Tags

Type your tag names separated by a space and hit enter

Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis.
Arterioscler Thromb Vasc Biol 2018; 38(8):1772-1784AT

Abstract

Objective- Nbeal2-/- mice, a model of human gray platelet syndrome, have reduced neutrophil granularity and impaired host defense against systemic Staphylococcus aureus infection. We here aimed to study the role of Nbeal2 deficiency in both leukocytes and platelets during gram-negative pneumonia and sepsis. Approach and Results- We studied the role of Nbeal2 in platelets and leukocytes during murine pneumonia and sepsis by Klebsiella pneumoniae. Apart from platelet α-granule deficiency and reduced neutrophil granularity, also monocyte granularity was reduced in Nbeal2-/- mice, whereas plasma levels of MPO (myeloperoxidase), elastase, NGAL (neutrophil gelatinase-associated lipocalin), and MMP-9 (matrix metalloproteinase 9), and leukocyte CD11b expression were increased. Nbeal2-/- leukocytes showed unaltered in vitro antibacterial response and phagocytosis capacity against Klebsiella, and unchanged reactive nitrogen species and cytokine production. Also during Klebsiella pneumonia and sepsis, Nbeal2-/- mice had similar bacterial growth in lung and distant body sites, with enhanced leukocyte migration to the bronchoalveolar space. Despite similar infection-induced inflammation, organ damage was increased in Nbeal2-/- mice, which was also seen during endotoxemia. Platelet-specific Nbeal2 deficiency did not influence leukocyte functions, indicating that Nbeal2 directly modifies leukocytes. Transfusion of Nbeal2-/- but not of Nbeal2+/+ platelets into thrombocytopenic mice was associated with bleeding in the lung but similar host defense, pointing at a role for platelet α-granules in maintaining vascular integrity but not host defense during Klebsiella pneumosepsis. Conclusions- These data show that Nbeal2 deficiency-resulting in gray platelet syndrome-affects platelets, neutrophils, and monocytes, with intact host defense but increased organ damage during gram-negative pneumosepsis.

Authors+Show Affiliations

From the Center for Experimental and Molecular Medicine (T.A.M.C., S.F.d.S., A.F.d.V., C.v.V., T.v.d.P.).From the Center for Experimental and Molecular Medicine (T.A.M.C., S.F.d.S., A.F.d.V., C.v.V., T.v.d.P.).From the Center for Experimental and Molecular Medicine (T.A.M.C., S.F.d.S., A.F.d.V., C.v.V., T.v.d.P.).Academic Medical Center, University of Amsterdam, The Netherlands; Electron Microscopy Center Amsterdam, Medical Biology, Academic Medical Center, The Netherlands (A.E.G., N.N.v.d.W.).Academic Medical Center, University of Amsterdam, The Netherlands; Electron Microscopy Center Amsterdam, Medical Biology, Academic Medical Center, The Netherlands (A.E.G., N.N.v.d.W.).Department of Pathology (J.J.T.H.R.).University of Arkansas for Medical Sciences, Little Rock (J.W.).From the Center for Experimental and Molecular Medicine (T.A.M.C., S.F.d.S., A.F.d.V., C.v.V., T.v.d.P.).From the Center for Experimental and Molecular Medicine (T.A.M.C., S.F.d.S., A.F.d.V., C.v.V., T.v.d.P.). Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, The Netherlands (T.v.d.P.).

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29930006

Citation

Claushuis, Theodora A M., et al. "Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 38, no. 8, 2018, pp. 1772-1784.
Claushuis TAM, de Stoppelaar SF, de Vos AF, et al. Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis. Arterioscler Thromb Vasc Biol. 2018;38(8):1772-1784.
Claushuis, T. A. M., de Stoppelaar, S. F., de Vos, A. F., Grootemaat, A. E., van der Wel, N. N., Roelofs, J. J. T. H., ... van der Poll, T. (2018). Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(8), pp. 1772-1784. doi:10.1161/ATVBAHA.118.311332.
Claushuis TAM, et al. Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis. Arterioscler Thromb Vasc Biol. 2018;38(8):1772-1784. PubMed PMID: 29930006.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nbeal2 Deficiency Increases Organ Damage but Does Not Affect Host Defense During Gram-Negative Pneumonia-Derived Sepsis. AU - Claushuis,Theodora A M, AU - de Stoppelaar,Sacha F, AU - de Vos,Alex F, AU - Grootemaat,Anita E, AU - van der Wel,Nicole N, AU - Roelofs,Joris J T H, AU - Ware,Jerry, AU - Van't Veer,Cornelis, AU - van der Poll,Tom, PY - 2018/6/23/pubmed PY - 2019/7/23/medline PY - 2018/6/23/entrez KW - endotoxemia KW - gray platelet syndrome KW - infection KW - neutrophils KW - sepsis SP - 1772 EP - 1784 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 38 IS - 8 N2 - Objective- Nbeal2-/- mice, a model of human gray platelet syndrome, have reduced neutrophil granularity and impaired host defense against systemic Staphylococcus aureus infection. We here aimed to study the role of Nbeal2 deficiency in both leukocytes and platelets during gram-negative pneumonia and sepsis. Approach and Results- We studied the role of Nbeal2 in platelets and leukocytes during murine pneumonia and sepsis by Klebsiella pneumoniae. Apart from platelet α-granule deficiency and reduced neutrophil granularity, also monocyte granularity was reduced in Nbeal2-/- mice, whereas plasma levels of MPO (myeloperoxidase), elastase, NGAL (neutrophil gelatinase-associated lipocalin), and MMP-9 (matrix metalloproteinase 9), and leukocyte CD11b expression were increased. Nbeal2-/- leukocytes showed unaltered in vitro antibacterial response and phagocytosis capacity against Klebsiella, and unchanged reactive nitrogen species and cytokine production. Also during Klebsiella pneumonia and sepsis, Nbeal2-/- mice had similar bacterial growth in lung and distant body sites, with enhanced leukocyte migration to the bronchoalveolar space. Despite similar infection-induced inflammation, organ damage was increased in Nbeal2-/- mice, which was also seen during endotoxemia. Platelet-specific Nbeal2 deficiency did not influence leukocyte functions, indicating that Nbeal2 directly modifies leukocytes. Transfusion of Nbeal2-/- but not of Nbeal2+/+ platelets into thrombocytopenic mice was associated with bleeding in the lung but similar host defense, pointing at a role for platelet α-granules in maintaining vascular integrity but not host defense during Klebsiella pneumosepsis. Conclusions- These data show that Nbeal2 deficiency-resulting in gray platelet syndrome-affects platelets, neutrophils, and monocytes, with intact host defense but increased organ damage during gram-negative pneumosepsis. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/29930006/Nbeal2_Deficiency_Increases_Organ_Damage_but_Does_Not_Affect_Host_Defense_During_Gram_Negative_Pneumonia_Derived_Sepsis_ L2 - http://www.ahajournals.org/doi/full/10.1161/ATVBAHA.118.311332?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -