Potential application of mesenchymal stromal cells as a new therapeutic approach in acute respiratory distress syndrome and pulmonary fibrosis.

While the COVID-19 outbreak and its complications are still under investigation, post-inflammatory pulmonary fibrosis (PF) has already been described as a long-term sequela of acute respiratory distress syndrome (ARDS) secondary to SARS-CoV2 infection. However, therapeutical strategies for patients with ARDS and PF are still limited and do not significantly extend lifespan. So far, lung transplantation remains the only definitive treatment for end-stage PF. Over the last years, numerous preclinical and clinical studies have shown that allogeneic mesenchymal stromal cells (MSCs) might represent a promising therapeutical approach in several lung disorders, and their potential for ARDS treatment and PF prevention has been investigated during the COVID-19 pandemic. From April 2020 to April 2022, we treated six adult patients with moderate COVID-19-related ARDS in a late proliferative stage with up to two same-dose infusions of third-party allogeneic bone marrow-derived MSCs (BM-MSCs), administered intravenously 15 days apart. No major adverse events were registered. Four patients completed the treatment and reached ICU discharge, while two received only one dose of MSCs due to multiorgan dysfunction syndrome (MODS) and subsequent death. All four survivors showed improved gas exchanges (PaO2/FiO2 ratio > 200), contrary to the others. Furthermore, LDH trends after MSCs significantly differed between survivors and the deceased. Although further investigations and shared protocols are still needed, the safety of MSC therapy has been recurrently shown, and its potential in treating ARDS and preventing PF might represent a new therapeutic strategy.

Improved pulmonary function and exercise tolerance despite persistent pulmonary fibrosis over 1 year after severe COVID-19 infection.

We conducted a prospective single-centre cohort study of 104 multi-ethnic severe COVID-19 survivors from the first wave of the pandemic 15 months after hospitalisation. Of those who were assessed at 4 and 15 months, improvement of ground glass opacities correlated with worsened fibrotic reticulations. Despite a high prevalence of fibrotic patterns (64%), pulmonary function, grip strength, 6 min walk distance and frailty normalised. Overall, dyspnoea, cough and exhaustion did not improve and were not correlated with pulmonary function or radiographic fibrosis at 15 months, suggesting non-respiratory aetiologies. Monitoring persistent, and often subclinical, fibrotic interstitial abnormalities will be needed to determine their potential for future progression.

Metabolism-driven glycosylation represents therapeutic opportunities in interstitial lung diseases.

Metabolic changes are coupled with alteration in protein glycosylation. In this review, we will focus on macrophages that are pivotal in the pathogenesis of pulmonary fibrosis and sarcoidosis and thanks to their adaptable metabolism are an attractive therapeutic target. Examples presented in this review demonstrate that protein glycosylation regulates metabolism-driven immune responses in macrophages, with implications for fibrotic processes and granuloma formation. Targeting proteins that regulate glycosylation, such as fucosyltransferases, neuraminidase 1 and chitinase 1 could effectively block immunometabolic changes driving inflammation and fibrosis, providing novel avenues for therapeutic interventions.

Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy.

Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissues became mechanically activated. The resulting co-alignment of macrophages, collagen fibers, and fibroblasts promoted widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMß2 and Rho-associated kinase 2. These results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by macrophages. The cocultured microtissue model is a powerful tool to study the immune-stromal cell interactions and the anti-fibrosis drug mechanism.

The Sphingolipid-Modulating Drug Opaganib Protects against Radiation-Induced Lung Inflammation and Fibrosis: Potential Uses as a Medical Countermeasure and in Cancer Radiotherapy.

