Activation of coagulation and inhibition of fibrinolysis in the human lung on bronchial instillation of lipoteichoic acid and lipopolysaccharide*

Abstract

This study is the first to describe the effects of LTA on hemostasis in humans, demonstrating that LTA induces similar changes in the human bronchoalveolar space as LPS, characterized by activation of coagulation with concurrent inhibition of anticoagulant and fibrinolytic pathways.

The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications

“…It therefore seems probable that loss of this function would cause an imbalance between thrombin and aPC, resulting in excessive thrombin formation and fibrin deposition in asthma. 80,81 On the other hand, given that aPC directly affects human pulmonary vascular permeability, conferring endothelial barrier protection via EPCR and S1P1, 82 and that thrombin can affect airway permeability, 83 the defective expression of EPCR on lung epithelium of asthmatic patients could alter the airway barrier, thereby exacerbating inflammation.…”

Intrabronchial activated protein C enhances lipopolysaccharide-induced pulmonary responses

“…Considering the bleeding risk associated with intravenous APC, we here for the first time investigated the potential of intrabronchial rhAPC administration to inhibit coagulation and inflammation in the human lung, arguing that this route of delivery would circumvent serious side-effects [17][18][19][20]. For this we used the established human model of lung inflammation induced by intrabronchial instillation of LPS via a bronchoscope [14][15][16]25]. The main finding of our study was remarkable: intrabronchially administered rhAPC induced a procoagulant and pro-inflammatory response in lung subsegments challenged with LPS rather than the expected inhibitory effects on coagulation and inflammation.…”

“…A bilateral bronchoalveolar lavage (BAL) was performed 6 h post-challenge in a standardised fashion [14,25]. Citrated and heparinised blood was taken by venipuncture before the first (t50 h) and the second (t56 h) bronchoscopy.…”

“…Intrabronchial instillation of LPS in healthy humans is also associated with a rise in TATc levels in BALF [14,15]. An earlier study showed that intravenously administered rhAPC could reduce LPS-induced elevations in TATc concentrations in BALF by approximately 30% [15].…”

“…We recently demonstrated that intrabronchial instillation of lipopolysaccharide (LPS), a constituent of the cell wall of Gram-negative bacteria, can reproduce haemostatic alterations found in inflammatory lung disorders, including a reduction in APC levels in the lungs of healthy volunteers [14,15]. This human model of intrabronchial LPS delivery has also been used to study the in vivo effects of intravenous recombinant human (rh)APC treatment on pulmonary inflammation and coagulation [15,16].…”