Lung fibrosis: “scar” is the problem for a condition with “scarce” options

Fibrosi polmonare idiopatica: nuovi sviluppi ed un altro farmaco all'orizzonte

In lung fibrosis, lung tissue thickens, stiffens and scars. It can no longer function normally. That’s why people with lung fibrosis have difficulty breathing. Around 100,000 Americans have lung fibrosis without a known cause, known as idiopathic pulmonary fibrosis (IPF). Another 50,000 have scleroderma, an autoimmune disease that often leads to lung fibrosis as well as thickening and tightening of the skin. There are currently no FDA-approved drugs that can either stop disease progression or reverse it in these patients. Mortality is high, in some cases higher than cancer, so finding therapies is critical. For these patients, transplant is often the only option. However, not all patients are eligible for lung transplant, and it is not without its complications. New therapies that can stop or reverse lung fibrosis are needed. In an article published online by Frontiers in Endocrinology, researchers at the Medical University of South Carolina (MUSC) report that they have identified a potential therapeutic target for lung fibrosis or scarring.

They showed in a preclinical model that the protein promotes fibrosis by turning on profibrotic genes and increasing levels of profibrotic factors, including itself. It is particularly attractive as a target because it exerts its influence early, before most other profibrotic factors emerge. Dr Carol Feghali-Bostwick, PhD, and her team showed that insulin-like growth factor-binding protein 5 (IGFBP-5) plays an important and early role in promoting fibrosis. IGFBP-5 is upstream of several molecules that are considered key molecules in fibrosis, such as TGF-beta. It increases profibrotic gene expression, resulting in excessive collagen being deposited to the extracellular matrix (ECM). The ECM is the network that surrounds cells and serves as the scaffold on which they can build tissue. This excess collagen causes the tissue to stiffen and become fibrotic. These profibrotic genes also help ensure that levels of IGFBP-5 and other profibrotic factors such as matrix crosslinking enzyme lysyl oxidase (LOX) stay high. LOX enables collagen fibrils to cross-link, making tissue stiffer.

IGFBP-5 induces its own gene expression and feedback loop; this means that IGFBP5 acts together with profibrotic genes to promote fibrosis and tissue remodeling. The MUSC used collagen-producing cells harvested from patients with IPF or scleroderma to explore the profibrotic effects of IGFBP-5. But they also went a step further, showing similar increases in human lung tissue cores. These cores more realistically mimic the physiologic conditions of living human tissue. Many therapies work in mice but fail in humans when you get to the human trials. So we have this system where we take lung tissues and put them in an environment that’s a human-based tissue. Next steps are to use collagen-producing cells and human lung tissue cores to better understand how the increased levels of LOX caused by IGFBP-5 further promote fibrosis. The MUSC team will also study LOX in a transgenic mouse model that is engineered to overexpress IGFBP-5.

Mucociliary dysfunction is an emerging paradigm in lung diseases . Previously considered a characteristic specific to obstructive diseases such as asthma and chronic obstructive pulmonary disease (COPD), and genetic diseases such as primary ciliary dyskinesia and cystic fibrosis, the importance of mucins, mucus, and mucociliary interactions has surfaced in diseases of the lung periphery, such as adenocarcinoma and IPF The overproduction of a lung mucin (MUC5B) has consistently been shown to be the strongest risk for the development of idiopathic pulmonary fibrosis (IPF) and most recently rheumatoid arthritis-interstitial lung disease. A team of investigators led by members of the University of Colorado School of Medicine faculty at CU Anschutz Medical Campus has identified a connection between mucus in the small airways and pulmonary fibrosis. The investigators hypothesized that the potential role for mucociliary dysfunction as a driver of IPF pathology is supported by unique gene expression signatures in IPF. The findings are published in the journal Nature Communications.

The investigators found that a specific genetic characteristic, known as the MUC5B promoter variant rs35705950, which results in a marked increase production of mucus in the lung is the strongest genetic risk factor for IPF. They also found this is the strongest risk factor for rheumatoid arthritis-interstitial lung disease. Dr. David Schwartz, MD, Chair of the Department of Medicine at the CU School of Medicine, explains: “The findings in our research provide a critical breakthrough in understanding the cause and potentially the treatment of IPF by demonstrating that excess mucus in the small airways can cause lung fibrosis, in part, by impairing the mechanism of lung clearance. In aggregate, these discoveries have provided the means to identify an at-risk population, diagnose the disease prior to the development of irreversible scarring, focus on a unique therapeutic target (MUC5B) and a specific location in the lung (distal airway), and create a novel pathway for therapeutic intervention for a disease that is currently incurable.”

The findings suggest that targeting either IGFBP-5 or MUC5B in the terminal airways of patients with preclinical stages of interstitial lung disease, could represents a revolutionary strategy to prevent the progression of preclinical pulmonary fibrosis.

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

Scientific references

Hancock LA et al., Schwartz DA. Nat Commun. 2018 Dec 18; 9(1):5363.

Schwartz DA. Ann Am Thorac Soc. 2018 Nov; 15(Supplement_3):S192-S197. 

Nguyen XX et al., Feghali-Bostwick C. Front Endocrinol (Lausanne) 2018; 9:601.

Dressen A, Abbas AR et al. Lancet Respir Med. 2018 Aug; 6(8):603-614.

Informazioni su Dott. Gianfrancesco Cormaci 1427 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty 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. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - 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, salute e benessere sui siti web salutesicilia.com e medicomunicare.it