Fibrosis is a chronic pathology resulting from excessive deposition of extracellular matrix components that leads to the loss of tissue function. Pulmonary fibrosis can follow a variety of diverse insults including ischemia, respiratory infection, or exposure to ionizing radiation. Consequently, treatments that attenuate the development of debilitating fibrosis are in desperate need across a range of conditions. Sphingolipid metabolism is a critical regulator of cell proliferation, apoptosis, autophagy, and pathologic inflammation, processes that are all involved in fibrosis. Opaganib (formerly ABC294640) is the first-in-class investigational drug targeting sphingolipid metabolism for the treatment of cancer and inflammatory diseases. Opaganib inhibits key enzymes in sphingolipid metabolism, including sphingosine kinase-2 and dihydroceramide desaturase, thereby reducing inflammation and promoting autophagy. Herein, we demonstrate in mouse models of lung damage following exposure to ionizing radiation that opaganib significantly improved long-term survival associated with reduced lung fibrosis, suppression of granulocyte infiltration, and reduced expression of IL-6 and TNFα at 180 days after radiation. These data further demonstrate that sphingolipid metabolism is a critical regulator of fibrogenesis, and specifically show that opaganib suppresses radiation-induced pulmonary inflammation and fibrosis. Because opaganib has demonstrated an excellent safety profile during clinical testing in other diseases (cancer and COVID-19), the present studies support additional clinical trials with this drug in patients at risk for pulmonary fibrosis.

Chlorogenic Acid Inhibits Progressive Pulmonary Fibrosis in a Diabetic Rat Model.

Background: Chlorogenic acid (CGA) is known to have antifibrotic and hypoglycemic effects and may play a role in preventing diabetes-induced pulmonary fibrosis. This study aimed to determine the effect and optimum dose of CGA on diabetes-induced pulmonary fibrosis. Methods: Thirty Wistar rats (two-month-old, 150-200 grams) were randomly divided into six groups, namely control, six weeks diabetes mellitus (DM1), eight weeks DM (DM2), and three DM2 groups (CGA1, CGA2, and CGA3) who received CGA doses of 12.5, 25, and 50 mg/Kg BW, respectively. After six weeks, CGA was administered intraperitoneally for 14 consecutive days. Lung tissues were taken for TGF-ß1, CTGF, SMAD7, Collagen-1, and α-SMA mRNA expression analysis and paraffin embedding. Data were analyzed using one-way ANOVA and the Kruskal-Wallis test. P<0.05 was considered statistically significant. Results: TGF-ß1 expression in the CGA1 group (1.01±0.10) was lower than the DM1 (1.33±0.25, P=0.05) and DM2 (1.33±0.20, P=0.021) groups. α-SMA expression in the CGA1 group (median 0.60, IQR: 0.34-0.64) was lower than the DM1 (median 0.44, IQR: 0.42-0.80) and DM2 (median 0.76, IQR: 0.66-1.10) groups. Collagen-1 expression in the CGA1 group (0.75±0.13) was lower than the DM1 (P=0.24) and DM2 (P=0.26) groups, but not statistically significant. CTGF expression in CGA groups was lower than the DM groups (P=0.088), but not statistically significant. There was an increase in SMAD7 expression in CGA groups (P=0.286). Histological analysis showed fibrosis improvement in the CGA1 group compared to the DM groups. Conclusion: CGA (12.5 mg/Kg BW) inhibited the expression of profibrotic factors and increased antifibrotic factors in DM-induced rats.

Lung cancer risk and occupational pulmonary fibrosis: systematic review and meta-analysis.

BACKGROUND: Molecular pathways found to be important in pulmonary fibrosis are also involved in cancer pathogenesis, suggesting common pathways in the development of pulmonary fibrosis and lung cancer. RESEARCH QUESTION: Is pulmonary fibrosis from exposure to occupational carcinogens an independent risk factor for lung cancer? STUDY DESIGN AND METHODS: A comprehensive search of PubMed, Embase, Web of Science and Cochrane databases with over 100 search terms regarding occupational hazards causing pulmonary fibrosis was conducted. After screening and extraction, quality of evidence and eligibility criteria for meta-analysis were assessed. Meta-analysis was performed using a random-effects model. RESULTS: 52 studies were identified for systematic review. Meta-analysis of subgroups identified silicosis as a risk factor for lung cancer when investigating odds ratios for silicosis in autopsy studies (OR 1.47, 95% CI 1.13-1.90) and for lung cancer mortality in patients with silicosis (OR 3.21, 95% CI 2.67-3.87). Only considering studies with an adjustment for smoking as a confounder identified a significant increase in lung cancer risk (OR 1.58, 95% CI 1.34-1.87). However, due to a lack of studies including cumulative exposure, no adjustments could be included. In a qualitative review, no definitive conclusion could be reached for asbestosis and silicosis as independent risk factors for lung cancer, partly because the studies did not take cumulative exposure into account. INTERPRETATION: This systematic review confirms the current knowledge regarding asbestosis and silicosis, indicating a higher risk of lung cancer in exposed individuals compared to exposed workers without fibrosis. These individuals should be monitored for lung cancer, especially when asbestosis or silicosis is present.

