Myeloid tissue factor does not modulate lung inflammation or permeability during experimental acute lung injury

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.

Myeloid but not epithelial tissue factor exerts protective anti‐inflammatory effects in acid aspiration‐induced acute lung injury

“…This is in line with previous findings showing that epithelial TF exerts protective effects, e.g. supporting the alveolar-capillary barrier, in various infectious and non-infectious ALI models [18,35,36]. For instance, in an LPS-induced lung inflammation model, the presence of epithelial cell TF determines the severity of the lung pathology [18,33].…”

“…For instance, in an LPS‐induced lung inflammation model, the presence of epithelial cell TF determines the severity of the lung pathology . Whereas, in LPS‐induced ALI, myeloid TF is of minor importance , we provide evidence that, in acid‐induced ALI, deficiency of myeloid TF promoted the inflammatory response and thereby significantly exacerbated disease progression. Increased inflammation may be the reason for increased TF expression in whole lung tissue, as observed in TF Δmye mice as compared with wild‐type mice during ALI.…”

“…These occurred independently of coagulation activation or the presence of TF on epithelial cells, and was solely dependent on myeloid TF. Although there was a tendency for there to be increased cytokine expression in TF Δmye mice during LPS‐induced ALI, no significant differences were observed .…”

The coagulation system in host defense

“…However, TF deficiency on both cell types did not significantly affect local lung inflammation . In line with this, myeloid TF had no effect on Klebsiella pneumonia–induced lung injury . Notably, a lack of myeloid TF increased the expression of KC/CXCL1, a neutrophil chemoattractant and the murine homolog to human IL‐8, in the lung after Klebsiella infection and local LPS administration .…”

ICAM-1–targeted thrombomodulin mitigates tissue factor–driven inflammatory thrombosis in a human endothelialized microfluidic model

“…It is challenging to discern the contribution of endothelial TF from other sources such as hematopoietic cells, epithelium, fibroblasts, pericytes, and smooth muscle. [22][23][24] While ECs express TF under inflammatory stimuli in vitro, studies have failed to (E) hTM/R6.5 binds strongly to TNF-a-stimulated HUVEC but only minimally to nonstimulated ECs. Cell-based enzyme-linked immunosorbent assays were performed on live cells as previously described 19 using anti-FLAG-HRP to probe for cell-bound fusion protein.…”