Excessive mechanical stress increases HMGB1 expression in human lung microvascular endothelial cells via STAT3

Rachel K. Wolfson, Brandon Mapes, Joe G.N. Garcia

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


Ventilator-induced lung injury (VILI) occurs when the lung parenchyma and vasculature are exposed to repetitive and excessive mechanical stress via mechanical ventilation utilized as supportive care for the adult respiratory distress syndrome (ARDS). VILI induces gene expression and systemic release of inflammatory mediators that contribute to the multi-organ dysfunction and morbidity and mortality of ARDS. HMGB1, an intracellular transcription factor with cytokine properties, is a late mediator in sepsis and ARDS pathobiology, however, the role of HMGB1 in VILI remains poorly described. We now report HMGB1 expression in human lung microvessel endothelial cells (ECs) exposed to excessive, equibiaxial mechanical stress, an in vitro correlate of VILI. We determined that high amplitude cyclic stretch (18% CS) increased HMGB1 expression (2-4-fold) via a signaling pathway with critical involvement of the transcription factor, STAT3. Concomitant exposure to 18% CS and oxidative stress (H2O2) augmented HMGB1 expression (~13 fold increase) whereas lipopolysaccharide (LPS) challenge increased HMGB1 expression in static EC, but not in 18% CS-challenged EC. In contrast, physiologic, low amplitude cyclic stretch (5% CS) attenuated both oxidative H2O2- and LPS-induced increases in HMGB1 expression, suggesting that physiologic mechanical stress is protective. These results indicate that HMGB1 gene expression is markedly responsive to VILI-mediated mechanical stress, an effect that is augmented by oxidative stress. We speculate that VILI-induced HMGB1 expression acts locally to increase vascular permeability and alveolar flooding, thereby exacerbating systemic inflammatory responses and increasing the likelihood of multi-organ dysfunction.

Original languageEnglish (US)
Pages (from-to)50-55
Number of pages6
JournalMicrovascular Research
StatePublished - Mar 2014

ASJC Scopus subject areas

  • Biochemistry
  • Cardiology and Cardiovascular Medicine
  • Cell Biology


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