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Neutrophil extracellular traps are associated with the pathogenesis of diffuse alveolar hemorrhage in murine lupus

2019; Elsevier BV; Volume: 100; Linguagem: Inglês

10.1016/j.jaut.2019.03.009

1095-9157

Pierre‐André Jarrot, Edwige Tellier, Léa Plantureux, Lydie Crescence, Stéphane Robert, Corinne Chareyre, Laurent Daniel, Véronique Secq, Stéphane Garcia, Françoise Dignat‐George, Laurence Panicot‐Dubois, Christophe Dubois, Gilles Kaplanski,

Nitric Oxide and Endothelin Effects

Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE) and systemic vasculitis. Although initially described to have antibacterial properties, increasing evidence suggests that neutrophil extracellular traps (NETs) have a detrimental role in both autoimmune diseases and acute lung injury. We investigated whether NETs could be detected in a murine model of pristane-induced lupus DAH and contribute to lung injury. Such NETs might constitute a therapeutic target. NETs were characterized by immunofluorescence staining of DNA, neutrophil elastase and citrullinated histones. Evaluation of lung injury was performed by haematoxylin-eosin staining and a quantification program. Clinical status of the mice was assessed by measurement of arterial oxygen saturation and survival curves after recombinant human deoxyribonuclease-1 (Rh-DNase-1) inhalations or polymorphonuclear neutrophil (PMN) depletion. Pristane was found to promote NETs formation in vitro and in vivo. Treatment of mice with Rh-DNase-1 inhalations cleared NETs and reduced lung injury. Clinical status improved significantly, with increased arterial oxygenation and survival. Following PMN depletion, NETs were absent with a subsequent reduction of lung injury and improved arterial oxygenation. These results support a pathogenic role of PMNs and NETs in lung injury during pristane-induced DAH. Targeting NETs with Rh-DNase-1 inhalations could constitute an interesting adjuvant therapy in human DAH.