Inhibition of TGFß1 activation prevents radiation-induced lung fibrosis.

BACKGROUND: Radiotherapy is the main treatment modality for thoracic tumours, but it may induce pulmonary fibrosis. Currently, the pathogenesis of radiation-induced pulmonary fibrosis (RIPF) is unclear, and effective treatments are lacking. Transforming growth factor beta 1 (TGFß1) plays a central role in RIPF. We found that activated TGFß1 had better performance for radiation pneumonitis (RP) risk prediction by detecting activated and total TGFß1 levels in patient serum. αv integrin plays key roles in TGFß1 activation, but the role of αv integrin-mediated TGFß1 activation in RIPF is unclear. Here, we investigated the role of αv integrin-mediated TGFß1 activation in RIPF and the application of the integrin antagonist cilengitide to prevent RIPF. METHODS: ItgavloxP/loxP ;Pdgfrb-Cre mice were generated by conditionally knocking out Itgav in myofibroblasts, and wild-type mice were treated with cilengitide or placebo. All mice received 16 Gy of radiation or underwent a sham radiation procedure. Lung fibrosis was measured by a modified Ashcroft score and microcomputed tomography (CT). An enzyme-linked immunosorbent assay (ELISA) was used to measure the serum TGFß1 concentration, and total Smad2/3 and p-Smad2/3 levels were determined via Western blotting. RESULTS: Conditional Itgav knockout significantly attenuated RIPF (p < .01). Hounsfield units (HUs) in the lungs were reduced in the knockout mice compared with the control mice (p < .001). Conditional Itgav knockout decreased active TGFß1 secretion and inhibited fibroblast p-Smad2/3 expression. Exogenous active TGFß1, but not latent TGFß1, reversed these reductions. Furthermore, cilengitide treatment elicited similar results and prevented RIPF. CONCLUSIONS: The present study revealed that conditional Itgav knockout and cilengitide treatment both significantly attenuated RIPF in mice by inhibiting αv integrin-mediated TGFß1 activation. HIGHLIGHTS: Activated TGFß1 has a superior capacity in predicting radiation pneumonitis (RP) risk and plays a vital role in the development of radiation-induced pulmonary fibrosis (RIPF). Conditional knock out Itgav in myofibroblasts prevented mice from developing RIPF. Cilengitide alleviated the development of RIPF by inhibiting αv integrin-mediated TGFß1 activation and may be used in targeted approaches for preventing RIPF.

Small extracellular vesicles from irradiated lung epithelial cells promote the activation of fibroblasts in pulmonary fibrosis.

BACKGROUND: Alveolar epithelial injury and dysfunction are the risk factors for radiation-induced pulmonary fibrosis (RIPF). However, it is not clear about the relationship between RIPF and the small extracellular vesicles (sEV) secreted by irradiated alveolar epithelial cells. Based on the activation of fibroblasts, this study explored the role of sEV derived from alveolar epithelial cells in RIPF and the potential mechanisms. METHODS: Transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting were used to characterize sEV. Western blotting was used to detect fibrosis-associated proteins. Cell counts and transwell assays were used to evaluate the proliferation and migration ability of fibroblasts. RT-PCR was used to observe the extracellular matrix (ECM) synthesized by fibroblasts, miRNA changes in the sEV were determined by second-generation sequencing. RESULTS: TEM, NTA, and western blotting showed the extracellular vesicles with a double-layer membrane structure of approximately 100 nm in diameter. The sEV derived from irradiated A549, HBEC3-KT, and MLE12 cells upregulated FN1 and alpha-SMA proteins expression in fibroblasts and drove the fibroblast to myofibroblast transition, and the sEV from irradiated mouse bronchoalveolar lavage fluid (BALF) affirmed the same results. In addition, the sEV derived from irradiated alveolar epithelial cells significantly increased the migration ability of fibroblasts and the expression of extracellular matrix proteins such as FN1. The results of miRNA sequencing of sEV in BALF of rats with RIPF showed that the metabolic pathway may be important for miRNA to regulate the activation of fibroblasts. CONCLUSION: The sEV derived from radiated pulmonary epithelial cells promote the activation, migration and extracellular matrix proteins expression of lung fibroblasts; miRNA in sEV may be an important molecular that affects the activation of lung fibroblasts.

