Abstract
Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). In the lung, TF is expressed diffusely on the lung epithelium and intensely on cells of the myeloid lineage. We recently reported that TF on the lung epithelium, but not on myeloid cells, was the major source of TF during intra-tracheal LPS-induced ALI. Because of a growing body of literature demonstrating important pathophysiologic differences between ALI caused by different etiologies, we hypothesized that TF on myeloid cells may have distinct contributions to airspace inflammation and permeability between direct and indirect causes of ALI. To test this, we compared mice lacking TF on myeloid cells (TF∆mye, LysM.Cre+/−TFflox/flox) to littermate controls during direct (bacterial pneumonia, ventilator-induced ALI, bleomycin-induced ALI) and indirect ALI (systemic LPS, cecal ligation and puncture). ALI was quantified by weight loss, bronchoalveolar lavage (BAL) inflammatory cell number, cytokine concentration, protein concentration, and BAL procoagulant activity. There was no significant contribution of TF on myeloid cells in multiple models of experimental ALI, leading to the conclusion that TF in myeloid cells is not a major contributor to experimental ALI.
Highlights
Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS)
Alveolar macrophages isolated from TF∆mye mice that were stimulated ex vivo with LPS had TF mRNA levels that were 90% lower than in cells isolated from wildtype littermates (p = 0.019)
Thioglycollate-induced peritoneal macrophages isolated from TF∆mye mice had TF mRNA levels 89.5% lower after LPS stimulation than cells isolated from wild-type littermates (p = 0.019)
Summary
Tissue factor (TF) is a critical mediator of direct acute lung injury (ALI) with global TF deficiency resulting in increased airspace inflammation, alveolar-capillary permeability, and alveolar hemorrhage after intra-tracheal lipopolysaccharide (LPS). We recently identified that TF expressed on the lung epithelium was the predominant source of TF in the lung during direct LPS-induced ALI16, with no significant contribution of TF from myeloid cells in this model This finding was in contrast to prior data showing that TF expressed on cells in the circulation was critical for the systemic response to LPS in a model of endotoxemia[17]. Because of these apparent differences in the role of TF in direct ALI compared to indirect ALI and because of the critical role of macrophages and neutrophils in pulmonary host defense, we sought to better understand the role of myeloid TF in different models of ALI. The myeloid lineage, we tested the hypothesis that TF on myeloid cells would be protective in models of direct ALI but detrimental in models of indirect ALI
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
