Related Experiment Videos
Intravascular macrophage depletion attenuates endotoxin lung injury in anesthetized sheep
Y Sone1, V B Serikov, N C Staub
1Cardiovascular Research Institute, University of California, San Francisco, California 94143, USA.
Abstract:
We recently showed that we can selectively and safely deplete most (average 85%) of the pulmonary intravascular macrophages in sheep by intravenously infusing liposomes containing dichloromethylene bisphosphonate. After a 1-h stable baseline, we made a 6-h comparison after a 30-min intravenous endotoxin infusion (1 microg/kg) between six anesthetized control lambs and six anesthetized lambs in which the intravascular macrophages had been depleted 24 h previously. Three of the control lambs had been macrophage depleted and allowed to recover their intravascular macrophage population for >/=2 wk. After depletion, both the early and late pulmonary arterial pressure rises were dramatically attenuated. Our main interest, however, was in the acute lung microvascular injury response. The early and late rises in lung lymph flow and the increase in lung lymph protein clearance (lymph flow x lymph-to-plasma protein concentration ratio) were >90% attenuated. We conclude the pulmonary intravascular macrophages are responsible for most of the endotoxin-induced pulmonary hypertension and increased lung microvascular leakiness in sheep, although the unavoidable injury of other intravascular macrophages by the depletion regime may also contribute something.
Insights
Pulmonary intravascular macrophages significantly contribute to endotoxin-induced lung injury in sheep. Depleting these macrophages dramatically reduced pulmonary hypertension and microvascular leakiness.
Area of Science:
- Immunology
- Pulmonary Medicine
- Pharmacology
Background:
- Pulmonary intravascular macrophages (PIMs) play a role in lung inflammation.
- Endotoxin can induce acute lung injury, characterized by pulmonary hypertension and increased vascular permeability.
Purpose of the Study:
- To investigate the role of PIMs in endotoxin-induced lung injury in sheep.
- To determine if PIM depletion attenuates the pulmonary and microvascular responses to endotoxin.
Main Methods:
- Sheep underwent intravenous infusion of liposomes containing dichloromethylene bisphosphonate to deplete PIMs.
- Endotoxin (1 microg/kg) was infused intravenously for 30 minutes.
- Pulmonary arterial pressure, lung lymph flow, and lymph-to-plasma protein clearance were measured in PIM-depleted and control lambs.
Main Results:
- PIM depletion averaged 85% and was safe.
- Both early and late pulmonary arterial pressure rises were significantly attenuated in PIM-depleted lambs.
- Early and late rises in lung lymph flow and lung lymph protein clearance were attenuated by over 90% in PIM-depleted lambs.
Conclusions:
- Pulmonary intravascular macrophages are primarily responsible for endotoxin-induced pulmonary hypertension in sheep.
- PIMs are crucial mediators of endotoxin-induced lung microvascular injury and leakiness.
- While PIM depletion is effective, potential injury to other macrophages should be considered.