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Pulmonary intravascular macrophages and hemodynamic effects of liposomes in sheep
K Miyamoto1, E Schultz, T Heath
1Department of Physiology, University of California, San Francisco 94143-0130.
Abstract:
We studied the effects of liposomes on the pulmonary circulation of sheep and found a close correlation between liposome retention in the lung and the intravascular macrophages. A test dose of liposomes (5.5 mumol of total lipids) injected intravenously transiently increased pulmonary arterial pressure from 24 +/- 2 to 55 +/- 16 (SD) cmH2O. The pulmonary arterial pressure responses were dose dependent and reproducible. The rise in pulmonary arterial pressure was blocked completely by indomethacin and 75% by a thromboxane synthase inhibitor. Systemic arterial thromboxane B2 concentration increased from a base-line level of less than 50 pg/ml to 250 +/- 130 pg/ml at the peak of the pressor response. Larger doses of liposomes (220 mumol of total lipids) infused intravenously over 1 h increased pulmonary arterial pressure maximally within the first 15 min. Lymph flow increased and lymph protein concentration decreased, suggesting venoconstriction. Over half (62.4 +/- 15.7%) of 111In-labeled liposomes remained in the lung after 2 h. Fluorescence and transmission electron microscopy showed that greater than 90% of the liposomes were associated with mononuclear cells in the lumen of the alveolar wall microvessels. We conclude that liposomes affect pulmonary arterial pressure transiently by a mechanism involving the arachidonate cascade, principally thromboxane. Our observations suggest that a population of pulmonary intravascular macrophages is likely to be the source of the thromboxane and the pulmonary hemodynamic and lymph dynamic changes that occur in a dose-dependent fashion, although interactions between liposomes, leukocytes, or endothelial cells, in addition to the macrophages, have not been completely ruled out. We believe this is the first demonstration that pulmonary intravascular macrophages may be the source of the arachidonate metabolites rather than endothelial cells, neutrophils, or perivascular interstitial cells.
Insights
Liposomes transiently increase sheep pulmonary arterial pressure via thromboxane, released by lung intravascular macrophages. This study identifies these macrophages as the primary source of arachidonate metabolites affecting pulmonary circulation.
Area of Science:
- Pulmonary circulation research
- Liposome-macrophage interactions
- Pharmacology of arachidonate cascade
Background:
- Liposomes are widely used drug delivery vehicles.
- Their effects on pulmonary hemodynamics are not fully understood.
- Pulmonary intravascular macrophages (PIMs) are key immune cells in the lung.
Purpose of the Study:
- To investigate the impact of liposomes on pulmonary circulation in sheep.
- To identify the cellular source of thromboxane (TX) and hemodynamic changes induced by liposomes.
- To elucidate the role of PIMs in liposome-induced pulmonary responses.
Main Methods:
- Intravenous administration of varying doses of liposomes to sheep.
- Measurement of pulmonary arterial pressure, systemic arterial thromboxane B2 levels, and lymph dynamics.
- Pharmacological blockade using indomethacin and a thromboxane synthase inhibitor.
- In vivo tracking of 111In-labeled liposomes and ex vivo microscopic analysis (fluorescence and transmission electron microscopy).
Main Results:
- Liposome injection caused a dose-dependent, transient increase in pulmonary arterial pressure.
- This pressor response was significantly inhibited by indomethacin and a thromboxane synthase inhibitor.
- Elevated systemic arterial thromboxane B2 levels correlated with the pressor response.
- Over 60% of liposomes were retained in the lung, primarily associated with mononuclear cells in microvessels.
- Increased lymph flow and decreased lymph protein concentration indicated venoconstriction.
Conclusions:
- Liposomes transiently affect pulmonary arterial pressure through the arachidonate cascade, mainly via thromboxane.
- Pulmonary intravascular macrophages are identified as the likely source of thromboxane and the observed hemodynamic and lymph dynamic changes.
- This study provides the first evidence implicating PIMs, rather than endothelial cells or neutrophils, as the source of arachidonate metabolites in this context.