title: Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus-infected mice.
abstract: Essentials H1N1 Influenza A virus (IAV) infection is a hemostatic challenge for the lung. Tissue factor (TF) on lung epithelial cells maintains lung hemostasis after IAV infection. Reduced TF-dependent activation of coagulation leads to alveolar hemorrhage. Anticoagulation might increase the risk for hemorrhages into the lung during severe IAV infection.
  
  
  
  Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of genetic deficiency of tissue factor (TF) in a mouse model of IAV infection. Methods Wild-type mice, low-TF (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage, and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in BALF, but also led to alveolar hemorrhage. LTF mice and mice with selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death than controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF-dependent activation of coagulation is required to limit alveolar hemorrhage and death after IAV infection.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, Chapel Hill, NC, USA.
authors.forename: S
authors.initials: S
authors.lastname: Antoniak
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, Chapel Hill, NC, USA.
authors.forename: K
authors.initials: K
authors.lastname: Tatsumi
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, Chapel Hill, NC, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Hisada
authors.affiliation: Department of Nutrition, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Milner
authors.affiliation: Department of Nutrition, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Neidich
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Shaver
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, Chapel Hill, NC, USA.
authors.forename: R
authors.initials: R
authors.lastname: Pawlinski
authors.affiliation: Department of Nutrition, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: M A
authors.initials: MA
authors.lastname: Beck
authors.affiliation: Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bastarache
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, UNC McAllister Heart Institute, Chapel Hill, NC, USA.
authors.forename: N
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001777:Blood Coagulation; D001992:Bronchoalveolar Lavage Fluid; D004847:Epithelial Cells / Q000821:virology*; D017353:Gene Deletion; D006470:Hemorrhage / Q000821:virology*; D006487:Hemostasis; D007249:Inflammation; D053118:Influenza A Virus, H1N1 Subtype; D019426:Integrases / Q000378:metabolism; D008168:Lung / Q000473:pathology / Q000821:virology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009976:Orthomyxoviridae Infections / Q000473:pathology*; D011650:Pulmonary Alveoli / Q000378:metabolism*; D013925:Thromboplastin / Q000172:deficiency* / Q000378:metabolism
chemical_list: D000925:Anticoagulants; D013925:Thromboplastin; C045073:Cre recombinase; D019426:Integrases
keywords: hemorrhage; hemostasis; influenza A virus; pneumonia; tissue factor