Tissue factor-dependent coagulation protease signaling in acute lung injury

Abstract

The coagulation cascade signals via protease activated receptors in the tissue factor-initiation phase and downstream via the effector protease, thrombin. Bleomycin-induced acute lung injury is an example of thrombin signaling-dependent pathology. Frequently, thrombin signaling is a major contributor to inflammation in the extravascular space but intravascular thrombin signaling is a threshold-regulated event. At low concentrations, intravascular thrombin activates the protein C pathway by converting protein C (bound to endothelial cell protein C receptor) to activated protein C and this generates antiinflammatory signals along the activated protein C-endothelial cell protein C receptor-protease activated receptor 1 pathway on endothelial cells. Direct thrombin signaling only occurs when intravascular thrombin concentrations exceed a coagulant threshold. In systemic bacterial toxin-mediated inflammation, inhibition of thrombin is not sufficient to limit inflammation, whereas tissue factor inhibition interrupts a self-sustaining inflammatory escalation in acute lung injury. Therefore, in the vasculature, inflammatory signaling by the tissue factor initiation complex is favored over thrombin signaling.

Indobufen inhibits tissue factor in human monocytes through a thromboxane-mediated mechanism

“…The beneficial effect may, indeed, stem both from inhibition of thrombin and from reduction of inflammation. Indobufen, by the concomitant inhibition of TF activity and prostanoid formation, represents therefore a good candidate drug to control the hypercoagulable state which goes in parallel with inflammation in various clinical settings, ranging from acute lung injury [57] to sepsis [58].…”

Cellular origin of pro-coagulant and (anti)-fibrinolytic factors in bleomycin-injured lungs

“…However, lung injury and fibrosis still develop in fibrinogen knockout mice after bleomycin treatment [29], suggesting that the cellular rather than the pro-coagulant effects of different proteases of the TF-VIIa-initiated coagulation pathway may play a key role in inflammatory and fibrotic processes following bleomycin challenge. TF-VIIa complexes themselves can activate PARs, including the thrombin-insensitive PAR-2, and upregulate the expression of pro-inflammatory cytokines and growth factors in different cell types [27,32,33]. Factor Xa stimulates fibroblast proliferation, pro-collagen production and connective tissue growth factor (CTGF) expression via proteolytic activation of PAR-1, and factor Xainduced expression of pro-inflammatory cytokines in EC was demonstrated to be PAR-2 mediated [10,13,14].…”

“…fibrin deposition) effects. Moreover, there is ongoing discussion about the mechanisms by which imbalances in alveolar haemostasis and fibrinolysis may contribute to inflammation and fibrosis in acutely and chronically injured lungs, and especially about the importance of cellular versus pro-coagulant functions of various proteases of the TF-VIIainitiated extrinsic coagulation cascade [1,[27][28][29][30]. Excessive extravascular deposition of fibrin may serve as a reservoir of pro-fibrotic growth factors [31] and is thought to inhibit surfactant function and to provide a provisional matrix on which fibroblasts proliferate and produce collagen [8].…”

Disorders of lung matrix remodeling

“…Apart from its initial role in fibrinous matrix formation (Figure 2a), thrombin signaling through its cognate receptor, especially protease-activated receptor-1 (PAR-1), evokes production of secondary profibrotic cytokines such as IL-1β and connective tissue growth factor (CTGF) (83,84). Inhibition of thrombin activity suppresses fibrosis in the bleomycininduced model of lung fibrosis in both rats and mice, supporting a mechanistic role for thrombin in tissue repair in the lung similar to that found at other sites of injury (85).…”