Glycyrrhetinic Acid Mitigates Radiation-Induced Pulmonary Fibrosis via Inhibiting the Secretion of TGF-ß1 by Treg Cells.

PURPOSE: Radiation-induced pulmonary fibrosis (RIPF) is a common side effect of radiation therapy for thoracic tumors without effective prevention and treatment methods at present. The aim of this study was to explore whether glycyrrhetinic acid (GA) has a protective effect on RIPF and the underlying mechanism. METHODS AND MATERIALS: A RIPF mouse model administered GA was used to determine the effect of GA on RIPF. The cocultivation of regulatory T (Treg) cells with mouse lung epithelial-12 cells or mouse embryonic fibroblasts and intervention with GA or transforming growth factor-ß1 (TGF-ß1) inhibitor to block TGF-ß1 was conducted to study the mechanism by which GA alleviates RIPF. Furthermore, injection of Treg cells into GA-treated RIPF mice to upregulate TGF-ß1 levels was performed to verify the roles of TGF-ß1 and Treg cells. RESULTS: GA intervention improved the damage to lung tissue structure and collagen deposition and inhibited Treg cell infiltration, TGF-ß1 levels, epithelial mesenchymal transition (EMT), and myofibroblast (MFB) transformation in mice after irradiation. Treg cell-induced EMT and MFB transformation in vitro were prevented by GA, as well as a TGF-ß1 inhibitor, by decreasing TGF-ß1. Furthermore, reinfusion of Treg cells upregulated TGF-ß1 levels and exacerbated RIPF in GA-treated RIPF mice. CONCLUSIONS: GA can improve RIPF in mice, and the corresponding mechanisms may be related to the inhibition of TGF-ß1 secreted by Treg cells to induce EMT and MFB transformation. Therefore, GA may be a promising therapeutic candidate for the clinical treatment of RIPF.

Long-term nintedanib treatment for progressive pulmonary fibrosis associated with Hermansky-Pudlak syndrome type 1 followed by lung transplantation.

Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disease that often causes progressive pulmonary fibrosis (HPS-PPF) in some genetic types with high mortality rates. No effective treatment for HPS-PPF other than lung transplantation has been established. Herein, we report a case of HPS type 1 with progressive pulmonary fibrosis treated with long-term nintedanib administration followed by lung transplantation. The resected lungs revealed diffuse interstitial lung lesions, including fibroblastic foci, suggesting the potential beneficial effects of anti-fibrotic drugs in HPS-PPF. Together with previous reports, the present case suggests that nintedanib might be a safe and effective drug for HPS-PPF.

Imbalance of TH17/TREG cells in Tunisian patients with systemic sclerosis.

Fibrosis is a pathological manifestation in which connective tissue replaces normal one. It can affect many tissues from the skin to internal organs such as the lungs. Manifestations of pulmonary involvement can be pulmonary arterial hypertension or pulmonary fibrosis. The latter one is currently the leading cause of death in various autoimmune diseases, including systemic sclerosis. Our study group consists of 50 patients with systemic sclerosis: 24 with limited cutaneous form and 26 with diffuse cutaneous form. This cohort was compared to 50 healthy controls (age and sex matched); our aim is to explore the distribution of TH17 cells (TH17) as well as regulatory T cells (TREG) and study their correlation with the disease's progress. Our results show an increase for IL17A in patients compared to controls and that this increase is correlated with a specific clinical involvement: Pulmonary fibrosis. This correlation suggests a crucial role of IL17A in fibrosis especially in systemic sclerosis. In addition, we have shown that the percentages of TH17 cells are higher in patients; however, the percentages of TREG cells are similar between patients and controls. A study of TREG cell activity showed that TREG lost suppressive activity by inactivating the FOXP3 transcription factor. This proves that despite their presence, TREG does not adequately carry out their regulatory activity. Finally, we analyzed the correlation between TH17/TREG and clinical damage; the results show a positive correlation with pulmonary involvement proving the role of TH17/TREG balance in induced fibrosis in systemic sclerosis. No significative difference was observed, for all the parameters, between the two different forms of the disease. In conclusion, the results associated with the TH17/TREG scale and their correlations with fibrosis in systemic sclerosis open a way for new tools to manage this autoimmune disease, which up to today has neither treatment nor accurate diagnosis.

