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Neutrophils released from the bone marrow by granulocyte colony-stimulating factor sequester in lung microvessels but
S F van Eeden1, E Lawrence, Y Sato
1University of British Columbia, Pulmonary Research Laboratory, St Paul's Hospital, Vancouver, Canada.
Abstract:
Inflammatory mediators such as granulocyte colony-stimulating factor (G-CSF) release polymorphonuclear leukocytes (PMNL) from the bone marrow. This growth factor is used to promote the host response to infection but its effect on the behaviour of leukocytes at the inflammatory site is unclear. This study examined the sequestration and migration of PMNL released from the bone marrow by G-CSF in a model of streptococcal pneumonia. Eight hours following the administration of either human G-CSF (n=6) or saline (n=3) in rabbits, a focal Streptococcus pneumoniae pneumonia was induced and the animals were followed for 2 h. The thymidine analogue 5'-bromo-2'-deoxyuridine (BrdU) was used to label PMNL (PMNL(BrdU)) in the marrow and as a marker of PMNL newly released by the bone marrow. The PMNL(BrdU) in the lung and blood were identified using immunohistochemistry. G-CSF pretreatment elevated the circulating PMNL (3.6+/-0.4 (mean+/-SEM) to 8.3+/-1X10(9) x L(-1), p<0.05) and PMNL(BrdU) (5.4+/-2.1 to 12.5+/-3.1%, p<0.05) counts at 8 h with little further increase caused by the subsequent 2 h pneumonia. These counts did not change in the control group. Morphometric studies of the lung showed that the total number of PMNL sequestered in lung capillaries were increased in the G-CSF group and the percentage of the these PMNL that were BrdU-labelled, was higher than in circulating blood (p<0.05). In the G-CSF group, only 11.2+/-2.6% of the PMNL that migrated into the airspaces were PMNL(BrdU) compared to 50.8+/-8% PMNL(BrdU) in the pulmonary capillaries. In vitro studies showed PMNL(BrdU) released from the bone marrow by G-CSF are less deformable than unlabelled circulating PMNL (p<0.01). It is concluded that granulocyte colony-stimulating factor treatment causes the marrow to release polymorphonuclear leukocytes that preferentially sequester in lung microvessels but are slow to migrate out of the vascular space into the airspace at the pneumonic site.
Insights
Granulocyte colony-stimulating factor (G-CSF) releases new polymorphonuclear leukocytes (PMNL) from bone marrow. These G-CSF-released PMNL preferentially accumulate in lung capillaries but migrate slowly into airspaces during pneumonia.
Area of Science:
- Immunology
- Pulmonary Medicine
- Hematology
Background:
- Granulocyte colony-stimulating factor (G-CSF) is used to enhance host defense against infection.
- The precise behavior of G-CSF-released leukocytes at inflammatory sites remains unclear.
- Understanding leukocyte dynamics is crucial for optimizing infection response strategies.
Purpose of the Study:
- To investigate the sequestration and migration patterns of G-CSF-released polymorphonuclear leukocytes (PMNL) in a rabbit model of Streptococcus pneumoniae pneumonia.
- To determine if G-CSF-primed PMNL exhibit altered behavior in the pulmonary vasculature and airspaces.
- To evaluate the deformability of G-CSF-released PMNL.
Main Methods:
- Rabbits were pretreated with human G-CSF or saline.
- Focal Streptococcus pneumoniae pneumonia was induced.
- The thymidine analogue 5'-bromo-2'-deoxyuridine (BrdU) was used to label newly released PMNL from the bone marrow.
- PMNL and PMNL(BrdU) counts in blood and lung were quantified using immunohistochemistry.
- Morphometric analysis of lung capillaries and airspaces was performed.
- In vitro studies assessed PMNL deformability.
Main Results:
- G-CSF pretreatment significantly increased circulating PMNL and BrdU-labeled PMNL (PMNL(BrdU)) counts.
- G-CSF treatment led to increased sequestration of PMNL in lung capillaries, with a higher proportion of PMNL(BrdU) compared to circulating blood.
- PMNL(BrdU) constituted a significantly lower percentage of PMNL that migrated into airspaces compared to those in pulmonary capillaries.
- G-CSF-released PMNL were found to be less deformable than unlabelled circulating PMNL.
Conclusions:
- G-CSF treatment mobilizes PMNL from the bone marrow that preferentially sequester in lung microvessels.
- These G-CSF-mobilized PMNL exhibit impaired migration from the vascular space into the airspaces at the site of pneumonia.
- The reduced deformability of G-CSF-released PMNL may contribute to their preferential sequestration in lung capillaries.