title: Shock-induced neutrophil mediated priming for acute lung injury in mice: divergent effects of TLR-4 and TLR-4/FasL deficiency.
abstract: Acute lung injury (ALI) leading to respiratory distress is a common sequela of shock/trauma, however, modeling this process in mice with a single shock or septic event is inconsistent. One explanation is that hemorrhage is often just a "priming insult," thus, secondary stimuli may be required to "trigger" ALI. To test this we carried out studies in which we assessed the capacity of hemorrhage alone or hemorrhage followed by septic challenge (CLP) to induce ALI. Lung edema, bronchoalveolar lavage interleukin (IL)-6, alveolar congestion, as well as lung IL-6, macrophage inflammatory protein (MIP)-2, and myeloperoxidase (MPO) activity were all increased in mice subjected to CLP at 24 but not 72 hours following hemorrhage. This was associated with a marked increase in the susceptibility of these mice to septic mortality. Peripheral blood neutrophils derived from 24 hours post-hemorrhage, but not Sham animals, exhibited an ex vivo decrease in apoptotic frequency and an increase in respiratory burst capacity, consistent with in vivo "priming." Subsequently, we observed that adoptive transfer of neutrophils from hemorrhaged but not sham-hemorrhage animals to neutropenic recipients reproduce ALI when subsequently septically challenged, implying that this priming was mediated by neutrophils. We also found marked general increases in lung IL-6, MIP-2, and MPO in mice deficient for toll-like receptor (TLR-4) or the combined lack of TLR-4/FasL. However, the TLR-4 defect markedly attenuated neutrophil influx into the lung while not altering the change in local cytokine/chemokine expression. Alternatively, the combined loss of FasL and TLR-4 did not inhibit the increase in MPO and exacerbated lung IL-6/MIP-2 levels even further.
authors.affiliation: Shock-Trauma Research Laboratories, Aldrich 227, Division of Surgical Research, Brown University School of Medicine and Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. aayala@lifespan.org
authors.forename: Alfred
authors.initials: A
authors.lastname: Ayala
authors.forename: Chun-Shiang
authors.initials: CS
authors.lastname: Chung
authors.forename: Joanne L
authors.initials: JL
authors.lastname: Lomas
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Song
authors.forename: Lesley A
authors.initials: LA
authors.lastname: Doughty
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Gregory
authors.forename: William G
authors.initials: WG
authors.lastname: Cioffi
authors.forename: Brian W
authors.initials: BW
authors.lastname: LeBlanc
authors.forename: Jonathan
authors.initials: J
authors.lastname: Reichner
authors.forename: H Hank
authors.initials: HH
authors.lastname: Simms
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Grutkoski
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002432:Cecum / Q000601:surgery; D054426:Chemokine CXCL2; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D029721:Drosophila Proteins; D053222:Fas Ligand Protein; D016179:Granulocyte Colony-Stimulating Factor; D016298:Hematopoietic Cell Growth Factors / Q000378:metabolism; D006470:Hemorrhage; D006801:Humans; D007377:Interleukin-3; D015850:Interleukin-6 / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D020556:Neutrophil Infiltration / Q000502:physiology; D009504:Neutrophils / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D016897:Respiratory Burst / Q000502:physiology; D012128:Respiratory Distress Syndrome / Q000503:physiopathology*; D018805:Sepsis / Q000503:physiopathology; D012769:Shock / Q000503:physiopathology*; D015996:Survival Rate; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
chemical_list: D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; D029721:Drosophila Proteins; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; C404145:myelopoietin; D016179:Granulocyte Colony-Stimulating Factor