HomeENGLISH MAGAZINELung fibrosis: a new mutation reveal an earlier thread to follow "on...

Lung fibrosis: a new mutation reveal an earlier thread to follow “on the path of death”

Idiopathic pulmonary fibrosis (IPF) is a progressive, and often fatal, lung disease characterized by a gradual buildup of scar tissue within the lungs, causing patients severe breathing difficulties. The environmental and genetic factors underlying IPF are largely unknown, and there are no effective approaches available to reverse development of the disease. Researchers in Japan have identified a genetic mutation that causes PF by killing the cells lining the lung’s airways. The study suggests that protecting these cells by inhibiting a cell death pathway called necroptosis could be a new therapeutic approach to treating IPF. Dr. Yasutomo and colleagues from Tokushima University Graduate School of Medicine in Japan identified two Japanese brothers who succumbed to IPF in their early thirties. Sequencing of the brothers’ DNA revealed that they carried a mutation (dubbed T622C) in both copies of a gene called SFTPA1. This gene encodes a protein, surfactant protein A1, that is secreted by the cells lining the lung’s alveoli, the tiny air sacs that mediate the exchange of oxygen and carbon dioxide. This usually helps to prevent the alveoli from collapsing and protects them from bacterial infection. Mutations in the SFTPA1 gene have been found in other patients with IPF, but how these mutations might cause disease is unclear.

The researchers generated mice carrying the T622C mutation and found that they, too, developed IPF. Similar to IPF patients, the animals’ condition was fatally exacerbated by influenza A infection. Yasutomo and colleagues determined that the T622C mutation in STFPA1 blocks the protein’s release from alveolar cells, causing the cells to die via a process known as necroptosis. This form of cell death induces high levels of inflammation that is likely to increase the formation of scar tissue within the lung. The researchers found that, instead of being secreted, the mutant form of SFTPA1 builds up inside the type II alveolar cells (AEII) and activates a cellular stress pathway (JNK) that boosts the levels of necroptosis-promoting proteins. Blocking this stress pathway, or otherwise reducing the levels of these necroptosis-promoting proteins, slowed the development of IPF in SFTPA1 mutant mice and allowed them to survive influenza A infection. In detail, Sftpa1-KI mice showed increased necroptosis of alveolar epithelial type II cells with phosphorylation of protein IRE-1α, activation of JNK kinase cascade and up-regulation of another kinase called Ripk3. The inhibition of JNK ameliorated pulmonary fibrosis in these mutant mice and overexpression of Ripk3 treated with a known JNK inhibitor worsened pulmonary fibrosis.

The study suggests that necroptosis is one of the crucial initiators of pulmonary fibrosis and that the necroptosis signaling pathway could be a potential target for its treatment. An invovement of this biological phenomenon in lung conditions was speculated earlier (Lee et al. 2018) and a possible involvement of other cellular stess signals in the onset of IPF as well as COPD was postulated. Alongside JNK stress, involvement of mitochondria and their derangement with another stress pathway was has been discovered very recently (Tsubouki et al 2018). There is on advantage in this rationale to hit this upstream signlaing before fibrosis impairs breathing functions. The current focus for treating IPF is to block the activation of kinase enzymes within the fibrotic regions of the lung. As the disease progresses, lung function declines, followeed by worsening of dyspnea, functional capacity and deterioration in quality of life. Pirfenidone and nintedanib are the only drugs available for an effective clinical control or delay of this disease. Clinical trials have demonstrated that nintedanib and pirfenidone reduce the decline in lung function in patients with IPF. However, according to scientists, inhibiting necroptosis in alveolar cells would suppress earlier events in IPF progression, which would be more beneficial to patients.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Takezaki A et al., Yasutomo K. J Exp Med. 2019 Oct 10.

Maher TM, Strek ME. Respir Res. 2019 Sep 6; 20(1):205.

Tsubouchi K et al. Inflamm Regen. 2018 Oct 24; 38:18.

Lee JM et al. Am J Respir Cell Mol Biol. 2018; 59(2):215.


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Dott. Gianfrancesco Cormaci

Medico Chirurgo, Specialista; PhD. a CoFood s.r.l.
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry residency in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Guardia medica presso strutture private dal 2010 - Detentore di due brevetti sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of patents concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica e salute sui siti web salutesicilia.com, medicomunicare.it e in lingua inglese sul sito www.medicomunicare.com
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