According to a study published on July 20, 2022, an AI-guided analysis of over 1,000 sets of human lung transcriptome data showed that COVID-19 resembles idiopathic pulmonary fibrosis (IPF) at a fundamental level.
After COVID-19, a significant number of patients develop fibrotic lung disease for which there is no understanding of pathogenesis, disease patterns, or treatment options, according to researchers Sinha and colleagues. This protracted form of the disease culminates in a fibrous type of interstitial lung disease (ILD). While the actual prevalence of post-COVID-19 ILD (PCLD) is still being established, early analysis suggests that more than a third of COVID-19 survivors develop fibrotic abnormalities, according to the authors.
Previous research has shown that one of the important determinants of PCLD is the duration of the illness. Among patients who developed fibrosis, about 4% of patients had disease duration less than 1 week; approximately 24% had a disease duration of 1 to 3 weeks; and about 61% had disease duration >3 weeks, the authors stated.
The lung transcriptome datasets compared in their study were associated with various lung conditions. The researchers used two viral pandemic signatures (ViP and sViP) and one pulmonary COVID signature. They found that the similarities include that COVID-19 repeats gene expression patterns (ViP and IPF signatures), cytokine storm (IL15-centric), and cytopathic changes in AT2, eg, damage, DNA damage, transient arrest, damage. induced progenitor state and aging-associated secretory phenotype (SASP).
In laboratory experiments, Sinha and colleagues were able to evoke the same immunocytopathic features in preclinical models of COVID-19 (adult lung organoid and hamster) and reverse them into a hamster model with effective anti-CoV-2 therapeutics.
The PPI network analyzes endoplasmic reticulum (ER) stress as one of the common early triggers of both IPF and COVID-19, and immunohistochemical studies have confirmed the same in the lungs of deceased subjects with COVID-19 and SARS-CoV-2. hamster lungs. In addition, the lungs of transgenic mice, in which ER stress was induced specifically in AT2 cells, significantly replicated the host immune response and alveolar cytopathic changes induced by SARS-CoV-2.
“In this work, we found that a blood-based gene expression biomarker that works for predictiveness in COVID also works for IPF,” said corresponding author Pradipta Ghosh, MD, professor in the University’s Department of Medicine and Cellular and Molecular Medicine. California, San Diego. “If this biomarker is proven in prospective studies, it could indicate who is most at risk for progressive fibrosis and may need a lung transplant,” she said in an interview.
Ghosh went on to state, “When it comes to treating COVID-19 of the lung or IPF, we have also found that common fundamental pathogenic mechanisms offer excellent opportunities for the development of therapeutics that can block fibrogenic factors in both diseases. One clue found is a specific cytokine that underlies the smoldering inflammation invariably associated with fibrosis. it’s interleukin 15 [IL-15] and its receptor. Ghosh noted that there are two drugs approved by the Food and Drug Administration for the treatment of IPF. “None of them are very effective in stopping this invariably deadly disease. Therefore, finding better treatment options for IPF is an urgent and unmet need.”
Preclinical hypothesis testing, according to Ghosh, is on its way to clinical trials. “We have the advantage that we use human lung organoids (mini-lungs grown from stem cells) in a dish, add additional cells (such as fibroblasts and immune cells) to the system, infect them with a virus, or expose them to IL-15. cytokines and monitoring the progression of pulmonary fibrosis in a dish. Anti-IL-15 therapy can then be initiated to observe reversal of the fibrogenic cascade.” Hamsters have also been shown to be suitable models for simulating pulmonary fibrosis, Ghosh said.
“The report by Sinha and colleagues describes a striking similarity between factors in post-COVID lung disease and idiopathic pulmonary fibrosis,” said David Boughton, MD, Professor Emeritus, Intensive Care Unit, Department of Anesthesiology, Wake Forest University School of Medicine. Winston-Salem, NC, in an interview. He added that “Central to the mechanisms of fibrosis induction in both diseases is endoplasmic reticulum (ER) stress in type II alveolar cells (AT2). ER stress induces the unfolded protein response (UPR), which stops protein translation and promotes the degradation of misfolded proteins. Prolonged UPR may reprogram the cell or trigger apoptotic pathways. ER stress in the lung has been reported in various cell lines including AT2 in IPF, bronchial and alveolar epithelial cells in asthma, and [chronic obstructive pulmonary disease]and endothelial cells in pulmonary hypertension.
Boughton further commented, including a caveat: “Sinha and colleagues suggest that the identification of these gene signatures and mechanisms will be a fruitful avenue for developing effective therapeutics for the treatment of IPF and other fibrotic lung diseases. I hope this data can provide clues that will speed up this process. However, the redundancy of effector pathway triggers in biological systems suggests that even if successful, this will [a] long and difficult process.
The study was supported by grants from the National Institutes of Health and funding from the Tobacco-Related Diseases Research Program.
Sinha, Ghosh, and Boughton did not report their respective disclosures.
electronic biomedicine. Published August 1, 2022 Full text.
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