SAA emerges as both marker and mediator of degenerative lung disease
22 May 2012 by Evoluted New Media
Gary P Anderson tells us about recent research on chronic obstructive pulmonary disease from the University of Melbourne
There is a global epidemic in chronic obstructive pulmonary disease (COPD) but hardly anyone outside the lung field is talking about it. World Health Organisation (WHO) modelling predicts that COPD will likely be the third most common cause of death world-wide by the middle of the century.
In Australia, COPD is one of the largest contributors to DALY (Disability Adjusted Life Year) disease burdens and accounts for a huge tranche of the money spent on direct hospital costs – around $1 billion a year, most of which is spent when COPD patients experience deteriorations or exacerbations. The collateral economic costs are much higher, and very few people are aware that diagnosis of COPD is linked to survival curves that are worse than most major malignancies. What then is COPD, what are its major research and clinical translation problems?
At the University of Melbourne, we have recently described the role of SAA (Serum Amyloid Protein A) as both a biomarker and mediator of COPD1,2. SAA represents a family of highly conserved proteins that are rapidly induced in the liver during infection or tissue damage and, in health, contribute to host defence and cholesterol transport. Our findings provide evidence that SAA blood levels predict the severity of exacerbations and that SAA may have a central role in sustained inflammation and steroid hyposensitivity in COPD. The research path to test the clinical relevance of our observations has been long but the story is an interesting case study of the advantages of contemporary translational research that brings clinical medicine and basic science together.
Our work started with trying to understand the driving mechanisms of COPD and to find useful ways to improve the condition.
The causal association of cigarette smoking with COPD is well appreciated but most are unaware that 15-30% of all disease, depending on geographical area, is not caused by smoking. This group of COPD patients are mostly poorer women exposed to noxious cooking fumes and domestic air irritants. A smaller percentage of never-smokers also develop the disease due to a range of genetic abnormalities, most famously alpha-1 anti-protease deficiency.
COPD is best known commonly (but incompletely) as emphysema. COPD is however an umbrella term covering a group of overlapping pathologies all of which lead to airflow limitation, felt as an increased resistance to breathing and difficultly in deflating the lungs during expiration. The main pathological components of COPD are emphysema (the loss of gas exchanging lung parenchyma), bronchiolitis (inflammation and fibrosis of small airways) and bronchitis accompanied by airway mucus hypersecretion.
Because much of this airflow limitation is due to structural change – specifically small airway fibrosis and loss of elastic recoil secondary to emphysema – it is only partially reversible with bronchodilators such as beta-agonists and anti-muscarinc agents. Until lung regeneration is achievable, these agents will most likely remain the mainstay of treatment used in combinations with anti-inflammatory drugs, mostly glucocorticosteroids. But unlike asthma, the inflammation in COPD is intrinsically highly resistant to steroid therapy.
COPD is a genetically complex group of conditions and, by definition, there is no single route to disease existing in humans. Where then does our work on SAA fit in?
In the absence of effective strategies to regenerate lung tissue – an area of very active research in our group – we have a pragmatic interest in finding ways to reduce the burden of disease and alleviate suffering. Our first work on SAA came about through trying to solve a simple clinical problem. Smoking is well known for its adverse effects on immunity and there is a major subset of COPD patients who experience recurrent chest infections. These patients, as well as being the major cost component of all COPD, are at very high risk of a fatal outcome and are known to deteriorate much more rapidly.
These recurrent chest infections that can easily progress to life-threatening pneumonia 
are not the only biological enigma in COPD. One major problem is that once inflammation is established in COPD it never remits, even when smoking has been stopped for years. As well as this persistence, there is also a clear and medically important defect in catabasis, the ability to resolve inflammatory injury. A further pharmacologically and clinically important problem is that lungs became refractory to the beneficial anti-inflammatory effects of inhaled glucocorticosteroids. This makes it very difficult to control inflammation without risking major side-effects, such as muscle wasting and bone weakness. Given that COPD patients already have enfeebled muscles that limit their activity as much as breathlessness, and that a simple rib or spinal fracture can prove fatal if it so weakens the patient as to cause pneumonia – these are very important medical problems.
From epidemiological microbiology studies, it was clear that about a third of all these exacerbations were due to viral infection, a third to bacterial chest infection and a third could be contributed to other causes. We applied proteomic methods to the blood of exacerbating patients studied in the community just as they were feeling the first change in symptoms at an onset of exacerbations. We were able to access these patients because we had established these community studies as a part of the Melbourne Longitudinal COPD Cohort study (MLCC).
What we were looking for was a simple blood biomarker that would readily distinguish bacterial infections from the rest as this could then be used to guide aggressive antibiotic therapy to prevent or reduce the severity of at least some events. What we found however was a substantial blood signal whose levels predicted the severity of the ensuing event with excellent receiver-operator curve characteristics. This signal turned out to be the hepatic acute phase protein SAA.
On one level, we were delighted because this was the first time a predictive biomarker that projected the future outcome of an exacerbation had ever been described. On another level, we were puzzled – why was SSA a much better predicator than the very widely studied C-reactive protein, which we had measured as a reference biomarker? They should have been about the same.
Both SAA and CRP are made very rapidly in the liver with a very similar kinetic, and induced by the same factors such as IL6 and IL1beta in response to distal inflammatory insults. (As it turned out neither of these markers or any other marker we have found to date discriminates bacterial from viral infection with diagnostic certainty.)
Studying this discrepancy led us to our most recent findings which have forced us to reassess our notions of COPD pathogenesis. We reasoned that one possible explanation for why SAA was so much better as a biomarker would be if it were made directly in the lungs. And we rapidly found that to be true: SAA was indeed made in the lungs of COPD patients and much of it by macrophages. We demonstrated that, because SAA has a positive steroid sensitive promoter, its levels are actually increased by anti-inflammatory steroid therapy, helping to explain why this class of drugs works so poorly in disease. Moreover, in a series of cell biology and in vivo experiments, we were able to demonstrate that SAA and Lipoxin A4 interfere with each other during negative allosteric competition at the ALX (FPR2) receptor. This is important because Lipoxin A4 is an endogenous beneficial pro-resolving lipid that normally helps to quell inflammations. Very unusually, it exerts its beneficial effects via the same G-protein coupled receptor as SAA. However, when SAA occupies ALX it sends a strong pro-inflammatory signal and blocks lipoxinA4. We think this helps us to understand one of the main mechanisms underlying the chronic, self-perpetuation inflammation that is a characteristic of COPD.
Our feeling is we are still far from the end of the story. We need to understand in much more detail why macrophages, and probably other cell types, begin to make SAA in the lung. Given that SAA is so pro-inflammatory, we need to understand whether it is a driver of disease co-morbidities in COPD. We are also very interested in finding safe ways to block the production or action of SAA to improve lung inflammation and, hopefully, restore the ability of substances like lipoxins to mediate natural healing of damaged lung tissue. We are hopeful that this will lead to improvement in the management of this currently incurable condition.
References
- Bozinovski, S., A. Hutchinson, et al. (2008). "Serum amyloid a is a biomarker of acute exacerbations of chronic obstructive pulmonary disease." Am J Respir Crit Care Med 177(3): 269-278
- Bozinovski, S., M. Uddin, et al. (2012). "Serum amyloid A opposes lipoxin A4 to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease." Proc Natl Acad Sci USA.
