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A J Duffy

Publications and source records attributed to A J Duffy.

5 recordsLinked to original sources
PubMed2000

Inhibition of alveolar neutrophil immigration in endotoxemia is macrophage inflammatory protein 2 independent.

BACKGROUND: Altered transendothelial migration and delayed apoptosis of neutrophils (PMN) have been implicated as contributing to infection in patients with gram-negative sepsis. Macrophage inflammatory protein 2 (MIP-2) signals PMN immigration and may alter other PMN functions. We tested the hypothesis that sequential endotoxin challenge in vivo alters PMN apoptosis and chemotactic responses. MATERIALS AND METHODS: Endotoxemia was induced in male Wistar rats (250 g) via intraperitoneal (IP) administration of LPS (4 mg/kg). After 18 h, intratracheal (IT) injection of LPS (400 microg/kg) was performed. Control animals received saline injections. Four hours after IT-LPS, circulating and bronchoalveolar lavage (BAL) PMN were isolated. PMN yields were calculated, and apoptosis was quantified after 18 h in culture by annexin V-fluorescein isothiocyanate FACS analysis. BAL MIP-2 concentrations were determined by ELISA. PMN chemotaxis to MIP-2 and IL-8 was determined using a fluorescent in vitro migration assay. RESULTS: Endotoxemia (IP-LPS) significantly decreases BAL PMN yield in response to an in vivo IT-LPS challenge. IT-LPS inhibits BAL PMN apoptosis to the same extent as sequential IP/IT-LPS. Alveolar MIP-2 concentrations are similar in the two groups. In vitro migration to IL-8 and MIP-2 was inhibited in PMN from endotoxemic versus control animals. CONCLUSIONS: These data demonstrate that endotoxemia inhibits PMN migration despite similar MIP-2 concentrations in the alveolus. Sequential insults do not affect the inhibition of apoptosis. In vitro, PMN from endotoxemic animals display impaired chemotaxis to MIP-2 and interleukin-8. This may result in an inadequate host defense that contributes to increased ICU-acquired pneumonia in septic patients.

Animals↗
PubMed1999

Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats.

Adenosine levels present in the interstitial fluid and coronary effluent of the aged heart exceed those of the young adult heart. The present study investigated mechanisms in the Fischer 344 rat heart which may be responsible for the observed differences. (1) Total production of adenosine was determined in isolated perfused hearts by measuring coronary effluent adenosine content while inhibiting adenosine deamination and rephosphorylation with erythrohydroxy-nonyladenosine (EHNA) and iodotubercidin (ITC), respectively. Total adenosine production was similar in both young (3-4 month) and aged (20-21 month) hearts at 31.8 +/- 6.6 and 38.4 +/- 3.3 nmol/min/g dry wt, respectively. However, stimulation with the beta-adrenergic agent, isoproterenol, elicited a significantly greater increase in adenosine production in the young vs. aged heart. (2) Adenosine transport was evaluated in isolated perfused hearts by determining 14C uptake by the myocardium after 20 min of 14C-adenosine perfusion. Adenosine uptake in the agent-free heart was found to be decreased 17 to 25% in aged compared to young adult hearts. (3) Adenosine transport characteristics were determined with nitrobenzylthioinosine saturation-binding studies in ventricular membrane preparations. The Bmax values were significantly lower in aged than young adult hearts (140.2 +/- 1.5 fmol/mg and 191.9 +/- 2.3 fmol/mg in aged and young hearts, respectively) indicating a decreased number of transporter sites in the aged heart. However, the values for Kd were decreased with aging, suggesting an increase in the affinity of the transporter for adenosine in the aged vs. young adult heart. (4) The activities and kinetics of adenosine kinase were determined in homogenates of aged and young adult ventricular myocardium. No statistical difference was found between the two activities. Taken together these results suggest that increased interstitial adenosine levels in the aged heart result from decreased uptake of adenosine by the ventricular myocardium.

Adenosine↗
PubMedDate not supplied

Sodium salicylate inhibits proliferation and induces G1 cell cycle arrest in human pancreatic cancer cell lines.

The mutations most common in pancreatic cancer decrease the ability to control G1 to S cell cycle progression and cellular proliferation. In colorectal cancer cells, nonsteroidal anti-inflammatory drugs inhibit proliferation and induce cell cycle arrest. We examined whether sodium salicylate, an aspirin metabolite, could inhibit proliferation in human pancreatic cancer cell lines (BxPC3 and Panc-1). Quiescent cells were treated with medium containing 10% fetal calf serum, with or without salicylate. Cellular proliferation was measured by MTT assay and bromodeoxyuridine incorporation. The fractions of cells in G0/G1, S, and G2/M phases of the cell cycle were quantitated by fluorescence-activated cell sorting. Results were compared between groups by two-tailed t test. Cyclin D1 expression was determined by Western blot analysis and prostaglandin E2 expression by enzyme-linked immunosorbent assay. Serum-starved cells failed to proliferate, with most arrested in the G1 phase. Salicylate significantly inhibited serum-induced progression from G1 to S phase, cellular proliferation, and the expression of cyclin D1. The concentrations at which 50% of serum-induced proliferation was inhibited were 1.2 mmol/L (Panc-1) and 1.7 mmol/L (BxPC3). The antiproliferative effect of sodium salicylate was not explained by inhibition of prostaglandin E2 production. This study provides further evidence in a noncolorectal cancer model for the antineoplastic effects of nonsteroidal anti-inflammatory drugs.

Adenocarcinoma↗