Florry E van den Boogaard1,2,3, Jorrit J Hofstra1,4, Xanthe Brands1,2, Marcel M Levi5, Joris J T H Roelofs6, Sebastiaan A J Zaat3,4, Cornelis Van't Veer2,3, Tom van der Poll2,3,7, Marcus J Schultz1,8. 1. 1 Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands . 2. 2 Center for Experimental and Molecular Medicine (CEMM), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands . 3. 3 Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands . 4. 4 Department of Medical Microbiology, University of Amsterdam , Amsterdam, The Netherlands . 5. 5 Department of Internal Medicine, University of Amsterdam , Amsterdam, The Netherlands . 6. 6 Department of Pathology, University of Amsterdam , Amsterdam, The Netherlands . 7. 7 Department of Infectious Diseases, University of Amsterdam , Amsterdam, The Netherlands . 8. 8 Department of Intensive Care Medicine, Academic Medical Center, University of Amsterdam , Amsterdam, The Netherlands .
Abstract
BACKGROUND: Critically ill patients are at a constant risk of direct (e.g., by pneumonia) or indirect lung injury (e.g., by sepsis). Excessive alveolar fibrin deposition is a prominent feature of lung injury, undermining pulmonary integrity and function. METHODS: We examined the effect of local administration of recombinant human tissue factor pathway inhibitor (rh-TFPI), a natural anticoagulant, in two well-established models of lung injury in rats. Rats received intratracheal instillation of Pseudomonas aeruginosa, causing direct lung injury, or they received an intravenous injection of Escherichia coli lipopolysaccharide (LPS), causing indirect lung injury. Rats were randomized to local treatment with rh-TFPI or placebo through repeated nebulization. RESULTS: Challenge with P. aeruginosa or LPS was associated with increased coagulation and decreased fibrinolysis in bronchoalveolar lavage fluid (BALF) and plasma. Rh-TFPI levels in BALF increased after nebulization, whereas plasma rh-TFPI levels remained low and systemic TFPI activity was not affected. Nebulization of rh-TFPI attenuated pulmonary and systemic coagulation in both models, without affecting fibrinolysis. Nebulization of rh-TFPI modestly reduced the inflammatory response and bacterial growth of P. aeruginosa in the alveolar compartment. CONCLUSIONS: Local treatment with rh-TFPI does not alter systemic TFPI activity; however, it attenuates both pulmonary and systemic coagulopathy. Furthermore, nebulized rh-TFPI modestly reduces the pulmonary inflammatory response and allows increased bacterial clearance in rats with direct lung injury caused by P. aeruginosa.
BACKGROUND:Critically illpatients are at a constant risk of direct (e.g., by pneumonia) or indirect lung injury (e.g., by sepsis). Excessive alveolar fibrin deposition is a prominent feature of lung injury, undermining pulmonary integrity and function. METHODS: We examined the effect of local administration of recombinant humantissue factor pathway inhibitor (rh-TFPI), a natural anticoagulant, in two well-established models of lung injury in rats. Rats received intratracheal instillation of Pseudomonas aeruginosa, causing direct lung injury, or they received an intravenous injection of Escherichia coli lipopolysaccharide (LPS), causing indirect lung injury. Rats were randomized to local treatment with rh-TFPI or placebo through repeated nebulization. RESULTS: Challenge with P. aeruginosa or LPS was associated with increased coagulation and decreased fibrinolysis in bronchoalveolar lavage fluid (BALF) and plasma. Rh-TFPI levels in BALF increased after nebulization, whereas plasma rh-TFPI levels remained low and systemic TFPI activity was not affected. Nebulization of rh-TFPI attenuated pulmonary and systemic coagulation in both models, without affecting fibrinolysis. Nebulization of rh-TFPI modestly reduced the inflammatory response and bacterial growth of P. aeruginosa in the alveolar compartment. CONCLUSIONS: Local treatment with rh-TFPI does not alter systemic TFPI activity; however, it attenuates both pulmonary and systemic coagulopathy. Furthermore, nebulized rh-TFPI modestly reduces the pulmonary inflammatory response and allows increased bacterial clearance in rats with direct lung injury caused by P. aeruginosa.
Authors: Gabriele Guglielmetti; Marco Quaglia; Pier Paolo Sainaghi; Luigi Mario Castello; Rosanna Vaschetto; Mario Pirisi; Francesco Della Corte; Gian Carlo Avanzi; Piero Stratta; Vincenzo Cantaluppi Journal: Crit Care Date: 2020-06-19 Impact factor: 9.097
Authors: Victor Edgar Fiestas Solórzano; Nieli Rodrigues da Costa Faria; Caroline Fernandes Dos Santos; Gladys Corrêa; Márcio da Costa Cipitelli; Marcos Dornelas Ribeiro; Luiz José de Souza; Paulo Vieira Damasco; Rivaldo Venâncio da Cunha; Flavia Barreto Dos Santos; Luzia Maria de Oliveira Pinto; Elzinandes Leal de Azeredo Journal: Viruses Date: 2021-09-08 Impact factor: 5.048