Olmesartan alleviates SARS-CoV-2 envelope protein induced renal fibrosis by regulating HMGB1 release and autophagic degradation of TGF-ß1.

Background and aims: Renal damage in severe coronavirus disease 2019 (COVID-19) is highly associated with mortality. Finding relevant therapeutic candidates that can alleviate it is crucial. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) have been shown to be harmless to COVID-19 patients, but it remains elusive whether ACEIs/ARBs have protective benefits to them. We wished to determine if ACEIs/ARBs had a protective effect on the renal damage associated with COVID-19, and to investigate the mechanism. Methods: We used the envelope (E) protein of severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) to induce COVID-19-like multiple organ damage and observed renal fibrosis. We induced the epithelial-mesenchymal transformation of HK-2 cells with E protein, and found that olmesartan could alleviate it significantly. The protective effects of olmesartan on E protein-induced renal fibrosis were evaluated by renal-function assessment, pathologic alterations, inflammation, and the TGF-ß1/Smad2/3 signaling pathway. The distribution of high-mobility group box (HMGB)1 was examined after stimulation with E protein and olmesartan administration. Results: E protein stimulated HMGB1 release, which triggered the immune response and promoted activation of TGF-ß1/Smad2/3 signaling: both could lead to renal fibrosis. Olmesartan regulated the distribution of HMGB1 under E protein stimulation. Olmesartan inhibited the release of HMGB1, and reduced the inflammatory response and activation of TGF-ß1/Smad2/3 signaling. Olmesartan increased the cytoplasmic level of HMGB1 to promote the autophagic degradation of TGF-ß1, thereby alleviating fibrosis further. Conclusion: Olmesartan alleviates E protein-induced renal fibrosis by regulating the release of HMGB1 and its mediated autophagic degradation of TGF-ß1.

The mechanism of Qingwen Gupi decoction on pulmonary fibrosis based on metabolomics and intestinal flora.

AIMS: To evaluate the effects of the Qingwen Gupi decoction (QGT) in a rat model of bleomycin-induced pulmonary fibrosis (PF), and explore the underlying mechanisms by integrating UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing of gut microbiota. METHODS AND RESULTS: The animals were randomly divided into the control, PF model, pirfenidone-treated, and low-, medium-, and high-dose QGT groups. The lung tissues were examined and the expression of TGF-ß, SMAD-3, and SMAD-7 mRNAs in the lung tissues were analyzed. Metabolomic profiles were analyzed by UPLC-QTOF/MS, and the intestinal flora were examined by prokaryotic 16 rDNA sequencing. Pathological examination and biochemical indices revealed that QGT treatment improved the symptoms of PF by varying degrees. Furthermore, QGT significantly downregulated TGF-ß1 and Smad-3 mRNAs and increased the expression levels of Smad-7. QGT-L in particular increased the levels of 18 key metabolic biomarkers that were associated with nine gut microbial species and may exert antifibrosis effects through arachidonic acid metabolism, glycerophospholipid metabolism, and phenylalanine metabolism. CONCLUSIONS: QGT alleviated PF in a rat model through its anti-inflammatory, antioxidant, and anti-fibrotic effects, and by reversing bleomycin-induced gut dysbiosis.This study lays the foundation for further research on the pathological mechanisms of PF and the development of new drug candidates.

Photobiomodulation therapy mitigates cardiovascular aging and improves survival.

