Anaesthesia, Critical Care and Inflammation

Overview

Anaesthesia and the trauma of surgery cause inflammation, which stimulates the patient's immune system and wound-healing defence mechanisms. This is essential for recovery, but any abnormality in the inflammatory response can cause infections that may lead to septicaemia (blood poisoning). A wide variation is seen in individuals' response to infection and recovery after surgery, and we are investigating whether a person's genetic make up may explain this.

It has even been proposed that patients could carry a silicon chip containing their genetic profile by the year 2010. Such technology could provide individually targeted therapy and improve clinical outcome after surgery.

Fibrin fragments and inflammation

In collaboration with Prof. Petzelbauer from Vienna, we have discovered that fibrin fragments (present in our blood stream and are derived from the clotting factor fibrinogen) play an important role in heart attacks. Interestingly, some of the fibrin fragments have pro- and others have anti-inflammatory effects. We have demonstrated that Bβ15-42 has potent anti-inflammatory properties and reduces the tissue damage during heart attacks. Furthermore, in a randomised controlled trial (RCT), we have confirmed the safety of Bβ15-42 in healthy man. Currently, we are recruiting patients for a multi center, double blind, randomized, placebo controlled study to measure the effect of Bβ15-42 on ischaemia reperfusion injury in patients undergoing primary percutaneous coronary intervention (PCI): The “F.I.R.E.” Study (www.clinicaltrials.gov).

Innate immunity

Rapid activation of adrenal steroid release is a key event in the organism’s first line of defense against sepsis and septic shock (blood poisoning). Each year approx. 50,000 people die in the UK due to sepsis. Toll-like receptors (TLRs) are critical in the early immune response upon bacterial infection, and recent data from our lab (in collaboration with Prof. Bornstein from Dresden and Prof. Schumann from Berlin) demonstrate a novel link between the innate immune system and the adrenal stress response mediated by TLRs. Glucocorticoids and TLRs regulate each other in a bi-directional way. Bacterial toxins acting through TLRs directly activate adrenocortical steroid release. TLR2 and TLR4 are expressed in human adrenals and TLR2 deficiency is associated with an impaired glucocorticoid response. Furthermore, TLR2 deficiency is associated with marked cellular alterations in adrenocortical tissue. In conclusion, TLRs play a crucial role in the immune–adrenal crosstalk. This close functional relationship needs to be considered in the treatment of inflammatory diseases requiring an intact adrenal stress response. We have conducted a first clinical trial studying the effects of TLR polymorphisms on patient’s outcome following cardiac surgery.