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Mechanism identified showing how air pollution affects lung tissue

Researchers at Nanjing University have identified a mechanism by which air pollutants affect the structure of lung tissue and increase cancer risk.

According to a research published today in eLife, scientists have discovered a mechanism that describes how small air pollution particulates may cause lung cancer. The discovery may pave the way for novel techniques to preventing or treating the disease’s early stages.

Fine particulate matter (FPM), a tiny, inhalable particle present in air pollution, has been identified as a Group 1 carcinogen and a significant hazard to world health. FPM’s cancer-causing mechanism, on the other hand, is unknown.

Zhenzhen Wang, first author of the study and a researcher at Nanjing University (NJU), told eLife, “Despite its potential to cause mutations, recent research suggests that FPM does not directly promote — and may even inhibit — the growth of lung cancer cells. This suggests that FPM might lead to cancer through indirect means that support tumour growth. For example, some studies suggest FPM can prevent immune cells from moving to where they are needed.”

To investigate this hypothesis, Wang and his colleagues gathered FPM from seven different areas in China and evaluated its impact on cytotoxic T-cells (CTLs), which are the key immune cells that fight tumor development. CTLs were attracted to the lungs of mice given lung cancer cells but not exposed to FPM to eliminate the tumor cells. CTL infiltration was delayed in mice whose lungs were exposed to FPM, presumably allowing tumor cells to establish themselves in lung tissue.

The scientists looked at both the CTLs and the lung tissue composition to figure out why the CTLs didn’t reach the lungs as rapidly in the FPM-exposed lungs. CTLs exposed to FPM preserved their migratory capabilities, but FPM treatment significantly constricted the lung tissue structure and the gaps between which immune cells migrate. Collagen — a peptide that gives structural reinforcement to cells and tissues — was also substantially greater. When the researchers looked at the mobility of CTLs in mice, they found that those in FPM-treated lung tissue struggled to move, but those in untreated tissue moved readily.

Significant increases in a collagen subtype, termed collagen IV, were shown to be the source of structural abnormalities in the tissue, but the researchers were still unsure how FPM triggered this. When they examined the structural alterations to collagen IV and the enzyme that causes them, termed peroxidasin, they discovered the explanation. This enzyme causes and aggravates a specific sort of cross-linking in lung tissue that has been linked to FPM exposure.

Wang told eLife, “The most surprising find was the mechanism by which this process occurred. The peroxidasin enzyme stuck to the FPM in the lung, which increased its activity. Taken together, this means that wherever FPM lands in the lung, increased peroxidasin activity leads to structural changes in the lung tissue that can keep immune cells out and away from growing tumour cells.”

Lei Dong, co-author of the paper, added, “Our study reveals a completely new mechanism by which inhaled fine particles promote lung tumour development. We provide direct evidence that proteins that stick to fine particulate matter can cause a significant and adverse effect, giving rise to pathogenic activity. Our discovery that peroxidasin is the mediator of this effect in lung tissue identifies it as a specific and unexpected target for preventing lung disease caused by air pollution.”

The study was published in eLife on April 19th, 2022.

Abstract. Although fine particulate matter (FPM) in air pollutants and tobacco smoke is recognized as a strong carcinogen and global threat to public health, its biological mechanism for inducing lung cancer remains unclear. Here, by investigating FPM’s bioactivities in lung carcinoma mice models, we discover that these particles promote lung tumor progression by inducing aberrant thickening of tissue matrix and hampering migration of anti-tumor immunocytes. Upon inhalation into lung tissue, these FPM particles abundantly adsorb peroxidasin (PXDN) – an enzyme mediating type IV collagen (Col IV) crosslinking – onto their surface. The adsorbed PXDN exerts abnormally high activity to crosslink Col IV via increasing the formation of sulfilimine bonds at the NC1 domain, leading to an overly dense matrix in the lung tissue. This disordered structure decreases the mobility of cytotoxic CD8+ T lymphocytes into the lung and consequently impairs the local immune surveillance, enabling the flourishing of nascent tumor cells. Meanwhile, inhibiting the activity of PXDN abolishes the tumor-promoting effect of FPM, indicating the key impact of aberrant PXDN activity on the tumorigenic process. In summary, our finding elucidates a new mechanism for FPM-induced lung tumorigenesis and identifies PXDN as a potential target for treatment or prevention of the FPM-relevant biological risks.

Wang Z, Zhai Z, Chen C, Tian X, Xing Z, Xing P, Yang Y, Zhang J, Wang C, Dong L. Air pollution particles hijack peroxidasin to disrupt immunosurveillance and promote lung cancer. Elife. 2022 Apr 19;11:e75345. doi: 10.7554/eLife.75345. Epub ahead of print. PMID: 35437145.

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