BACKGROUND: Photobiomodulation (PBM) therapy, a form of low-dose light therapy, has been noted to be effective in several age-associated chronic diseases such as hypertension and atherosclerosis. Here, we examined the effects of PBM therapy on age-associated cardiovascular changes in a mouse model of accelerated cardiac aging. METHODS: Fourteen months old Adenylyl cyclase type VIII (AC8) overexpressing transgenic mice (n = 8) and their wild-type (WT) littermates (n = 8) were treated with daily exposure to Near-Infrared Light (850 nm) at 25 mW/cm2 for 2 min each weekday for a total dose of 1 Einstein (4.5 p.J/cm2 or fluence 3 J/cm2 ) and compared to untreated controls over an 8-month period. PBM therapy was administered for 3.5 months (Early Treatment period), paused, due to Covid-19 restrictions for the following 3 months, and restarted again for 1.5 months. Serial echocardiography and gait analyses were performed at monthly intervals, and serum TGF-ß1 levels were assessed following sacrifice. RESULTS: During the Early Treatment period PBM treatments: reduced the age-associated increases in left ventricular (LV) mass in both genotypes (p = 0.0003), reduced the LV end-diastolic volume (EDV) in AC8 (p = 0.04); and reduced the left atrial dimension in both genotypes (p = 0.02). PBM treatments substantially increased the LV ejection fraction (p = 0.03), reduced the aortic wall stiffness (p = 0.001), and improved gait symmetry, an index of neuro-muscular coordination (p = 0.005). The effects of PBM treatments, measured following the pause, persisted. Total TGF-ß1 levels were significantly increased in circulation (serum) in AC8 following PBM treatments (p = 0.01). We observed a striking increase in cumulative survival in PBM-treated AC8 mice (100%; p = 0.01) compared to untreated AC8 mice (43%). CONCLUSION: PBM treatment mitigated age-associated cardiovascular remodeling and reduced cardiac function, improved neuromuscular coordination, and increased longevity in an experimental animal model. These responses correlate with increased TGF-ß1 in circulation. Future mechanistic and dose optimization studies are necessary to assess these anti-aging effects of PBM, and validation in future controlled human studies is required for effective clinical translation.

Association of TNF-α, TGF-ß1, amphiregulin, IL-2, and EGFR WITH pulmonary fibrosis in COVID-19.

Pulmonary fibrosis is a well-recognized sequela associated with coronavirus disease 2019 (COVID-19), however the mechanism is yet to be clearly understood. The study was designed to evaluate the association of TNF-α, TGF- ß1, amphiregulin, IL-2, and EGFR with pulmonary fibrosis after COVID-19 pneumonia. Non-severe, severe, and critical COVID-19 pneumonia patients were included in this study after the patients agreed and gave written informed consent. Blood samples were analyzed with the ELISA method for cytokine examination. The non-contrast chest CT scan was performed after patients were discharged from hospital. Seventy-nine patients with a mean age of 54 years (57 % men, 43 % women) were fully evaluated. Pulmonary fibrosis was found in 74 patients (93.7 %). Serum levels of TGF-ß1 60.55 pg/mL (11.42-2001.16), TNF-α 13.31 pg/mL (3.54-200.32), EGFR 14.9 pg/mL(6.4-53.6), IL-2 12.41 pg/mL(11-14.13), amphiregulin 156.5 pg/mL (21.7-1234). Serum levels of TNF-α increase according to the severity of clinical classification. A significant association between serum levels of TGF-ß1, TNF- α, and pulmonary fibrosis with rs-0.247, p = 0.027; rs 0.259, p = 0.046 was found. According to this study, TNF-α and TGF-ß1 potentially participate in the process of pulmonary fibrosis in COVID-19.

Microvascular significance of TGF-ß axis activation in COVID-19.

As 2023 approaches, the COVID-19 pandemic has killed millions. While vaccines have been a crucial intervention, only a few effective medications exist for prevention and treatment of COVID-19 in breakthrough cases or in unvaccinated or immunocompromised patients. SARS-CoV-2 displays early and unusual features of micro-thrombosis and immune dysregulation that target endothelial beds of the lungs, skin, and other organs. Notably, anticoagulation improves outcomes in some COVID-19 patients. The protein transforming growth factor-beta (TGF-ß1) has constitutive roles in maintaining a healthy microvasculature through its roles in regulating inflammation, clotting, and wound healing. However, after infection (including viral infection) TGF-ß1 activation may augment coagulation, cause immune dysregulation, and direct a path toward tissue fibrosis. Dysregulation of TGF-ß signaling in immune cells and its localization in areas of microvascular injury are now well-described in COVID-19, and such events may contribute to the acute respiratory distress syndrome and skin micro-thrombosis outcomes frequently seen in severe COVID-19. The high concentration of TGF-ß in platelets and in other cells within microvascular thrombi, its ability to activate the clotting cascade and dysregulate immune pathways, and its pro-fibrotic properties all contribute to a unique milieu in the COVID-19 microvasculature. This unique environment allows for propagation of microvascular clotting and immune dysregulation. In this review we summarize the physiological functions of TGF-ß and detail the evidence for its effects on the microvasculature in COVID-19. In addition, we explore the potential role of existing TGF-ß inhibitors for the prevention and treatment of COVID-19 associated microvascular thrombosis and immune dysregulation.

