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Lung inflammation and damage induced by extracellular histones
#MMPMID26052542
Grailer JJ
; Ward PA
Inflamm Cell Signal
2014[]; 1
(4
): ? PMID26052542
show ga
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.
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