Sftpb-KO Mouse

SFTPB, encoding pulmonary surfactant-associated protein B, is crucial for the formation and function of pulmonary surfactant. Pulmonary surfactant is essential for reducing surface tension in the alveoli, preventing alveolar collapse during expiration, and maintaining normal gas exchange in the lungs [1,2,3,4,5,6,7,8,9,10]. It is involved in fibrosis-related pathways and lung development and function [1,2,3,8]. Genetic models can help understand its precise role.

In research, SFTPB in serum extracellular vesicles (EVs) can predict the progression of interstitial lung diseases (ILDs) better than known biomarkers like serum KL-6 and SP-D. Pro-SFTPB levels increase in both serum EVs and lungs of patients with progressive pulmonary fibrosis (PPF), and in a mouse model, pro-SFTPB levels from alveolar epithelial type 2 cells increase in serum EVs and lungs, reflecting pro-fibrotic changes [1]. Biallelic pathogenic variants in SFTPB have been associated with fatal forms of ILD in newborns and pulmonary fibrosis in adults. A new homozygous SFTPB pathogenic variant in adults led to abnormal splicing and almost complete loss of SP-B expression, causing epithelial cell dysfunction and ILD [2]. The SFTPB gene CC genotype increases the risk of acute respiratory distress syndrome in COVID-19 patients, while the TT genotype requires shorter respiratory support [3]. Footprint-free CRISPR-based gene correction of PSCs derived from patients with a homozygous surfactant mutation (SFTPB121ins2) restores surfactant processing in alveolar epithelial type 2 cells (AEC2s), indicating its role in surfactant processing [4]. Homozygous, intragenic tandem duplication of SFTPB causes neonatal respiratory failure [5]. Proteome-wide Mendelian randomization studies suggest SFTPB as a potential therapeutic target for lung cancer [6,7]. Pulmonary epithelial cell-specific knockdown of NAMPT up-regulates SFTPB expression and attenuates acute lung injury in a mouse model [8]. Gene polymorphisms of SFTPB rs7316, rs9752 affect the diagnostic value of plasma Pro-SFTPB in Chinese Han non-small-cell lung cancer patients [9]. SCGB3A2+ SFTPB+ terminal airway-enriched secretory cells (TASCs) are unique to distal airways but are lost in COPD pre-terminal and terminal bronchioles [10].

In conclusion, SFTPB is vital for pulmonary surfactant function and lung health. Research using models has revealed its significance in various lung-related diseases such as ILDs, COVID-19-associated lung damage, neonatal respiratory failure, and lung cancer. Understanding SFTPB's role through these models provides insights into disease mechanisms and potential therapeutic strategies for lung-related conditions.

References:

1. Enomoto, Takatoshi, Shirai, Yuya, Takeda, Yoshito, Inoue, Yoshikazu, Kumanogoh, Atsushi. 2024. SFTPB in serum extracellular vesicles as a biomarker of progressive pulmonary fibrosis. In JCI insight, 9, . doi:10.1172/jci.insight.177937. https://pubmed.ncbi.nlm.nih.gov/38855869/

2. Desroziers, Tifenn, Prévot, Grégoire, Coulomb, Aurore, Legendre, Marie, Nathan, Nadia. 2023. Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis. In European journal of human genetics : EJHG, 31, 1083-1087. doi:10.1038/s41431-023-01413-w. https://pubmed.ncbi.nlm.nih.gov/37380697/

3. Fishchuk, Liliia, Rossokha, Zoia, Pokhylko, Valeriy, Kovtun, Serhii, Gorovenko, Nataliia. 2022. SFTPB (rs11130866) and NR3C1 (rs41423247) gene variants as potential clinical biomarkers for personalized treatment strategy selection in patients with severe COVID-19 pneumonia. In Respiratory investigation, 61, 103-109. doi:10.1016/j.resinv.2022.10.008. https://pubmed.ncbi.nlm.nih.gov/36460583/

4. Jacob, Anjali, Morley, Michael, Hawkins, Finn, Beers, Michael F, Kotton, Darrell N. 2017. Differentiation of Human Pluripotent Stem Cells into Functional Lung Alveolar Epithelial Cells. In Cell stem cell, 21, 472-488.e10. doi:10.1016/j.stem.2017.08.014. https://pubmed.ncbi.nlm.nih.gov/28965766/

5. Wambach, Jennifer A, Wegner, Daniel J, Kitzmiller, Joseph, Whitsett, Jeffrey A, Cole, F Sessions. . Homozygous, Intragenic Tandem Duplication of SFTPB Causes Neonatal Respiratory Failure. In American journal of respiratory cell and molecular biology, 70, 78-80. doi:10.1165/rcmb.2023-0156LE. https://pubmed.ncbi.nlm.nih.gov/38156804/

6. Ren, Feihong, Jin, Qiubai, Liu, Tongtong, Ren, Xuelei, Zhan, Yongli. 2023. Proteome-wide mendelian randomization study implicates therapeutic targets in common cancers. In Journal of translational medicine, 21, 646. doi:10.1186/s12967-023-04525-5. https://pubmed.ncbi.nlm.nih.gov/37735436/

7. Wang, Kun, Yi, Hang, Wang, Yan, Zhang, Guochao, Mao, Yousheng. 2024. Proteome-Wide Multicenter Mendelian Randomization Analysis to Identify Novel Therapeutic Targets for Lung Cancer. In Archivos de bronconeumologia, 60, 553-558. doi:10.1016/j.arbres.2024.05.007. https://pubmed.ncbi.nlm.nih.gov/38824092/

8. Bi, Guangliang, Wu, Lei, Huang, Peixin, Easley, Ronald Blaine, Ye, Shui Qing. 2018. Up-regulation of SFTPB expression and attenuation of acute lung injury by pulmonary epithelial cell-specific NAMPT knockdown. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 32, 3583-3596. doi:10.1096/fj.201701059R. https://pubmed.ncbi.nlm.nih.gov/29452569/

9. Wang, Kun, Huang, Qiubo, Zhao, Guangqiang, Yang, Kaiyun, Huang, Yunchao. 2019. Gene polymorphisms of SFTPB rs7316, rs9752 and PAOX rs1046175 affect the diagnostic value of plasma Pro-SFTPB and DAS in Chinese Han non-small-cell lung cancer patients. In Journal of cellular biochemistry, 120, 14804-14812. doi:10.1002/jcb.28741. https://pubmed.ncbi.nlm.nih.gov/31016788/

10. Rustam, Samir, Hu, Yang, Mahjour, Seyed Babak, Elemento, Olivier, Shaykhiev, Renat. . A Unique Cellular Organization of Human Distal Airways and Its Disarray in Chronic Obstructive Pulmonary Disease. In American journal of respiratory and critical care medicine, 207, 1171-1182. doi:10.1164/rccm.202207-1384OC. https://pubmed.ncbi.nlm.nih.gov/36796082/