Ivermectin Attenuates CCl4-Induced Liver Fibrosis in Mice by Suppressing Hepatic Stellate Cell Activation.

Liver fibrosis, a common liver dysfunction with high morbidity and mortality rates, is the leading cause of cirrhosis and hepatocellular carcinoma, for which there are no effective therapies. Ivermectin is an antiparasitic drug that also has been showing therapeutic actions in many other diseases, including antiviral and anticancer actions, as well as treating metabolic diseases. Herein, we evaluated the function of ivermectin in regulating liver fibrosis. Firstly, carbon tetrachloride (CCl4)-injected Balb/c mice were used to assess the antifibrosis effects of ivermectin in vivo. Further, CFSC, a rat hepatic stellate cell (HSC) line, was used to explore the function of ivermectin in HSC activation in vitro. The in vivo data showed that ivermectin administration alleviated histopathological changes, improved liver function, reduced collagen deposition, and downregulated the expression of profibrotic genes. Mechanistically, the ivermectin treatment inhibited intrahepatic macrophage accumulation and suppressed the production of proinflammatory factors. Importantly, the ivermectin administration significantly decreased the protein levels of α-smooth muscle actin (α-SMA) both in vivo and in vitro, suggesting that the antifibrotic effects of ivermectin are mainly due to the promotion of HSC deactivation. The present study demonstrates that ivermectin may be a potential therapeutic agent for the prevention of hepatic fibrosis.

25-Hydroxycholesterol Mediates Cholesterol Metabolism to Restrict Porcine Deltacoronavirus Infection via Suppression of Transforming Growth Factor ß1.

Porcine deltacoronavirus (PDCoV), an emerging enteropathogenic coronavirus in pigs, is one of the major pathogens for lethal watery diarrhea in piglets and poses a threat to public health because of its potential for interspecies transmission to humans. 25-Hydroxycholesterol (25HC), a derivative of cholesterol, exhibits multiple potential modulating host responses to pathogens, including viruses and bacteria, as well as pathogen-induced inflammation, while its antiviral effect on PDCoV and how it mediates the biological process of host cells to counter against infections remain poorly understood. Here, we thoroughly explored the antiviral effect of 25HC on PDCoV infection and tried to elucidate the underlying mechanisms. 25HC showed no toxic effect in LLC-PK1 cells and exerted antiviral ability against PDCoV infection in vitro. The viral cycle and time-of-addition analyses showed that 25HC mainly restricted the early and middle periods of the PDCoV postentry stage to inhibit infection. 25HC regulated disordered cholesterol metabolism induced by PDCoV infection and stimulated interferon-related lipid droplet accumulation. Transforming growth factor ß1 (TGF-ß1), screened by bioinformatic analyses, seemed to play an important role in PDCoV infection and was downregulated by 25HC. One interesting finding is that inhibition of TGF-ß1 with the inhibitor asiaticoside exhibited a similar antiviral capacity to 25HC and demonstrated regulation of cholesterol metabolism. Taking all of the findings together, we verified the antiviral effect of 25HC on PDCoV through interference with cholesterol metabolism, which may be related to its suppression of TGFß1. IMPORTANCE As an emerging enteropathogenic coronavirus in pigs, porcine deltacoronavirus (PDCoV) causes giant economic loss in the pig industry because of lethal diarrhea and possesses the potential for transmission from animals to humans. Several pieces of evidence have suggested the antiviral potential of cholesterol-25-hydroxylase and importance of cholesterol in viral infection. This study reports that 25-hydroxycholesterol (25HC) significantly restricted PDCoV infection through modulation of cholesterol metabolism, and we identified that lipid droplets play important roles in interferon response against virus infection. Moreover, this study identified the importance of TGF-ß1 in CoV infection by bioinformatic analysis and verified that the inhibition of TGF-ß1 showed anti-PDCoV capacity. Moreover, we uncovered the relationship between TGF-ß and cholesterol metabolism initially. Given that the importance of cholesterol in viral infection, 25HC has a great potential to treat PDCoV infection and TGF-ß1 can be a crucial antiviral target.

Investigating the possible mechanisms of pirfenidone to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2.

