Our research into tissue injury and remodelling spans many chronic inflammatory diseases of the lungs, skin, liver, GI tract, kidney and joints. Tissue (wound) repair is an intricate process that occurs after injury but normally resolves, allowing complete restitution of the organ structure and function.
We are investigating how these injury and repair mechanisms become persistently activated in many chronic inflammatory diseases leading to ‘tissue remodelling' involving alterations in tissue architecture, leading to substantial impairment of the normal function of the affected organ. These changes frequently arise due to an imbalance in the biosynthesis of fibrous extracellular matrix (ECM) proteins by specialized cells called myofibroblasts and its degradation by proteases, especially those of the Matrix Metalloproteinase superfamily.
In pathological conditions where the balance favours a net synthesis of ECM proteins, the organ becomes fibrotic due to infiltration with fibrous connective tissue (eg. fibrosis of thfe liver caused by viral infection or alcohol induced liver damage). Fibrosis results in reduced function of the organ because of loss of functional cells and, in the lungs and skin, reduced elasticity that has additional implications for function. If the balance favours net ECM degradation, tissue destruction can occur (eg. emphysema in the lungs caused by long term cigarette smoking). A better knowledge of the molecular mechanisms controlling tissue fibrosis or destruction in different pathological situations is useful for planning of preventative or development of new therapeutic strategies.
Tumour research has historically concentrated on the molecular features of the cancer cells; however it has become increasingly apparent that the normal components of the tumour stroma (including fibroblasts, inflammatory cells, endothelial cells) play an important role in promoting tumour progression. We are investigating the role of myofibroblasts in cancer, and have found that cancers, which contain a prominent myofibroblastic stroma behave aggressively. Myofibroblasts can originate from several cell types, including fibroblasts, fibrocytes and circulating mesenchymal stem cells. Some of the key we are attempting to address is the cellular origin of cancer myofibroblasts, the mechanisms regulating myofibroblast differentiation and their functional role, particularly in modulating tumour invasion and the immune response.
Our work in each of the above areas involves a range of in vivo models, complemented by ex vivo and in vitro primary human tissue explant and cell culture models which offer novel, highly informative platforms for drug toxicology screening and drug discovery.
Most damaged tissues have some capacity to replace damaged cells by proliferation, although this varies depending on the organ and tissue. Stem cells are activated in response to cell loss and wounding and play an important role in tissue repair. Read more about our research into stem cells and regenerative medicine (Link to stem cells and tissue regeneration)?
Research into tissue injury and remodelling is conducted by the following investigators :
Airway injury and remodelling in asthma, rhinitis and COPD
(
Peter Howarth
,
Donna Davies
,
Stephen Holgate
,
Ratko Djukanovic
, Hans Michael Haitchi,
John Holloway
,
Rami Salib
, Clark,
Jane Warner
,
Jane Collins
,
Tilman Sanchez-Elsner
)
Interstitial lung disease
(
Kate O'Reilly,
Donna Davies
,
Jane Collins
)
Kidney injury
(
Jane Collins
)
Liver Fibrosis
(Nick Sheron,
Julie Parkes
,
Paul Little
)
Inflammatory bowel disease
(
Sylvia Pender
,
Tilman Sanchez-Elsner
,
Jane Collins
)
Corneal Inflammatory Disease
(
Parwez Hossain
)
Skin remodelling in eczema
(
Michael Ardern-Jones
)
Vascular remodelling
(
Geraldine Clough
,
Christopher Torrens
)
Proteases
(
Andrew Walls
- mast cell proteases,
Hans Michael Haitchi,
Donna Davies
and
Stephen Holgate
- ADAM proteases;
Sylvia Pender
,
Jane Warner
, Parwez Hossain
- MMPs)
Myofibroblast tumour microenvironment
(
Gareth Thomas
,
Alex Mirnezami
,
Tim Underwood
(covering cancers of the head and neck, pancreas, colorectum, oesophagus))