RATIONALE: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. OBJECTIVES: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. METHODS: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2(hi) monocytes. MEASUREMENTS AND MAIN RESULTS: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1(hi) and Gr1(lo) PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. CONCLUSIONS: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.
RATIONALE: Acute lung injury (ALI) is an important cause of morbidity and mortality, with no currently effective pharmacological therapies. Neutrophils have been specifically implicated in the pathogenesis of ALI, and there has been significant research into the mechanisms of early neutrophil recruitment, but those controlling the later phases of neutrophil emigration that characterize disease are poorly understood. OBJECTIVES: To determine the influence of peripheral blood monocytes (PBMs) in established ALI. METHODS: In a murine model of LPS-induced ALI, three separate models of conditional monocyte ablation were used: systemic liposomal clodronate (sLC), inducible depletion using CD11b diphtheria toxin receptor (CD11b DTR) transgenic mice, and antibody-dependent ablation of CCR2(hi) monocytes. MEASUREMENTS AND MAIN RESULTS: PBMs play a critical role in regulating neutrophil emigration in established murine LPS-induced lung injury. Gr1(hi) and Gr1(lo) PBM subpopulations contribute to this process. PBM depletion is associated with a significant reduction in measures of lung injury. The specificity of PBM depletion was demonstrated by replenishment studies in which the effects were reversed by systemic PBM infusion but not by systemic or local pulmonary infusion of mature macrophages or lymphocytes. CONCLUSIONS: These results suggest that PBMs, or the mechanisms by which they influence pulmonary neutrophil emigration, could represent therapeutic targets in established ALI.
Authors: Jean François Cailhier; Deborah A Sawatzky; Tiina Kipari; Kris Houlberg; Dave Walbaum; Simon Watson; Richard A Lang; Spike Clay; David Kluth; John Savill; Jeremy Hughes Journal: Am J Respir Crit Care Med Date: 2005-12-15 Impact factor: 21.405
Authors: Franco R D'Alessio; Kenji Tsushima; Neil R Aggarwal; Erin E West; Matthew H Willett; Martin F Britos; Matthew R Pipeling; Roy G Brower; Rubin M Tuder; John F McDyer; Landon S King Journal: J Clin Invest Date: 2009-09-21 Impact factor: 14.808
Authors: Jörg Reutershan; Margaret A Morris; Tracy L Burcin; David F Smith; Daniel Chang; Mary S Saprito; Klaus Ley Journal: J Clin Invest Date: 2006-02-16 Impact factor: 14.808
Authors: Kieran P O'Dea; Arnold J Young; Hirotoshi Yamamoto; James L Robotham; Fionula M Brennan; Masao Takata Journal: Am J Respir Crit Care Med Date: 2005-08-04 Impact factor: 21.405
Authors: Zhikun Zheng; Stephen Chiu; Mahzad Akbarpour; Haiying Sun; Paul A Reyfman; Kishore R Anekalla; Hiam Abdala-Valencia; Daphne Edgren; Wenjun Li; Daniel Kreisel; Farida V Korobova; Ramiro Fernandez; Alexandra McQuattie-Pimentel; Zheng J Zhang; Harris Perlman; Alexander V Misharin; G R Scott Budinger; Ankit Bharat Journal: Sci Transl Med Date: 2017-06-14 Impact factor: 17.956
Authors: Jing Yao; Di Pan; Yue Zhao; Li Zhao; Jie Sun; Yu Wang; Qi-Dong You; Tao Xi; Qing-Long Guo; Na Lu Journal: Immunology Date: 2014-10 Impact factor: 7.397
Authors: Alexander V Misharin; Luisa Morales-Nebreda; Gökhan M Mutlu; G R Scott Budinger; Harris Perlman Journal: Am J Respir Cell Mol Biol Date: 2013-10 Impact factor: 6.914
Authors: Desiree Anthony; Jonathan L McQualter; Maria Bishara; Ee X Lim; Selcuk Yatmaz; Huei Jiunn Seow; Michelle Hansen; Michelle Thompson; John A Hamilton; Louis B Irving; Bruce D Levy; Ross Vlahos; Gary P Anderson; Steven Bozinovski Journal: FASEB J Date: 2014-05-20 Impact factor: 5.191