Abstract
Despite decades of research, acute respiratory distress syndrome (ARDS) remains an important clinical challenge due to an incomplete understanding of the pathophysiological mechanisms. No FDA-approved drug therapy currently exists for treatment of humans with ARDS. There is accumulating evidence in rodents and humans suggesting that extracellular histones are strong drivers of inflammation and tissue damage. We recently described an important role for extracellular histones during acute lung injury (ALI) in mice (Bosmann et al., FASEB J. 27:5010-5021 (2013)). Extracellular histones were detected in bronchoalveolar lavage fluids (BALF) from patients with ARDS but not in BALF from non-ARDS patients in intensive care units. Extracellular histones were also detected in BALF from mice during experimental ALI. The presence of extracellular histones was dependent on the two C5a receptors (C5aR and C5L2) and availability of neutrophils. Extracellular histones were highly pro-inflammatory, and caused severe damage to respiratory function. Intratracheal instillation of histones resulted in pro-inflammatory mediator production, epithelial cell damage, disturbances in alveolar-capillary gas exchange, lung consolidation, activation of the coagulation cascade, and in some cases, death. Antibody-mediated neutralization of extracellular histones attenuated C5a-induced ALI. Together, these data suggested a prominent role for extracellular histones in the pathophysiology of ALI. The predominant source of histones in ALI may be neutrophils that have been activated by C5a to form neutrophil extracellular traps (NETs). Therapeutic targeting of extracellular histones may provide a novel approach to combat ARDS in humans.
Highlights
To cite this article: Grailer JJ, et al Lung inflammation and damage induced by extracellular histones
The presence of extracellular histones was dependent on the two C5a receptors (C5aR and C5L2) and availability of neutrophils
The predominant source of histones in acute lung injury (ALI) may be neutrophils that have been activated by C5a to form neutrophil extracellular traps (NETs)
Summary
Histone neutralization significantly reduced the presence of inflammatory cytokines (e.g., TNF, IL-1β, IL6, IL-12(p40), G-CSF) and chemokines (e.g., MCP-1, MIP1α, MIP-1β) found in the BALF during C5a-induced ALI, compared to an isotype control antibody. Instillation of exogenous histones (100 μg) into the airway resulted in the production of high levels of pro-inflammatory cytokines and chemokines, the accumulation of neutrophils in the lung, and severe ALI. When exogenous histones (20 μg/g body weight) were administered to mice i.t., BALF levels of lactate dehydrogenase (LDH) were elevated after 1 hour indicating extensive tissue damage in lung. Whole-body plethysmography revealed increased respiratory rate, while analysis of blood showed arterial acidification, elevated pCO2, and reduced oxyhemoglobin saturation as early as 15 minutes after histone instillation Together, these data indicate that extracellular histones resulted in lung tissue damage, and severe and immediate ALI
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