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

TitleExcessive mechanical stress increases HMGB1 expression in human lung microvascular endothelial cells via STAT3.
Publication TypeJournal Article
Year of Publication2014
AuthorsWolfson RK, Mapes B, Garcia JGN
JournalMicrovasc Res
Volume92
Pagination50-55
Date Published2014 Mar
ISSN Number1095-9319
KeywordsAdult, Cells, Cultured, Endothelial Cells, Gene Expression, HMGB1 Protein, Humans, Lipopolysaccharides, Lung, Microvessels, Models, Biological, Multiple Organ Failure, Oxidative Stress, Respiratory Distress Syndrome, Adult, STAT3 Transcription Factor, Stress, Mechanical, Ventilator-Induced Lung Injury
Abstract

<p>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.</p>

DOI10.1016/j.mvr.2013.12.005
Alternate JournalMicrovasc. Res.
PubMed ID24370952
PubMed Central IDPMC4327945
Grant ListR01-HL91889 / HL / NHLBI NIH HHS / United States
R01 HL094394 / HL / NHLBI NIH HHS / United States
P01-HL98050 / HL / NHLBI NIH HHS / United States
K08 HL093359 / HL / NHLBI NIH HHS / United States
R01-HL73994 / HL / NHLBI NIH HHS / United States
K08-HL093359 / HL / NHLBI NIH HHS / United States
P50 HL073994 / HL / NHLBI NIH HHS / United States
P01 HL098050 / HL / NHLBI NIH HHS / United States
P01-HL58064 / HL / NHLBI NIH HHS / United States
P01 HL058064 / HL / NHLBI NIH HHS / United States
R01 HL091889 / HL / NHLBI NIH HHS / United States