Overview

Severe burns injury produces overwhelming levels of systemic inflammation, described clinically as the ‘systemic inflammatory response syndrome’ (SIRS), a condition that also occurs in patients with severe infection (sepsis) and major traumatic injuries. SIRS can lead to multi-organ failure with significant mortality and morbidity in the intensive care unit (ICU), and in burns patients considerably delays wound healing, affecting surgical outcomes and long-term quality of life in surviving patients. For all SIRS conditions, there remains an unacceptable lack of specific treatments, representing a major unmet clinical need. A significant obstacle in achieving this goal is the identification of strategies that specifically target systemic inflammation and resultant organ dysfunction, without suppressing beneficial immune and tissue repair functions. 

Our group is investigating ‘microvesicles’ as a novel therapeutic target for the treatment of severe burns injury patients. Microvesicles are membrane-enclosed particles released from activated or dying cells that represent a novel and emerging pathway of long-range intercellular communication. Although microvesicles have been investigated in sepsis, their production and role in severe burns-induced SIRS was completely unknown until we began investigating this question.  In a recently published pilot study conducted at Chelsea and Westminster hospital in collaboration with burns ICU clinical staff, we found that circulating levels of microvesicles are elevated following major burns injury and correlated with clinical severity. In parallel to clinical studies, we are investigating the basic mechanisms of microvesicle production and function, focussing on the unique pathways associated with thermal injury and sterile inflammation.

Previous attempts to treat SIRS based on inhibiting circulating mediators (e.g. anti-cytokine therapies) have had little success, suggesting that they may not be the dominant factors for ‘long-range’ inter-cellular signalling in SIRS. In contrast to soluble, non-membrane encapsulated mediators, microvesicles have the potential to deliver inflammatory signals to remote cells without dilution or neutralisation by natural antagonists. Reduction of local microvesicle production or their interactions with remote target cells, has potential application in selectively controlling propagation of systemic inflammation.

Summary of current research

Our aim is to determine the role that microvesicles play in the development of burn-related SIRS and organ injury, to enhance our basic knowledge of burns pathogenesis and ultimately to identify novel therapeutic strategies:

• Characterise microvesicle release from tissue into the blood circulation following burn injury
• Define circulating microvesicle dynamics and interaction with intravascular cells in relation to acute organ inflammation
• Evaluate microvesicle function and relationship to clinical severity in patients with major burns injuries