title: Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor.
abstract: Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.
authors.affiliation: Department of Surgery, The Toronto General Hospital and the University of Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.forename: A
authors.initials: A
authors.lastname: Kapus
authors.forename: Y H
authors.initials: YH
authors.lastname: Li
authors.forename: S
authors.initials: S
authors.lastname: Rizoli
authors.forename: J C
authors.initials: JC
authors.lastname: Marshall
authors.forename: O D
authors.initials: OD
authors.lastname: Rotstein
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use; D001778:Blood Coagulation Disorders / Q000209:etiology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019559:Capillary Leak Syndrome / Q000517:prevention & control; D004211:Disseminated Intravascular Coagulation / Q000209:etiology* / Q000517:prevention & control; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis; D005786:Gene Expression Regulation; D008070:Lipopolysaccharides / Q000633:toxicity; D008074:Lipoproteins / Q000502:physiology / Q000627:therapeutic use; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000276:immunology; D018384:Oxidative Stress; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D011650:Pulmonary Alveoli / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012128:Respiratory Distress Syndrome / Q000097:blood / Q000209:etiology / Q000378:metabolism*; D012771:Shock, Hemorrhagic / Q000097:blood / Q000150:complications*; D012772:Shock, Septic / Q000097:blood / Q000150:complications*; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000975:Antioxidants; D008070:Lipopolysaccharides; D008074:Lipoproteins; D016328:NF-kappa B; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D013925:Thromboplastin; D000111:Acetylcysteine