Doxycycline attenuates burn-Induced microvascular hyperpermeability

Hayden Wilson Stagg, John Greg Whaley, Binu Tharakan, Felicia A. Hunter, Daniel Jupiter, Danny C. Little, Matthew L. Davis, William Roy Smythe, Ed W. Childs

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

BACKGROUND: Burns induce systemic microvascular hyperpermeability resulting in shock, and if untreated, cardiovascular collapse. Damage to the endothelial cell adherens junctional complex plays an integral role in the pathophysiology of microvascular hyperpermeability. We hypothesized that doxycycline, a known inhibitor of matrix metalloproteinases (MMPs), could attenuate burn-induced adherens junction damage and microvascular hyperpermeability. METHODS: Male Sprague-Dawley rats were divided into sham, burn, and burn + doxycycline (n = 5). The experimental groups underwent a 30% total body surface area full-thickness burn. Fluorescein isothiocyanateYalbumin was administered intravenously. Mesenteric postcapillary venules were examined with intravital microscopy to determine flux of albumin from the intravascular space to the interstitium. Fluorescence intensity was compared between the intravascular space to the interstitium at 30, 60, 80, 100, 120, 140, 160, and 180 minutes after burn. Parallel experimentswere performed in which rat lung microvascular endothelial cellswere treated with sera from sham or burn animals as well as separate groups pretreated with either doxycycline or a specific inhibitor of MMP-9. Monolayer permeability was determined by fluorescein isothiocyanate albumin-flux across Transwell plates and immunofluorescense staining for the adherens junction protein A-catenin was performed. Western blot and gelatin zymography were performed to assess MMP-9 level and activity. RESULTS: MMP-9 levels were increased after burn. Monolayer permeability was significantly increased with burn serum treatment; this was attenuated with doxycycline as well as the specific MMP-9 inhibitor ( p G 0.05). Damage of the endothelial cell adherens junction complex was induced by serum from burned rats, and doxycycline restored the integrity of the adherens junction similar to the MMP-9 inhibitor. Intravital microscopy revealed microvascular hyperpermeability after burn; this was attenuated with doxycycline ( p G 0.05). CONCLUSION: Burns induce microvascular hyperpermeability via endothelial adherens junction disruption associated with MMP-9, and this is attenuated with doxycycline.

Original languageEnglish (US)
Pages (from-to)1040-1046
Number of pages7
JournalJournal of Trauma and Acute Care Surgery
Volume75
Issue number6
DOIs
StatePublished - Dec 2013
Externally publishedYes

Fingerprint

Doxycycline
Burns
Matrix Metalloproteinase 9
Adherens Junctions
Matrix Metalloproteinase Inhibitors
Fluorescein
Albumins
Permeability
Endothelial Cells
Serum
Catenins
Intercellular Junctions
Venules
Body Surface Area
Staphylococcal Protein A
Gelatin
Sprague Dawley Rats
Shock
Fluorescence
Western Blotting

Keywords

  • Burn shock
  • Doxycycline
  • MMP-9
  • Rats
  • Vascular permeability

ASJC Scopus subject areas

  • Critical Care and Intensive Care Medicine
  • Surgery

Cite this

Stagg, H. W., Whaley, J. G., Tharakan, B., Hunter, F. A., Jupiter, D., Little, D. C., ... Childs, E. W. (2013). Doxycycline attenuates burn-Induced microvascular hyperpermeability. Journal of Trauma and Acute Care Surgery, 75(6), 1040-1046. https://doi.org/10.1097/TA.0b013e3182aa9c79

Doxycycline attenuates burn-Induced microvascular hyperpermeability. / Stagg, Hayden Wilson; Whaley, John Greg; Tharakan, Binu; Hunter, Felicia A.; Jupiter, Daniel; Little, Danny C.; Davis, Matthew L.; Smythe, William Roy; Childs, Ed W.

In: Journal of Trauma and Acute Care Surgery, Vol. 75, No. 6, 12.2013, p. 1040-1046.

Research output: Contribution to journalArticle

Stagg, HW, Whaley, JG, Tharakan, B, Hunter, FA, Jupiter, D, Little, DC, Davis, ML, Smythe, WR & Childs, EW 2013, 'Doxycycline attenuates burn-Induced microvascular hyperpermeability', Journal of Trauma and Acute Care Surgery, vol. 75, no. 6, pp. 1040-1046. https://doi.org/10.1097/TA.0b013e3182aa9c79
Stagg, Hayden Wilson ; Whaley, John Greg ; Tharakan, Binu ; Hunter, Felicia A. ; Jupiter, Daniel ; Little, Danny C. ; Davis, Matthew L. ; Smythe, William Roy ; Childs, Ed W. / Doxycycline attenuates burn-Induced microvascular hyperpermeability. In: Journal of Trauma and Acute Care Surgery. 2013 ; Vol. 75, No. 6. pp. 1040-1046.
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abstract = "BACKGROUND: Burns induce systemic microvascular hyperpermeability resulting in shock, and if untreated, cardiovascular collapse. Damage to the endothelial cell adherens junctional complex plays an integral role in the pathophysiology of microvascular hyperpermeability. We hypothesized that doxycycline, a known inhibitor of matrix metalloproteinases (MMPs), could attenuate burn-induced adherens junction damage and microvascular hyperpermeability. METHODS: Male Sprague-Dawley rats were divided into sham, burn, and burn + doxycycline (n = 5). The experimental groups underwent a 30{\%} total body surface area full-thickness burn. Fluorescein isothiocyanateYalbumin was administered intravenously. Mesenteric postcapillary venules were examined with intravital microscopy to determine flux of albumin from the intravascular space to the interstitium. Fluorescence intensity was compared between the intravascular space to the interstitium at 30, 60, 80, 100, 120, 140, 160, and 180 minutes after burn. Parallel experimentswere performed in which rat lung microvascular endothelial cellswere treated with sera from sham or burn animals as well as separate groups pretreated with either doxycycline or a specific inhibitor of MMP-9. Monolayer permeability was determined by fluorescein isothiocyanate albumin-flux across Transwell plates and immunofluorescense staining for the adherens junction protein A-catenin was performed. Western blot and gelatin zymography were performed to assess MMP-9 level and activity. RESULTS: MMP-9 levels were increased after burn. Monolayer permeability was significantly increased with burn serum treatment; this was attenuated with doxycycline as well as the specific MMP-9 inhibitor ( p G 0.05). Damage of the endothelial cell adherens junction complex was induced by serum from burned rats, and doxycycline restored the integrity of the adherens junction similar to the MMP-9 inhibitor. Intravital microscopy revealed microvascular hyperpermeability after burn; this was attenuated with doxycycline ( p G 0.05). CONCLUSION: Burns induce microvascular hyperpermeability via endothelial adherens junction disruption associated with MMP-9, and this is attenuated with doxycycline.",
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AU - Stagg, Hayden Wilson

