of graft failure and were excluded from analysis. CONCLUSIONS: Our observations indicate that selectin inhibition effectively reduces PMN adhesion, migration, and subsequent reperfusion injury in preserved canine lung allografts.

Animals↗

PubMed1996

G-protein and tyrosine kinase receptor cross-talk in rat aortic smooth muscle cells: thrombin- and angiotensin II-induced tyrosine phosphorylation of insulin receptor substrate-1 and insulin-like growth factor 1 receptor.

Insulin-like growth factor I is an autocrine/paracrine factor for vascular smooth muscle cells and is required for angiotensin II- and thrombin-induced mitogenesis. The insulin-like growth factor I-triggered signaling pathway involves autophosphorylation of the beta-subunit of its tyrosine kinase receptor and phosphorylation of insulin receptor substrate-1, the latter providing binding sites for proteins with src homology-2 domains. In rat aortic smooth muscle cells we observed that both angiotensin II and thrombin induced rapid tyrosine phosphorylation of insulin receptor substrate-1. Our results also demonstrated that these mitogens rapidly stimulated phosphorylation of the insulin-like growth factor 1 receptor beta-chain. These data demonstrate a novel interaction between the G-protein coupled angiotensin II and thrombin receptors and the tyrosine-kinase insulin-like growth factor I receptor.

Angiotensin II↗

PubMed1996

Inspiratory muscle endurance in patients with chronic heart failure.

OBJECTIVE: To assess the significance of changes in respiratory muscle endurance in relation to respiratory and limb muscle strength in patients with mild to moderate chronic heart failure using a threshold loading technique. SUBJECTS: 20 patients with chronic heart failure (17 male) aged 63.8 (SD 7.4) years and 10 healthy men aged 63.1 (5.6) years. Heart failure severity was New York Heart Association (NYHA) grade II (n = 11) and NYHA grade III/IV (n = 9). METHODS: Respiratory muscle strength was measured from mouth pressures during maximum inspiratory effort (MIP) at functional residual capacity (FRC) and limb muscle strength was measured using a hand grip dynamometer. Inspiratory muscle endurance was measured using a threshold loading technique. The total endurance duration, the maximum threshold pressure achieved (P-Max), and the inspiratory load (% ratio of P-Max/MIP) were recorded in all subjects. RESULTS: Inspiratory muscles were weaker in patients with heart failure than in the controls [MIP 53.6 (16.5) v 70.9 (20.2) cm H2O, P < 0.05]. Hand grip strength was similar in both subject groups [31.6 (SD) v 36.1 (15.9) dynes]. Total endurance duration was significantly reduced in the patient group [494 (223) v 996 (267) s, P < 0.01], as was the maximal threshold pressure achieved [P-Max 18.5 (6.4) v 30.7 (6.6) cm H2O, P < 0.01]. When expressed as a percentage of MIP, P-Max was also lower in the patients [35.2 (11.8) v 44.8 (11.4)%, P < 0.05]. There was no significant correlation between any measure of endurance and limb muscle strength. CONCLUSIONS: Respiratory muscle endurance is reduced in patients with chronic heart failure. These changes probably reflect a generalised skeletal myopathy and provide further evidence of respiratory muscle dysfunction in patients with this disease. Respiratory muscle endurance needs now to be related to symptoms and the effects of treatment and respiratory muscle training should also be explored.

Chronic Disease↗

PubMed1996