Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease

Carlos A. Barrero, Oscar Perez-Leal, Mark Aksoy, Camilo Moncada, Rong Ji, Yolanda Lopez, Karthik Mallilankaraman, Muniswamy Madesh, Gerard J. Criner, Steven G. Kelsen, Salim Merali

Research output: Contribution to journalArticlepeer-review

30 Scopus citations


Rationale: Shifts in the gene expression of nuclear protein in chronic obstructive pulmonary disease (COPD), a progressive disease that is characterized by extensive lung inflammation and apoptosis, are common; however, the extent of the elevation of the core histones, which are the major components of nuclear proteins and their consequences in COPD, has not been characterized, which is important because extracellular histones are cytotoxic to endothelial and airway epithelial cells. Objectives: To investigate the role of extracellular histones in COPD disease progression. Methods: We analyzed the nuclear lung proteomes of ex-smokers with and without the disease. Further studies on the consequences of H3.3 were also performed. Measurements and Main Results: A striking finding was a COPDspecific eightfold increase of hyperacetylated histone H3.3. The hyperacetylation renders H3.3 resistant to proteasomal degradation despite ubiquitination; when combined with the reduction in proteasome activity that is known for COPD, this resistance helps account for the increased levels of H3.3. Using anti-H3 antibodies, we found H3.3 in the airway lumen, alveolar fluid, and plasma of COPD samples. H3.3 was cytotoxic to lung structural cells via a mechanism that involves the perturbation of C 2+ homeostasis and mitochondrial toxicity. We used the primary human airway epithelial cells and found that the antibodies to either the C or N terminus of H3 could partially reverse H3.3 toxicity. Conclusions: Our data indicate that there is an uncontrolled positive feedback loop in which the damaged cells release acetylated H3.3, which causes more damage, adds H3.3 release, and contributes toward the disease progression.

Original languageEnglish (US)
Pages (from-to)673-683
Number of pages11
JournalAmerican Journal of Respiratory and Critical Care Medicine
Issue number6
StatePublished - Sep 15 2013
Externally publishedYes


  • Acetylation
  • Chronic obstructive pulmonary disease
  • Cytotoxicity
  • Histone H3.3
  • Proteomics

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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