Adriano Rossi's lab aims to gain a better understanding of the mechanisms controlling inflammatory processes with a view to help develop novel therapies for chronic inflammatory diseases.
We aim to gain a better understanding of the mechanisms controlling inflammatory processes with a view to help develop novel therapies for chronic inflammatory diseases. For this we aim to elucidate the mechanism regulating inflammatory cell behaviour and apoptosis and manipulate the processes controlling the resolution of inflammation in order to develop new therapeutic strategies to remove unwanted and dysregulated inflammation.
Although neutrophilic and eosinophilic granulocytes are key effector cells in host defence against invading bacteria and parasites, over-recruitment, uncontrolled activation and defective removal by macrophages of these cells plays a prominent role in the initiation and propagation of chronic inflammatory conditions including, emphysema, bronchitis, rheumatoid arthritis, inflammatory bowel disease, asthma, etc. Apoptosis or programmed cell death is a fundamental process regulating inflammatory cell survival providing an efficient non-inflammatory mechanism for removal of potentially histotoxic cells from inflamed sites by resident or recruited macrophages and is critically involved in the successful resolution of inflammation.
My group has been investigating how neutrophil and eosinophil apoptosis as well as macrophage phagocytosis of apoptotic cells can be regulated by pharmacological intervention, and we believe that selective interference of these fundamental processes may be harnessed for therapeutic gain. Signalling pathways, including those involving transcription factors (eg, NF-kB) and kinases (eg, MAPK and PI3K) have been shown by my research team to be key regulators of inflammatory cell survival and apoptosis in vitro. In addition, we have demonstrated that manipulation of such pathways in vivo has indicated that they also play a role in the resolution of inflammation. Furthermore, we have shown that anti-inflammatory glucocorticoids dramatically enhance the capability of macrophage to phagocytose apoptotic granulocytes and are currently investigating how other mediators of inflammation regulate this process. Furthermore, we have shown that manipulation of proteins directly involved in the control of apoptosis, such as Bcl-2 family members and caspases, can also be targeted in vivo to influence inflammatory resolution. Recently we have shown that cyclin-dependent kinase (CDK) inhibitor drugs, under development for the treatment of cancer, induce caspase-dependent human neutrophil apoptosis possibly by altering levels of the anti-apoptotic Bcl-2 family member, Mcl-1. Importantly, we have provided evidence that CDK inhibitor drugs augment the resolution of established 'neutrophil dominant' models of inflammation (including pleurisy, pulmonary fibrosis and arthritis) by promoting apoptosis of neutrophils. Thus we believe that manipulation of apoptotic pathways together with ensuring macrophage clearance of apoptotic cells appear to be viable pharmacological targets for reducing established inflammation. Our approach to understanding the molecular mechanisms governing inflammatory cell function and the resolution of inflammation involves an integrated in vitro, in vivo and translational strategy using wide-ranging technologies.
Inflammatory diseases and especially inflammatory lung diseases like chronic bronchitis and emphysema (COPD) and scarring conditions are responsible for a huge burden of illness and untimely deaths in the UK, but current treatments are at best poorly-effective. Over the past 20 years we have been taking an alternative approach to harness the mechanisms by which some inflammatory responses are known to get better spontaneously. Specifically we have identified a mechanism by which key inflammatory cells called neutrophils can be made to 'commit suicide' and be removed silently by local scavenger cells called macrophages. Unfortunately this suicide process is usually overcome by powerful survival factors present in the inflamed lung. In work newly-published in the leading international medical science journal 'Nature Medicine' we have shown that a CDK inhibitor called R-roscovitine, currently under clinical trial in cancer patients, causes a hitherto unexpected induction of neutrophil suicide, even in the presence of survival factors, and makes relevant models of human inflammatory lung disease resolve. This work has recently been publicised in the lay press. A part of our proposed programme of research will define exactly how drugs such as R-roscovitine works, an approach which may lead to the discovery of other useful anti-inflammatory drugs. We will also in the processes of carrying out a clinical study of the drug's effectiveness using cutting-edge imaging technology to monitor the progress of the disease non-invasively and demonstrate its response to treatment.