AU - Whaley, John Greg

AU - Tharakan, Binu

AU - Hunter, Felicia A.

AU - Jupiter, Daniel

AU - Little, Danny C.

AU - Davis, Matthew L.

AU - Smythe, William Roy

AU - Childs, Ed W.

PY - 2013/12

Y1 - 2013/12

N2 - BACKGROUND: Burns induce systemic microvascular hyperpermeability resulting in shock, and if untreated, cardiovascular collapse. Damage to the endothelial cell adherens junctional complex plays an integral role in the pathophysiology of microvascular hyperpermeability. We hypothesized that doxycycline, a known inhibitor of matrix metalloproteinases (MMPs), could attenuate burn-induced adherens junction damage and microvascular hyperpermeability. METHODS: Male Sprague-Dawley rats were divided into sham, burn, and burn + doxycycline (n = 5). The experimental groups underwent a 30% total body surface area full-thickness burn. Fluorescein isothiocyanateYalbumin was administered intravenously. Mesenteric postcapillary venules were examined with intravital microscopy to determine flux of albumin from the intravascular space to the interstitium. Fluorescence intensity was compared between the intravascular space to the interstitium at 30, 60, 80, 100, 120, 140, 160, and 180 minutes after burn. Parallel experimentswere performed in which rat lung microvascular endothelial cellswere treated with sera from sham or burn animals as well as separate groups pretreated with either doxycycline or a specific inhibitor of MMP-9. Monolayer permeability was determined by fluorescein isothiocyanate albumin-flux across Transwell plates and immunofluorescense staining for the adherens junction protein A-catenin was performed. Western blot and gelatin zymography were performed to assess MMP-9 level and activity. RESULTS: MMP-9 levels were increased after burn. Monolayer permeability was significantly increased with burn serum treatment; this was attenuated with doxycycline as well as the specific MMP-9 inhibitor ( p G 0.05). Damage of the endothelial cell adherens junction complex was induced by serum from burned rats, and doxycycline restored the integrity of the adherens junction similar to the MMP-9 inhibitor. Intravital microscopy revealed microvascular hyperpermeability after burn; this was attenuated with doxycycline ( p G 0.05). CONCLUSION: Burns induce microvascular hyperpermeability via endothelial adherens junction disruption associated with MMP-9, and this is attenuated with doxycycline.

AB - BACKGROUND: Burns induce systemic microvascular hyperpermeability resulting in shock, and if untreated, cardiovascular collapse. Damage to the endothelial cell adherens junctional complex plays an integral role in the pathophysiology of microvascular hyperpermeability. We hypothesized that doxycycline, a known inhibitor of matrix metalloproteinases (MMPs), could attenuate burn-induced adherens junction damage and microvascular hyperpermeability. METHODS: Male Sprague-Dawley rats were divided into sham, burn, and burn + doxycycline (n = 5). The experimental groups underwent a 30% total body surface area full-thickness burn. Fluorescein isothiocyanateYalbumin was administered intravenously. Mesenteric postcapillary venules were examined with intravital microscopy to determine flux of albumin from the intravascular space to the interstitium. Fluorescence intensity was compared between the intravascular space to the interstitium at 30, 60, 80, 100, 120, 140, 160, and 180 minutes after burn. Parallel experimentswere performed in which rat lung microvascular endothelial cellswere treated with sera from sham or burn animals as well as separate groups pretreated with either doxycycline or a specific inhibitor of MMP-9. Monolayer permeability was determined by fluorescein isothiocyanate albumin-flux across Transwell plates and immunofluorescense staining for the adherens junction protein A-catenin was performed. Western blot and gelatin zymography were performed to assess MMP-9 level and activity. RESULTS: MMP-9 levels were increased after burn. Monolayer permeability was significantly increased with burn serum treatment; this was attenuated with doxycycline as well as the specific MMP-9 inhibitor ( p G 0.05). Damage of the endothelial cell adherens junction complex was induced by serum from burned rats, and doxycycline restored the integrity of the adherens junction similar to the MMP-9 inhibitor. Intravital microscopy revealed microvascular hyperpermeability after burn; this was attenuated with doxycycline ( p G 0.05). CONCLUSION: Burns induce microvascular hyperpermeability via endothelial adherens junction disruption associated with MMP-9, and this is attenuated with doxycycline.

KW - Burn shock

KW - Doxycycline

KW - MMP-9

KW - Rats

KW - Vascular permeability

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