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Selectins and neutrophil traffic: margination and Streptococcus pneumoniae-induced emigration in murine lungs
J P Mizgerd1, B B Meek, G J Kutkoski
1Physiology Program, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Abstract:
The roles of selectins in the pulmonary margination and emigration of neutrophils were investigated by using mice genetically deficient in both E- and P-selectins (E/P mutants) and/or by intravenous injections of fucoidin (inhibiting both L- and P-selectins). E/P mutants were neutrophilic (14.7 +/- 4.9 x 10(6) vs. 0.8 +/- 0.1 x 10(6) neutrophils/ml). This neutrophilia was associated with increased margination of neutrophils within pulmonary capillaries (39.7 +/- 9.4 vs. 4.6 +/- 1.1 neutrophil profiles per 100 red blood cell profiles) but no change in margination within noncapillary pulmonary microvessels. After intratracheal instillation of Streptococcus pneumoniae, lungs of E/P mutants displayed increased neutrophil emigration (564 +/- 92 vs. 116 +/- 19 neutrophils per 100 alveolar profiles), edema (5.3 +/- 1.5 vs. 1.5 +/- 0.4 microliter/g body weight), and histologic evidence of lung injury compared with those in wild-type (WT). Fucoidin treatment did not affect neutrophil emigration during streptococcal pneumonia in WT or E/P mice. During pneumonia, the number of white blood cells (WBC) tethered to or spread upon the noncapillary vessel endothelium increased in both WT and E/P lungs. These are the first data demonstrating that neutrophil margination in uninfected pulmonary capillaries does not require E- and P-selectins; that streptococcal pneumonia induces an E- and P-selectin-independent increase in WBC interactions with noncapillary endothelium; and that migration of neutrophils to alveoli can occur despite deficiency or inhibition of all of the known selectins.
Insights
Neutrophil margination in lung capillaries and emigration during pneumonia do not require E- and P-selectins. This study shows neutrophil migration to alveoli can occur even without selectin function.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Selectins mediate leukocyte adhesion and migration.
- Neutrophil recruitment is crucial in lung inflammation and infection.
Purpose of the Study:
- To investigate the roles of E-, P-, and L-selectins in neutrophil margination and emigration in the lungs.
- To determine if neutrophil migration to alveoli can occur independently of selectins.
Main Methods:
- Used mice genetically deficient in E- and P-selectins (E/P mutants).
- Administered intravenous fucoidin to inhibit L- and P-selectins.
- Induced pneumonia via intratracheal Streptococcus pneumoniae instillation.
- Quantified neutrophil margination, emigration, edema, and lung injury.
Main Results:
- E/P mutants exhibited neutrophilia and increased neutrophil margination in pulmonary capillaries.
- Streptococcal pneumonia in E/P mutants led to increased neutrophil emigration, edema, and lung injury.
- Fucoidin treatment did not affect neutrophil emigration in either WT or E/P mice.
- Pneumonia induced E- and P-selectin-independent white blood cell interactions with noncapillary endothelium.
Conclusions:
- Neutrophil margination in uninfected pulmonary capillaries is independent of E- and P-selectins.
- Neutrophil recruitment to alveoli during pneumonia can occur without functional E-, P-, or L-selectins.
- These findings highlight alternative pathways for neutrophil migration in the lungs.