Am J Respir Crit Care Med Clinical Value of Fibroblast Activation Markers in Early Diagnosis of Interstitial Lung Diseases Confirmed2022-08-22104
Recently, the SKLRD’s research group led by Su Jin worked with Professor Luo Qun and Director Wang Xinlu of the Nuclear Medicine Department of the First Affiliated Hospital of Guangzhou Medical University. They had made some important findings in the field of early diagnosis markers of interstitial lung disease (ILD), which were published in Am J Respir Crit Care Med (IF: 30.528) with the title of “Comprehensive analysis of fibroblast activation protein (FAP) expression in interstitial lung diseases (ILDs)”. With several technological means, the study has proved that FAP is highly expressed in the active fibrosis phase of ILD patients. Further clinically documented PET / CT studies showed that nuclear drug probes targeting FAP could non-invasively and dynamically monitor the location and abundance of activated fibroblasts in vivo, and that their signal intensity was positively correlated with the decline of lung function. This study not only provides a sensitive visual early diagnosis technology for the evaluation of fibrosis activity in ILD patients, but also provides a method for the early warning of disease progression.
The first authors of the paper are Yang Penghui, Fang Qi, Fu Zhenli, Li Jia of Guangzhou Medical University, and the corresponding authors are Professor Su Jin, Professor Luo Qun and Professor Wang Xinlu. The work was funded by the key project of Guangzhou Institute of Respiratory Health and the special COVID-19 project of Guangdong Provincial Department of Science and Technology.
Research background and significance
At present, the common clinical diagnosis methods of pulmonary fibrosis mainly include: lung biopsy and High Resolution CT (HRCT). Although the pathology after lung biopsy is the “gold standard” for diagnosis, the invasive nature of the biopsy and the risk of worsening the disease have limited the widespread use of this method. The diagnosis of fibrosis with HRCT requires the presentation of a “cord” or a “honeycomb” -like structure in the lungs, by which time fibrosis has entered the irreversible middle and advanced stages (Stage3 or Stage4,
Figure 1). In the past decade, 145 clinical trials of IPF have been conducted worldwide, but only two drugs that are relatively effective, though unable to improve overall survival rate of patients were approved in 2014 in the context that no anti-fibrosis drugs were available in the world. Some experts wrote in Lancet Respiration that the high failure rate of IPF drug development is directly related to the lag in diagnosis.
FAP has been shown to be particularly highly expressed in activated fibroblasts in various disease states. After its failure in drug development, the specifically identified compound in FAP extracellular region (FAPI) was coupled to positron nuclide 68Ga by nuclear chemistry experts at the University of Heidelberg in 2019, which was successfully used in the imaging of 28 kinds of human tumors. This breakthrough was selected as the annual progress of nuclear medicine in 2019.
Figure 1 Analysis of pathological characteristics in different stages of the fibrosis process
In this study, we first confirmed the high expression of FAP in different types of ILD using tissue samples from lung transplantation and lung biopsy, and based on single-cell transcriptomic data, we found that 91% of FAP-positive cells in ILD lung tissues were fibroblasts. With the support of previous basic studies, 83 ILD patients from our hospital were recruited for PET / CT studies targeting FAP, and found significant differences in the imaging characteristics of nuclear drug probes in IPF and non-IPF patients. Further association analysis with lung function revealed that the total volume SUVtotal of nuclide signal uptake was significantly correlated with lung function, whereas the common evaluation parameter for PET / CT in tumor patients, SUVmean, had nothing to do with lung function.
Research innovation and clinical significance
① It provides the basis for the use of non-invasive and sensitive visual PET / CT technology to monitor pulmonary fibrosis activity, and is expected to rewrite the guidelines of pulmonary fibrosis diagnosis;
② It is one of the typical cases of the rapid clinical transformation of basic research findings of the SKLRD;
③ It provides ideas for the discovery of hematological markers of pulmonary fibrosis. At present, the detection of blood FAP auto-antibodies has been authorized by the regional invention patent in China and Hong Kong (ZL 202011236638.7, HK40039496), and the FAP autoantibody detection kit developed based on immunofluorescence technology has also started model cooperation with the JinYu's LDT (self built laboratory detection) .
④ It provides ideas and reference for the early diagnosis of other types of interstitial lung fibrosis (such as slow discharge after lung transplantation).
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