Transforming growth factor β-induced protein promotes severe vascular inflammatory responses

Am J Respir Crit Care Med. 2014 Apr 1;189(7):779-86. doi: 10.1164/rccm.201311-2033OC.

Abstract

Rationale: Sepsis is a systemic inflammatory condition resulting from bacterial infections; it has a high mortality rate and limited therapeutic options. Despite extensive research into the mechanisms driving bacterial sepsis, the target molecules controlling vascular leakage are still largely unknown. Transforming growth factor β-induced protein (TGFBIp) is an extracellular matrix protein expressed in several cell types, which is known to interact with integrins.

Objectives: The aim of this study was to determine the roles of TGFBIp in vascular proinflammatory responses, and the mechanisms of action driving these responses.

Methods: Circulating levels of TGFBIp were measured in patients admitted to the hospital with sepsis, severe sepsis, and septic shock and in cecal ligation and puncture (CLP)-induced septic mice. Effects of TGFBIp knockout on CLP-induced septic mortality and effects of TGFBIp on multiple vascular proinflammatory responses were determined.

Measurements and main results: Circulating levels of TGFBIp were significantly elevated compared with healthy controls, and were strongly correlated with disease severity. High blood TGFBIp levels were also observed in CLP-induced septic mice. The absence of the TGFBIp gene in mice attenuated CLP-induced sepsis. TGFBIp enhanced vascular proinflammatory responses including vascular permeability, adhesion and migration of leukocytes, and disruption of adherence junctions through interacting with integrin αvβ5.

Conclusions: Collectively, our findings demonstrate that the TGFBIp-αvβ5 axis can elicit severe inflammatory responses, suggesting it to be a potential target for development of diagnostics and therapeutics for sepsis.

MeSH terms

  • Animals
  • Biomarkers / blood
  • Case-Control Studies
  • Cecum / surgery
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiopathology*
  • Extracellular Matrix Proteins / blood*
  • Humans
  • Leukocytes / physiology
  • Ligation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Permeability
  • Receptors, Vitronectin / blood
  • Sepsis / blood
  • Sepsis / etiology
  • Sepsis / mortality
  • Sepsis / physiopathology*
  • Severity of Illness Index
  • Transforming Growth Factor beta / blood*

Substances

  • Biomarkers
  • Extracellular Matrix Proteins
  • Receptors, Vitronectin
  • Transforming Growth Factor beta
  • integrin alphaVbeta5
  • betaIG-H3 protein