Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema Journal Article


Authors: Zampell, J. C.; Yan, A.; Avraham, T.; Andrade, V.; Malliaris, S.; Aschen, S.; Rockson, S. G.; Mehrara, B. J.
Article Title: Temporal and spatial patterns of endogenous danger signal expression after wound healing and in response to lymphedema
Abstract: While acute tissue injury potently induces endogenous danger signal expression, the role of these molecules in chronic wound healing and lymphedema is undefined. The purpose of this study was to determine the spatial and temporal expression patterns of the endogenous danger signals high-mobility group box 1 (HMGB1) and heat shock protein (HSP)70 during wound healing and chronic lymphatic fluid stasis. In a surgical mouse tail model of tissue injury and lymphedema, HMGB1 and HSP70 expression occurred along a spatial gradient relative to the site of injury, with peak expression at the wound and greater than twofold reduced expression within 5 mm (P < 0.05). Expression primarily occurred in cells native to injured tissue. In particular, HMGB1 was highly expressed by lymphatic endothelial cells (>40% positivity; twofold increase in chronic inflammation, P < 0.001). We found similar findings using a peritoneal inflammation model. Interestingly, upregulation of HMGB1 (2.2-fold), HSP70 (1.4-fold), and nuclear factor (NF)-κβ activation persisted at least 6 wk postoperatively only in lymphedematous tissues. Similarly, we found upregulation of endogenous danger signals in soft tissue of the arm after axillary lymphadenectomy in a mouse model and in matched biopsy samples obtained from patients with secondary lymphedema comparing normal to lymphedematous arms (2.4-fold increased HMGB1, 1.9-fold increased HSP70; P < 0.01). Finally, HMGB1 blockade significantly reduced inflammatory lymphangiogenesis within inflamed draining lymph nodes (35% reduction, P < 0.01). In conclusion, HMGB1 and HSP70 are expressed along spatial gradients and upregulated in chronic lymphatic fluid stasis. Furthermore, acute expression of endogenous danger signals may play a role in inflammatory lymphangiogenesis. © 2011 by the American Physiological Society.
Keywords: signal transduction; human tissue; protein expression; histopathology; nonhuman; protein function; protein localization; lymphadenectomy; animal cell; mouse; animal experiment; animal model; inflammation; immunoglobulin enhancer binding protein; endothelium cell; lymph vessel endothelium; lymphedema; wound healing; upregulation; heat shock protein 70; tissue injury; high mobility group b1 protein; high-mobility group box 1
Journal Title: American Journal of Physiology - Cell Physiology
Volume: 300
Issue: 5
ISSN: 0363-6143
Publisher: American Physiological Society  
Date Published: 2011-05-01
Start Page: C1107
End Page: C1121
Language: English
DOI: 10.1152/ajpcell.00378.2010
PROVIDER: scopus
PUBMED: 21248077
PMCID: PMC3093946
DOI/URL:
Notes: --- - "Export Date: 23 June 2011" - "CODEN: AJPCD" - "Source: Scopus"
Altmetric
Citation Impact
MSK Authors
  1. Babak Mehrara
    295 Mehrara
  2. Tomer Avraham
    33 Avraham
  3. Jamie Christine Zampell
    29 Zampell
  4. Victor Piana De Andrade
    27 Andrade
  5. Alan Yan
    20 Yan
  6. Seth Aschen
    13 Aschen