Pirfenidone (PFD) is a non-peptide synthetic chemical that inhibits the production of transforming growth factor-beta 1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), Interleukin 1 beta (IL-1ß), and collagen 1 (COL1A1), all of which have been linked to the prevention or removal of excessive scar tissue deposition in many organs. PFD has been demonstrated to decrease apoptosis, downregulate angiotensin-converting enzyme (ACE) receptor expression, reduce inflammation through many routes, and alleviate oxidative stress in pneumocytes and other cells while protecting them from COVID-19 invasion and cytokine storm. Based on the mechanism of action of PFD and the known pathophysiology of COVID-19, it was recommended to treat COVID-19 patients. The use of PFD as a treatment for a range of disorders is currently being studied, with an emphasis on outcomes related to reduced inflammation and fibrogenesis. As a result, rather than exploring the molecule's chemical characteristics, this review focuses on innovative PFD efficacy data. Briefly, herein we tried to investigate, discuss, and illustrate the possible mechanisms of actions for PFD to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2 candidate.

Pathophysiology of Pulmonary Fibrosis in the Context of COVID-19 and Implications for Treatment: A Narrative Review.

Pulmonary fibrosis (PF) is a feared outcome of many pulmonary diseases which results in a reduction in lung compliance and capacity. The development of PF is relatively rare, but it can occur secondary to viral pneumonia, especially COVID-19 infection. While COVID-19 infection and its complications are still under investigation, we can look at a similar outbreak in the past to gain better insight as to the expected long-term outcomes of COVID-19 patient lung function. In the current article, we review the literature relative to PF via PubMed. We also performed a literature search for COVID-related pathological changes in the lungs. Finally, the paper was reviewed and summarized based on the studies' integrity, relative, or power calculations. This article provides a narrative review that endeavors to elucidate the current understanding of the pathophysiological mechanisms underlying PF and therapeutic strategies. We also discussed the potential for preventing progression to the fibrotic state within the context of the COVID-19 pandemic. With the massive scale of the COVID-19 pandemic, we expect there should more instances of PF due to COVID-19 infection. Patients who survive severe COVID-19 infection may suffer from a high incidence of PF.

Antifibrotic Mechanism of Piceatannol in Bleomycin-Induced Pulmonary Fibrosis in Mice.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by myofibroblast accumulation and extracellular matrix deposition, which lead to irreversible damage of the lung's architecture and the formation of fibrotic lesions. IPF is also a sequela in serious patients with the coronavirus disease 2019 (COVID-19). The molecular mechanisms under pulmonary fibrosis remain unclear, and there is no satisfactory treatment currently available. Piceatannol (PIC) is a naturally occurring resveratrol analog found in a variety of dietary sources such as grapes, passion fruit, and white tea. It has been reported to inhibit liver fibroblast growth and exhibited various antitumor activities, although its role in pulmonary fibrosis has not been established yet. In the present study, we evaluated the anti-fibrotic role of PIC in bleomycin (BLM)-induced pulmonary fibrosis in mice. Methods: Mice with BLM-induced pulmonary fibrosis were treated with PIC, and fibrotic changes were measured by hematoxylin-eosin (H&E) staining and hydroxyproline assay. Luciferase assay, Western blot assay, histological analysis, and immunofluorescence staining were used to evaluate the effect of PIC on fibroblast activation and autophagy in mouse embryonic fibroblast cells (NIH-3T3) and human lung fibroblast cells (HFL1). The anti-fibrotic mechanisms of PIC were either confirmed in vivo. Results: Our results showed that PIC significantly alleviated the bleomycin-induced collagen deposition and myofibroblast accumulation. In vitro and in vivo studies indicated that PIC plays a role in activating autophagy in the process of anti-fibroblast activation. Further mechanism studies demonstrated that PIC can promote autophagy via inhibiting the TGF-ß1-Smad3/ERK/P38 signaling pathway, which leads to a decreased number of activated myofibroblasts. Conclusion: Our study demonstrated for the first time that PIC possesses the protective effects against bleomycin-induced pulmonary fibrosis due to the direct pulmonary protective effects which enhance the effect of autophagy in vitro and in vivo and finally leads to the decreased number of activated myofibroblasts. PIC may serve as a candidate compound for pulmonary fibrosis therapy and attenuates the sequelae of SARS-COV-2 pulmonary fibrosis.

