Mesenchymal Stem Cell (MSC) regulation of pulmonary macrophage populations in Acute Respiratory Distress Syndrome (ARDS).

Acute Respiratory Distress Syndrome (ARDS) is a severe clinical syndrom that affects 20% of all critically ill patients in intensive care. Unfortunately, around 30-50% of these people will die from the condition and the quality of life of the survivers can be seriously reduced due to the consequent chronic lung problems.There is no effective treatments for this condition at this time and therefore new medicines are urgently needed. ARDS is characterised by an excessive and disregulated inflammation in the lung that leads to inappropriate infiltration of immune cells, lungs fill with water and fail to maintain its main function - breathing. In order to breath these patients require mechanical ventilation.
ARDS results from multiple causes, although pneumonia induced ARDS is the most common and the most devastating. Inflammation is the way in which the body reacts to infection, irritation or other injury. Normally, inflammation is one way the body heals and copes with the infection, however, when disregulated in certain condition such as ARDS it can lead to severe damages and impair of the the lung function. Immune cells called macrophages have increasingly been recognized to play a key role in the development and resolution of ARDS functioning as a coordinators of inflammatory responses. Recently more and more attention of clinicians and basic scientists working in the field of ARDS research is drawn to cell-based therapies. A key advantage of cell based therapy compared to pharmacologic treatment is that cells can actively respond to the local microenvironment and exert multiple beneficial effects, modulating several injurious and reparative pathways in this complex disease process.
One of the most promising candidate for a cell based therapy for ARDS are cells termed Mesenchymal Stem Cells (MSC), which represent one kind of adult stem cells (can be easily isolated from tissues of adult patients or healthy volunteers), because of this there is no ethical issues that are related to use of embryonic tissues. MSC could easily be propagated and manipulated under laboratory conditions and have capacity to differentiate into multiple different cell types of the body. Importantly, long term research has shown their safety in terms of developing tumors.
Multiple preclinical animal studies conducted by our group as well as by other investigators showed that MSC indeed have protective effect when administered as a treatment for ARDS. Among several beneficial effects, their administration always is associated with drastically reduced inflammation, however the mechanisms of this phenomenon are still unclear and data on their interaction with the immune cells of the lung remain unsufficient and controversial. To translate MSC into the clinical practice it is essential that we have more precise understanding of their mechanism of action.
The main question we are keen to address in the proposed research is: how MSC treatment influence the lung macrophages? What alterations do MSC induce in their functions and what molecular mechanisms mediate those changes.
Based on our preliminary data and results from other studies we have reasons to hypothesize that MSC will promote polarization of macrophages towards the state in which they will supress the inflammation and promote the resolution of ARDS- so called "alternatively activated macrophages" or M2 macrophages.
The mechanistic data from this study will bring development of new therapy on the MSC basis closer to the patients. Additionally, it will broaden the existing knowledge of lung macrophage biology and their role in the resolution of ARDS which could lead to other new treatments. Importantly, findings from the proposed study may also have relevance for other macrophage dependent inflammatory conditions.

Acute Respiratory Distress Syndrome (ARDS) is a major cause of acute respiratory failure in critically ill patients, with no effective treatment. The main characteristic of ARDS is excessive pulmonary inflammation. Lung macrophages play an important role in the pathogenesis and resolution of ARDS by orchestrating immune responses. As shown in several preclinical animal studies Mesenchymal Stem Cells (MSC) have strong protective effect in the ARDS and might constitute novel approach to therapy for this devastating disease. However, to develop a new therapy based on MSC, we need a better understanding of the mechanisms mediating their protective effect. Prior publications and our preliminary data suggest that MSC may have a role in promoting alternative activation of macrophages/monocytes, which play an important role in the resolution of ARDS. In this project we propose to study the mechanistic alterations in lung macrophages, induced by MSC in the clinically relevant in vitro and in vivo models of ARDS. This work is important because it will determine the mechanisms and importance of MSC-macrophage interactions in experimental ARDS which is critical for rationale development of MSC-based therapy for these condition, broaden our knowledge about MSC and macrophage biology and could point to new molecular therapeutic targets, with implications for other conditions with macrophage driven pathophysiology.

The mortality associated with ARDS remains high, between 30-40%. It is a common condition affecting all age groups with an estimated incidence of 79 per 100, 000 patient years. ARDS has significant resource implications, prolonging intensive care unit (ICU) and hospital stay, and requiring rehabilitation in the community. The cost per ICU bed-day in the UK exceeds £1800 and delivery of critical care to patients with ARDS accounts for a significant proportion of ICU capacity. Only 54% of survivors are able to return to work 12 months after hospital discharge. The high incidence, mortality, long-term consequences and economic costs mean that ARDS is an extremely important problem.

Understanding how MSC regulate macrophage phenotype in ARDS may lead to the development of specific new therapies to reprogram inflammatory cells into a cell population that drives resolution. Hastening the recovery from ARDS would lead to a shorter ICU stay, with attendant reductions in nosocomial infection, and other critical illness complications including neuropathy/myopathy/ delirium. This would have direct short term benefits to the patients themselves, including reduced hospital stay and complications, leading hopefully to a better long term functional outcome, with more patients returning to work. Additionally this would lead to a reduced burden for carers and reduced cost of stay and long term healthcare provision.

Understanding the mechanisms mediating effect of MSC on macrophages in ARDS will lead to identification of other therapeutic targets (independently of MSC), (e.g. SOCS proteins or paracrine factors secreted by MSC with immunomodulatory properties) with the potential for further development as a pharmacological treatment for ARDS.

In addition to this condition, the understanding of mechanisms mediating of MSC-macrophage reprogramminig will open new avenues of research for other diseases mediated by excessive inflammation, both in the lung and in other organs.

With this in mind, this research is likely to impact other researchers both academically and industrially in development of follow-on therapeutics and biomaterials that can exploit these effects. Therefore it is tangible that if successful, this project could lead on to the development of other daughter therapeutics that could not only help patients suffering other inflammatory diseases, but also generate new R & D jobs and revenue for the UK.