The Anthony Harmar Memorial Lecture 2018: Prof. Tracy Hussell

Prof. Tracy Hussell

Lung Disease: think about disease in a different way

Hussell Tracey (Altered)Tracy Hussell is Director, Manchester Collaborative Centre for Inflammation Research (MCCIR) and Professor of Inflammatory Disease, University of Manchester, Oxford Road, Manchester, M13 9PT.

To be healthy is an active process so health must be continually maintained. Is disease a process that can’t sense it is healthy again? We all have different set points. Sterile inflammation can be created by a single missing factor. Generally, while the lung epithelium is intact, then the tissue is non-activated. Epithelial damage is a critical driver, which may permanently change macrophages and the basal state in the lung. Airways macrophages are critical – when washed out, tissues change very quickly.

CD200R transmits negative signal to macrophages and ligand is on epithelium cells. Then antigen relieves signal. Axl continually recognises gas 6 on apoptosis so don’t activate with apoptosis.

Resolution of inflammation gives a different macrophage population – twice as many as before inflammation, which may survey the environment, resolving from a severe inflammatory event, to a new state. There are therapeutic ways of going back, but chronic obstructive pulmonary disease (COPD) and asthma have a permanently active state. MiRNAs are changed in resolved inflammation, therefore let-7b is increased, modifying Toll response changes. Patient becomes less responsive to bacteria – patients are retuned to not die when challenged, but have also lost miRNAs. The basement membrane is normally very thin but becomes permanently changed (Burgstaller et al., 2017, Eur Respir J. 2017 doi: 10.1183/13993003. PMID: 28679607). The tissue is changed, so not just immune effects.

Hyaluranon is a major constituent of the inflamed lung. Is the lung inflamed or is it just because there are a lot of retained immune cells? The latter. Why does matrix persist? Hyaluronic acid synthase is increased (clearance unchanged, hyaluronase unchanged). Matrix turnover means that there are more activated immune cells. The impact of viral infections on lung matrix affects its mechanical stability and structural support. The composition of matrix also indirectly controls inflammation by influencing cell adhesion, migration, survival, proliferation and differentiation. Hyaluronan is a significant component of the lung extracellular matrix and production and degradation must be carefully balanced. Tracy discovered an imbalance in hyaluronan production following resolution of a severe lung influenza virus infection, driven by hyaluronan synthase 2 from epithelial cells, endothelial cells and fibroblasts. Furthermore hyaluronan, due to elevated TNF, sequesters CD44-expressing macrophages. Intranasal hyaluronidase reduces lung hyaluronan restoring function. Hyaluronidase is already used clinically. Digestion of HA restores lung function. Hyaluronidase (available for clinical trials) appears an interesting option. (Hussell T et al., Eur Respir Rev., 2018, doi: 10.1183/16000617.0032-2018. PMID: 29950305).

In cancer the matrix is abnormal, and the immune system is paralysed. In many instances the matrix is stiff. It may be possible to think differently about reactivating the immune system here.

In severe cell death, macrophages clear apoptotic cells, TAMs recognise external phosphatidyl serine. Reverse signalling to STAT1 turning off inflammation, so while apoptosis is going on the tissue is vulnerable to bacterial attack. Axl receptor only in lung so this represents a unique opportunity for targeted therapy. Changed matrix, lost apoptosis, but poorly cleared even if immunity suppressed.

Eight days after influenza, basal cells proliferate requiring Axl receptor to show that damage has happened. Basal cell show hyperplasia if apoptosis continues – most lung disease has this as a hallmark. Axl antagonists allows faster repair. Type 1 interferons (IFNs): Neuropeptide receptors alter away homeostasis Gfra2 part of GDNF family massively increased on lung TAMs. Needs to co-stimulate with ret which is induced by type 1 IFNs. The virus may act via TLR7/8, in epithelium. MMP2 is specifically increased to degrade collagen type IV to degrade basement membrane. Two chemokines bind CXCR2. CCL18 macrophages that drive resolution, no homologue in rodents.

Is COPD then associated with inflamed tissues or trapped inflammatory cells? Possibly like tumours. Will check-point inhibitors also release antigen presenting cells? New therapeutic options await validation.

Slide Downloads: PPTX | PDF


tonyharmar

Anthony Harmar, Professor of Pharmacology in Edinburgh.

In addition to being a brilliant pharmacologist, Tony set up the IUPHAR Edinburgh database group which initiated IUPHAR-DB, which expanded into the IUPHAR/BPS Guide to Pharmacology database (www.guidetopharmacology.org).

 

Advertisements
Tagged with: , , , , , ,
Posted in Events
One comment on “The Anthony Harmar Memorial Lecture 2018: Prof. Tracy Hussell

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google+ photo

You are commenting using your Google+ account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

%d bloggers like this: