Discovery could lead to the development of biological drugs to treat chronic lung disease.
National University of Singapore researchers have found a novel property of a protein found in human lungs, which has the potential to open opportunities for biological drugs to treat chronic obstructive pulmonary disease (COPD), a progressive chronic lung disease that is one of the leading causes of death worldwide.
The research was led by Associate Professor Ge Ruowen from NUS Biological Sciences and published in the prestigious scientific journal Proceedings of the National Academy of Sciences (PNAS).
Living with COPD
COPD can be caused by long-term exposure to irritants or particulate matter such as cigarette smoke and symptoms include coughing, breathing difficulties and wheezing. Patients with chronic lung disease display two key conditions – emphysema (the destruction of alveolar walls and enlargement of the alveoli) and chronic obstructive bronchitis (inflamed small airways). This leads to persistent respiratory symptoms that progress to lung function decline. However, the current treatment options for this chronic lung disease only provide symptomatic relief.
“COPD patients have difficulty breathing, which hinders their ability to work or exercise. They do not absorb enough oxygen, and this affects their heart function too. COPD is a very dangerous condition, but public awareness of it is very low,” said Associate Professor Ge.
Maintaining health whilst dealing with a chronic lung disease
Alveolar macrophages (AMs) are immune cells residing in the airspace of lung breathing structures called alveoli and they can display either pro-inflammatory or anti-inflammatory properties. In COPD, the pro-inflammatory AMs are amplified, which is the main cause of chronic lung disease.
Ge’s team discovered that a lung-resident protein, called isthmin 1 (ISM1), is critical for restraining inflammation in a healthy lung by selectively eliminating the pro-inflammatory type of AMs. In their laboratory studies, they found that the absence of this protein was associated with large numbers of pro-inflammatory AMs, leading to lung inflammation, progressive emphysema and significant lung function decline even without exposure to irritants.
Furthermore, ISM1 helps maintain healthy lungs by targeting the GRP78 signalling receptor (csGRP78) that is present on the surface of the pro-inflammatory AM, triggering apoptosis (cell death), thereby reducing inflammation.
Potential therapeutic developments
The research team noted that endogenous – or internal – ISM1 proteins may not be sufficient to counteract lung inflammation in COPD. To tackle this, the researchers worked with Professor Fred Wong at NUS Pharmacology to carry out laboratory studies to examine the effectiveness of delivering recombinant ISM1 protein directly via droplets into the airway. The team observed a reduction in lung inflammation, suppression of emphysema development and restoration of lung functions that were once affected by chronic lung disease.
“By directly targeting pro-inflammatory AMs using recombinant ISM1 protein, our novel treatment suppresses the root cause of COPD, and opens up the possibility of developing this into a viable treatment for this debilitating disease that affects many patients around the world,” said Ge.
“These findings not only provide a new avenue to develop novel and effective drugs for COPD but also warrant studies of ISM1 in other inflammatory respiratory diseases,” added Professor Wong.
