Empty Liposomes (E-Lipo) Reduce Inflammatory Lung Injury (ILI) and Boost PMN Fungal Clearance in a Corticosteroid-Immunosuppressed Murine Model of Acute Invasive Pulmonary Aspergillosis (IPA).

R. E. LEWIS1, G. CHAMILOS 2, R. A. PRINCE 1, D. P. KONTOYIANNIS 2;

Author address: 

1Univ. of Houston Coll. of Pharmacy, Houston, TX, 2The Univ. of Texas M.D. Anderson Cancer Ctr., Houston, TX.

Abstract: 

Background: L-AMB enhances PMN antifungal activity and attenuates pro-inflammatory effects in a TLR-dependent mechanism. We compared the activity of E-Lipo versus L-AMB to attenuate ILI and reduce fungal burden in a non-neutropenic murine model of IPA. Methods: Balb-C mice were immunosuppressed with cortisone and infected intranasally with A. fumigatus 293. Saline (controls), L-AMB or E-Lipo (both 10 mg/kg/day, IV) was then administered daily for 8d beginning 4d prior to infection. Peripheral PMNs were then collected for analysis of CD11b or CD49d+ populations (flow cytometry), TLR expression (multiplex rt-PCR), and hyphal killing (XTT assay). Lungs were harvested for analysis of fungal burden (real-time PCR) and tissue damage (histopathology). Finally, survival was compared following pre-treatment with either E-Lipo or L-AMB in both corticosteroid and neutropenic (cyclophosphamide-treated) mice with IPA. Results: L-AMB treatment increased TLR4 and TLR7 expression, reduced peripheral CD49d+ PMNs (21.3% vs. 62%), and increased PMN hyphal killing vs. controls (24 +/- 4% vs. 4 +/- 2%). Relative to L-AMB, E-Lipo treatment was associated with increased TLR7, comparably low CD49d+ PMNs(17.8% vs. 21.3%), similar hyphal killing (28 +/- 5%), and similar lung fungal burden clearance at 72 hr (3.46 log vs. 4.06 CE, P=0.70). Focal PMN infiltrates surrounding damaged hyphae (E-Lipo) or damaged conidia (L-AMB) was observed by histopathology. E-Lipo effectively prolonged survival in the steroid-treated, but not the neutropenic model, of IPA (120 hr survival; 90% vs. 0%, P
2006

abstract No: 

M-1686

Full conference title: 

46th Interscience Conference on Antimicrobial Agents and Chemotherapy
    • ICAAC 46th