The mechanism behind the progression of idiopathic pulmonary fibrosis-a disease in which the lungs harden for unknown reasons-has been uncovered by a team of Korean researchers.

On April 28, the Korea National Institute of Health, under the Korea Disease Control and Prevention Agency, announced that it has identified a new function of the gene 'ATF3(Activating Transcription Factor 3)', which regulates abnormal immune responses during the progression of idiopathic pulmonary fibrosis.

ATF3 is an activating transcription factor that is triggered when cells are exposed to inflammation or various types of stress, and it is known to regulate metabolic activity and immune responses in the body.

Idiopathic pulmonary fibrosis is an intractable lung disease of unclear origin in which the lung tissue gradually hardens, leading to a decline in respiratory function. As the disease progresses, shortness of breath makes daily life difficult, and the prognosis is extremely poor, with many patients dying within a few years of diagnosis.

Currently, two therapeutic drugs-pirfenidone and nintedanib-have been developed and are in use, but they cannot cure the disease and can only slow its progression. In response, the Korea National Institute of Health has been conducting research to identify the mechanisms behind pulmonary fibrosis and to discover key factors that regulate the progression of fibrosis.

The research team sought to verify how ATF3, a well-known transcription factor that is rapidly activated in response to inflammation or stress, regulates immune mechanisms and fibrosis in the lungs. To do so, they induced pulmonary fibrosis in experimental animal models deficient in ATF3.

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The results showed that the absence of ATF3 led to a more pronounced decline in lung function. In the experimental group lacking ATF3, lung capacity decreased by 20-25% compared to a 15-20% decrease in the control group, lung elasticity increased, and lung compliance decreased, indicating that the lungs became even stiffer. This demonstrates that ATF3 deficiency can accelerate the progression of pulmonary fibrosis and exacerbate the decline in lung function.

ATF3 deficiency was also found to significantly increase inflammatory responses in lung tissue. The number of neutrophils, which are responsible for the initial inflammatory response, increased more than tenfold, and M2c phenotype macrophages, which promote fibrosis, increased by 6.5 times-indicating abnormal changes in immune cell composition. Additionally, expression of genes related to fibrosis was increased, resulting in the simultaneous intensification of inflammation and tissue damage.

Transcriptomic analysis revealed that in the ATF3-deficient group, expression of genes related to inflammation and fibrosis increased by more than 1.5 times, and immune and inflammation-related pathways were activated. This supports the crucial role of ATF3 in suppressing the progression of pulmonary fibrosis by regulating immune responses.

The researchers explained, "We have identified a new molecular mechanism that simultaneously regulates the inflammatory response of immune cells and tissue fibrosis during the progression of pulmonary fibrosis. It is significant that we confirmed the ATF3 gene, which responds to early stress, plays a key role in suppressing excessive activation of the inflammatory response and mitigating the progression of pulmonary fibrosis."

Wonho Kim, Director of the Division of Chronic Disease Convergence Research at the Korea National Institute of Health, stated, "Since pulmonary fibrosis is a chronic lung disease that is difficult to treat, new therapeutic strategies are extremely important. We will continue to investigate the mechanisms behind chronic respiratory diseases and pursue research that can be applied to actual patient treatment strategies."

This research was published in February in 'Clinical Science', a top international academic journal in the field of allergy and immunology.