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Idiopathic pulmonary fibrosis: Epidemiology, natural history and pathophysiology
Published in Muhunthan Thillai, David R Moller, Keith C Meyer, Clinical Handbook of Interstitial Lung Disease, 2017
Zulma Yunt, Jeffrey J Swigris, Amy L Olson
Clues to the importance of a genetic component in the development of pulmonary fibrosis came from the recognition of familial disease and from specific known genetic disorders including dyskeratosis congenita and Hermansky–Pudlak syndrome. Dyskeratosis congenita is a rare, heritable condition characterized by bone marrow failure and mucocutaneous features, and is commonly complicated by pulmonary fibrosis (63,64). The disease is caused by genetic mutations in genes responsible for telomerase maintenance. This observation led to an examination of telomerase genes in familial forms of lung fibrosis not associated with dyskeratosis congenita. This identified an association between familial pulmonary fibrosis (FPF) and mutations in TERT and TERC (65,66). Similarly, other studies identified variants in genes encoding surfactant protein C (SFTPC), surfactant protein A2 (SFTPA2) (67–69). Together however, these mutations account for only a minority of cases of pulmonary fibrosis.
The Use of Placenta-Derived Cells in Inflammatory and Fibrotic Disorders
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Euan M. Wallace, Anna Cargnoni, Rebecca Lim, Alex Hodge, William Sievert
In support of these early observations, more recently there has been much evidence supporting the role of macrophages in therapeutic effects of hAECs in lung injury. Murphy and collaborators used surfactant protein C–deficient (Sftpc-/-) mice, which are highly susceptible to pulmonary injury as a result of impairment of macrophage function, to show that the beneficial effects observed after hAEC treatment depend upon on macrophage recruitment and polarization (Murphy et al. 2012a). Specifically, hAEC treatment to bleomycin-injured Sftpc-/- mice did not mitigate the inflammatory and fibrotic injuries, and no preservation of lung function was observed. This was in stark contrast to hAEC-treated bleomycin-injured Sftpc+/+ mice where injury was prevented. Furthermore, they showed a lower neutrophil infiltration, but no effect was observed on lung macrophage levels, whereas in Sftpc+/+ mice hAEC administration was associated with increased polarization of macrophages toward alternatively activated (M2) phenotype. No hAECs were detected in the host lungs at day 7 posttransplantation (Murphy et al. 2012a).
Pediatric Lung Disease
Published in Philip T. Cagle, Timothy C. Allen, Mary Beth Beasley, Diagnostic Pulmonary Pathology, 2008
In contrast to the PAP pattern of SP-B deficiency, lung biopsies from infants with SPC deficiency typically show a pattern of CPI, characterized by less conspicuous proteinosis material and more prominent cholesterol clefts and lobular remodeling (Fig. 5) (44, 45). While significant fibrosis is not a manifestation in infancy, lobular remodeling is reflected by irregular enlargement of airspaces, diffuse interstitial widening, and prominent interstitial extension of airway smooth muscle. These patients tend to be biopsied later than infants with SP-B deficiency and generally have a much wider range of age at presentation and diagnosis. SFTPC mutations have been recognized in some families as a cause of chronic interstitial pneumonia and pulmonary fibrosis in adults (46, 47).
Association analysis of the surfactant protein-C gene to childhood asthma
Published in Journal of Asthma, 2022
Malek Nefzi, Imen Wahabi, Sondess Hadj Fredj, Rym Othmani, Rym Dabboubi, Khedija Boussetta, Pascale Fanen, Taieb Messaoud
Our results show that sequence variations in the coding region of SFTPC gene are not common and that it is a relatively conserved region. Furthermore, only two common non-synonymous variants T138N (rs4715) and S186N (rs1124) have been identified. These two variations are statistically associated with neonatal respiratory distress syndrome (17,18) and T138N-S186N haplotypes were associated with severe respiratory syncytial virus (RSV) infections (15). These variants are located in the C-Terminal region of the pro-SP-C which is crucial for the targeting and processing of pro-SP-C to mature protein (18). The two variations are located in the BRICHOS domain, a domain of approximately 100 amino acids, which as thus far been found as a constituent of 12 otherwise different protein families associated with degenerative and proliferative disease (25). Interestingly, other sequence variations identified in the BRICHOS domain reported previously as polymorphisms could contribute to abnormal function, alteration, or major deficiency of SP-C protein (3,25). On the other hand, the location of the p.Thr138Asn and p.Ser186Asn were adjacent to some mutations (p.Gln145His, p.Leu188Arg, and p.Leu188Gln) associated with severe respiratory phenotypes.
MiR-629-3p-induced downregulation of SFTPC promotes cell proliferation and predicts poor survival in lung adenocarcinoma
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Bin Li, Yu-Qi Meng, Zheng Li, Ci Yin, Jun-Ping Lin, Duo-Jie Zhu, Shao-Bo Zhang
In this study, we observed that surfactant protein C (SFTPC) expression was downregulated in human lung adenocarcinoma tissues and cell lines, and low SFTPC expression correlated with poor overall survival of lung adenocarcinoma patients. Moreover, we found that overexpression of SFTPC could inhibit lung cancer cell proliferation in vitro and in vivo, but downregulation of SFTPC showed the opposite results. Besides, it was observed that miR-629-3p expression was upregulated in human lung adenocarcinoma tissues and cell lines. More importantly, we found that miR-629-3p could downregulate SFTPC expression by directly binding to the SFTPC 3'-UTR, and inhibit the regulatory effect of SFTPC on lung adenocarcinoma cell proliferation. Thus, it could be hypothesized that miR-629-3p-mediated downregulation of SFTPC could contribute to lung adenocarcinoma progression.
Current models of pulmonary fibrosis for future drug discovery efforts
Published in Expert Opinion on Drug Discovery, 2020
Toyoshi Yanagihara, Sy Giin Chong, Megan Vierhout, Jeremy A. Hirota, Kjetil Ask, Martin Kolb
A heterozygous mutation in SFTPC in FIP patients was identified in 2001 [36], and subsequently, additional mutations in SFTPC were reported [37–39]. Transgenic mice expressing mutant L188Q SP-C discovered in FIP patients showed endoplasmic reticulum (ER) stress in type II AECs and exaggerated lung fibrosis after bleomycin administration [50]. In 2018, Nureki et al. demonstrated transgenic mice expressing mutant I73 T SP-C in type II AECs develop ER stress and spontaneous lung fibrosis which recapitulates many features of the human IPF phenotype, strengthening the role of type II AEC dysfunction as a critical upstream driver of IPF pathogenesis [51]. Thus, there is a potential for this transgenic system to become a new preclinical platform.