Integrin/TGF-ß1 Inhibitor GLPG-0187 Blocks SARS-CoV-2 Delta and Omicron Pseudovirus Infection of Airway Epithelial Cells In Vitro, Which Could Attenuate Disease Severity.

As COVID-19 continues to pose major risk for vulnerable populations, including the elderly, immunocompromised, patients with cancer, and those with contraindications to vaccination, novel treatment strategies are urgently needed. SARS-CoV-2 infects target cells via RGD-binding integrins, either independently or as a co-receptor with surface receptor angiotensin-converting enzyme 2 (ACE2). We used pan-integrin inhibitor GLPG-0187 to demonstrate the blockade of SARS-CoV-2 pseudovirus infection of target cells. Omicron pseudovirus infected normal human small airway epithelial (HSAE) cells significantly less than D614G or Delta variant pseudovirus, and GLPG-0187 effectively blocked SARS-CoV-2 pseudovirus infection in a dose-dependent manner across multiple viral variants. GLPG-0187 inhibited Omicron and Delta pseudovirus infection of HSAE cells more significantly than other variants. Pre-treatment of HSAE cells with MEK inhibitor (MEKi) VS-6766 enhanced the inhibition of pseudovirus infection by GLPG-0187. Because integrins activate transforming growth factor beta (TGF-ß) signaling, we compared the plasma levels of active and total TGF-ß in COVID-19+ patients. The plasma TGF-ß1 levels correlated with age, race, and number of medications upon presentation with COVID-19, but not with sex. Total plasma TGF-ß1 levels correlated with activated TGF-ß1 levels. Moreover, the inhibition of integrin signaling prevents SARS-CoV-2 Delta and Omicron pseudovirus infectivity, and it may mitigate COVID-19 severity through decreased TGF-ß1 activation. This therapeutic strategy may be further explored through clinical testing in vulnerable and unvaccinated populations.

CVD and COVID-19: Emerging Roles of Cardiac Fibroblasts and Myofibroblasts.

Cardiovascular disease (CVD) is the leading cause of death worldwide. Current data suggest that patients with cardiovascular diseases experience more serious complications with coronavirus disease-19 (COVID-19) than those without CVD. In addition, severe COVID-19 appears to cause acute cardiac injury, as well as long-term adverse remodeling of heart tissue. Cardiac fibroblasts and myofibroblasts, being crucial in response to injury, may play a pivotal role in both contributing to and healing COVID-19-induced cardiac injury. The role of cardiac myofibroblasts in cardiac fibrosis has been well-established in the literature for decades. However, with the emergence of the novel coronavirus SARS-CoV-2, new cardiac complications are arising. Bursts of inflammatory cytokines and upregulation of TGF-ß1 and angiotensin (AngII) are common in severe COVID-19 patients. Cytokines, TGF-ß1, and Ang II can induce cardiac fibroblast differentiation, potentially leading to fibrosis. This review details the key information concerning the role of cardiac myofibroblasts in CVD and COVID-19 complications. Additionally, new factors including controlling ACE2 expression and microRNA regulation are explored as promising treatments for both COVID-19 and CVD. Further understanding of this topic may provide insight into the long-term cardiac manifestations of the COVID-19 pandemic and ways to mitigate its negative effects.

Comparative Metabolomics and Proteomics Reveal Vibrio parahaemolyticus Targets Hypoxia-Related Signaling Pathways of Takifugu obscurus.

Coronavirus disease 2019 (COVID-19) raises the issue of how hypoxia destroys normal physiological function and host immunity against pathogens. However, there are few or no comprehensive omics studies on this effect. From an evolutionary perspective, animals living in complex and changeable marine environments might develop signaling pathways to address bacterial threats under hypoxia. In this study, the ancient genomic model animal Takifugu obscurus and widespread Vibrio parahaemolyticus were utilized to study the effect. T. obscurus was challenged by V. parahaemolyticus or (and) exposed to hypoxia. The effects of hypoxia and infection were identified, and a theoretical model of the host critical signaling pathway in response to hypoxia and infection was defined by methods of comparative metabolomics and proteomics on the entire liver. The changing trends of some differential metabolites and proteins under hypoxia, infection or double stressors were consistent. The model includes transforming growth factor-ß1 (TGF-ß1), hypoxia-inducible factor-1α (HIF-1α), and epidermal growth factor (EGF) signaling pathways, and the consistent changing trends indicated that the host liver tended toward cell proliferation. Hypoxia and infection caused tissue damage and fibrosis in the portal area of the liver, which may be related to TGF-ß1 signal transduction. We propose that LRG (leucine-rich alpha-2-glycoprotein) is widely involved in the transition of the TGF-ß1/Smad signaling pathway in response to hypoxia and pathogenic infection in vertebrates as a conserved molecule.

