Autophagy the new target in airways remodelling

Dr Pawan Sharma, UTS

Dr Pawan Sharma

The cellular mechanism of autophagy, previously linked with tissue fibrosis in organs such as the kidney and liver, is selectively enhanced in asthma patients and drives airway remodeling in the lungs. According to research led by the University of Technology Sydney (UTS), the findings provide a new therapeutic target in difficult-to-treat asthma and possibly other fibrosing pulmonary diseases.

The Limbic asked Dr Pawan Sharma, from the UTS, about the research and its likely clinical implications.

Autophagy is a normal physiological process for keeping cells healthy, but it can be abnormally activated. How do you explain why autophagy goes wrong in the context of asthma?

Autophagy is a fundamental mechanism to maintain normal cellular homeostasis under health and disease. It is an evolutionarily conserved phenomenon that is tightly regulated and is highly adaptive to meet the dynamic needs of the cell. The nature of this protective response may vary from one cell-type to another to meet cellular demand, while it is still unclear why, when and how this adaptive homeostatic mechanism goes wrong in asthma. What we do know from both our own research and research coming out from other labs is that it is dysregulated in asthma, i.e. this protective homeostatic mechanism supersedes the physiological (basal) autophagy in response to chronic allergen exposure, inflammation, and participates in the development of long-term structural changes in the airways that dictates reduced lung function and ultimately breathlessness in asthma.

Elevated levels of transforming growth factor β (TGFβ) were associated with autophagy and airway remodeling. How might this and other biomarkers be useful in understanding or managing refractory asthma?

Transforming growth factor β, and in the context of our study TGFβ1 is a multi-functional cytokine, very important right from the early stages of lung development in humans. Interestingly, in addition to its role in maintaining cellular physiology, there is solid evidence that autophagy has conserved roles in differentiation and development and it is one of the key pathways that regulate embryonic development. Autophagy signaling is tightly regulated and under the influence of TGFβ1 to facilitate proper organogenesis and the same is true for lung development and growth both in utero and later in life.

Can TGFβ1 can be a biomarker in refractory asthma? Though great strides have been made in other diseases especially in advanced cancers where plasma TGFβ1 level correlates with cancer severity, this is not true in severe asthma. Elevated levels of TGFβ1 have been observed in serum and bronchoalveolar lavage fluid of asthmatics but definitive studies are lacking to demonstrate its clear correlation with asthma severity. I believe larger clinical studies are warranted to test this as a biomarker with a particular emphasis on clinical phenotypes of asthma subjects where it can be a target for individualised therapy.

You’ve also been able to show chloroquine is an autophagy inhibitor that can mediate airway remodeling. What is the potential for reversing structural changes in the lung?

Chloroquine is an antimalarial drug with a long history of use and known safety profile. This is a perfect example of ‘repurposing medicine’ as it also affects other pathways and is widely used as an experimental drug to investigate autophagy-mediated signalling. At the dose used in our study we found chloroquine reduced key autophagy markers along with concomitant reduction in TGFβ1-mediated signalling – both in human cells and murine models – that leads to structural changes in the lung. Therefore, this intervention has promise as suggested from our preclinical data using a treatment model of chronic allergic asthma to reverse structural changes in the airways.

What’s the important next step in this line of research?

This has been a great learning experience on how one of the fundamental cellular mechanisms can be exploited for therapeutic gain in asthma. I believe our research will drive focus on designing new drugs that can selectively target autophagy in the airways and are devoid of off-target effects. Our focus is to test newer compounds that are selective in our asthma models and also to investigate the role of autophagy with severity of the disease with a focus on refractory-uncontrolled asthma. We are learning a lot from cancer research where the emphasis is on identifying the right target to select the best available drug for the patient. Our research will further bolster efforts to personalise asthma treatment by complementing existing treatments such as biologics and bronchial thermoplasty, and importantly, can reduce the cost of treating severe asthma.

Already a member?

Login to keep reading.

Email me a login link

© 2023 the limbic