Cardiac Fibrosis Is a Risk Factor for Severe COVID-19.

Increased left ventricular fibrosis has been reported in patients hospitalized with coronavirus disease 2019 (COVID-19). It is unclear whether this fibrosis is a consequence of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection or a risk factor for severe disease progression. We observed increased fibrosis in the left ventricular myocardium of deceased COVID-19 patients, compared with matched controls. We also detected increased mRNA levels of soluble interleukin-1 receptor-like 1 (sIL1-RL1) and transforming growth factor ß1 (TGF-ß1) in the left ventricular myocardium of deceased COVID-19 patients. Biochemical analysis of blood sampled from patients admitted to the emergency department (ED) with COVID-19 revealed highly elevated levels of TGF-ß1 mRNA in these patients compared to controls. Left ventricular strain measured by echocardiography as a marker of pre-existing cardiac fibrosis correlated strongly with blood TGF-ß1 mRNA levels and predicted disease severity in COVID-19 patients. In the left ventricular myocardium and lungs of COVID-19 patients, we found increased neuropilin-1 (NRP-1) RNA levels, which correlated strongly with the prevalence of pulmonary SARS-CoV-2 nucleocapsid. Cardiac and pulmonary fibrosis may therefore predispose these patients to increased cellular viral entry in the lung, which may explain the worse clinical outcome observed in our cohort. Our study demonstrates that patients at risk of clinical deterioration can be identified early by echocardiographic strain analysis and quantification of blood TGF-ß1 mRNA performed at the time of first medical contact.

Protective Effect of Remdesivir Against Pulmonary Fibrosis in Mice.

Pulmonary fibrosis is a known sequela of severe or persistent lung damage. Existing clinical, imaging and autopsy studies have shown that the lungs exhibit a pathological pulmonary fibrosis phenotype after infection with coronaviruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Pulmonary fibrosis may be one of the most serious sequelae associated with coronavirus disease 2019 (COVID-19). In this study, we aimed to examine the preventative effects of the antiviral drug remdesivir on pulmonary fibrosis. We used a mouse model of bleomycin-induced pulmonary fibrosis to evaluate the effects of remdesivir on pulmonary fibrosis in vivo and further explored the potential pharmacological mechanisms of remdesivir in lung fibroblasts and alveolar epithelial cells in vitro. The preventive remdesivir treatment was started on the day of bleomycin installation, and the results showed that remdesivir significantly alleviated bleomycin-induced collagen deposition and improved pulmonary function. In vitro experiments showed that remdesivir dose-dependently suppressed TGF-ß1-induced lung fibroblast activation and improved TGF-ß1-induced alveolar epithelial to mesenchymal transition. Our results indicate that remdesivir can preventatively alleviate the severity of pulmonary fibrosis and provide some reference for the prevention of pulmonary fibrosis in patients with COVID-19.

Serum levels of the IgA isotype switch factor TGF-ß1 are elevated in patients with COVID-19.

We previously observed enhanced immunoglobulin A (IgA) responses in severe COVID-19, which might confer damaging effects. Given the important role of IgA in immune and inflammatory responses, the aim of this study was to investigate the dynamic response of the IgA isotype switch factor TGF-ß1 in COVID-19 patients. We observed, in a total of 153 COVID-19 patients, that the serum levels of TGF-ß1 were increased significantly at the early and middle stages of COVID-19, and correlated with the levels of SARS-CoV-2-specific IgA, as well as with the APACHE II score in patients with severe disease. In view of the genetic association of the TGF-ß1 activator THBS3 with severe COVID-19 identified by the COVID-19 Host Genetics Initiative, this study suggests TGF-ß1 may play a key role in COVID-19.