The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential.

Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.

NXC736 Attenuates Radiation-Induced Lung Fibrosis via Regulating NLRP3/IL-1ß Signaling Pathway.

Radiation-induced lung fibrosis (RILF) is a common complication of radiotherapy in lung cancer. However, to date no effective treatment has been developed for this condition. NXC736 is a novel small-molecule compound that inhibits NLRP3, but its effect on RILF is unknown. NLRP3 activation is an important trigger for the development of RILF. Thus, we aimed to evaluate the therapeutic effect of NXC736 on lung fibrosis inhibition using a RILF animal model and to elucidate its molecular signaling pathway. The left lungs of mice were irradiated with a single dose of 75 Gy. We observed that NXC736 treatment inhibited collagen deposition and inflammatory cell infiltration in irradiated mouse lung tissues. The damaged lung volume, evaluated by magnetic resonance imaging, was lower in NXC736-treated mice than in irradiated mice. NXC736-treated mice exhibited significant changes in lung function parameters. NXC736 inhibited inflammasome activation by interfering with the NLRP3-ASC-cleaved caspase-1 interaction, thereby reducing the expression of IL-1ß and blocking the fibrotic pathway. In addition, NXC736 treatment reduced the expression of epithelial-mesenchymal transition markers such as α-SMA, vimentin, and twist by blocking the Smad 2,3,4 signaling pathway. These data suggested that NXC736 is a potent therapeutic agent against RILF.

Bronchial Asthma, Airway Remodeling and Lung Fibrosis as Successive Steps of One Process.

Bronchial asthma is a heterogeneous disease characterized by persistent respiratory system inflammation, airway hyperreactivity, and airflow obstruction. Airway remodeling, defined as changes in airway wall structure such as extensive epithelial damage, airway smooth muscle hypertrophy, collagen deposition, and subepithelial fibrosis, is a key feature of asthma. Lung fibrosis is a common occurrence in the pathogenesis of fatal and long-term asthma, and it is associated with disease severity and resistance to therapy. It can thus be regarded as an irreversible consequence of asthma-induced airway inflammation and remodeling. Asthma heterogeneity presents several diagnostic challenges, particularly in distinguishing between chronic asthma and other pulmonary diseases characterized by disruption of normal lung architecture and functions, such as chronic obstructive pulmonary disease. The search for instruments that can predict the development of irreversible structural changes in the lungs, such as chronic components of airway remodeling and fibrosis, is particularly difficult. To overcome these challenges, significant efforts are being directed toward the discovery and investigation of molecular characteristics and biomarkers capable of distinguishing between different types of asthma as well as between asthma and other pulmonary disorders with similar structural characteristics. The main features of bronchial asthma etiology, pathogenesis, and morphological characteristics as well as asthma-associated airway remodeling and lung fibrosis as successive stages of one process will be discussed in this review. The most common murine models and biomarkers of asthma progression and post-asthmatic fibrosis will also be covered. The molecular mechanisms and key cellular players of the asthmatic process described and systematized in this review are intended to help in the search for new molecular markers and promising therapeutic targets for asthma prediction and therapy.

Methods to assess radiation-induced fibrosis in mice.

Therapeutic radiation is used to treat a variety of cancers in organs and tissues throughout the body. Exposure of benign normal tissue to radiation can result in late injury in a subset of patients. Radiation induced fibrosis is one chronic, progressive late toxicity of radiation exposure that can occur in many organs and tissues, including skin and lung. Radiation fibrosis has few effective treatments. The process of radiation fibrosis is known to involve many mitogenic and immunomodulatory cytokines, inflammatory programs, and processes such as stem cell senescence. Murine models of radiation fibrosis can be used to evaluate agents that may prevent, mitigate, or treat this injury. Here, we provide a detailed protocol for the development of radiation induced dermal and pulmonary fibrosis in mice and describe protocols for the measurement of this injury in treated tissue.

A phosphodiesterase-4 inhibitor reduces lung inflammation and fibrosis in a hamster model of SARS-CoV-2 infection.

Introduction: The Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infection involves pulmonary inflammation that can progress to acute respiratory distress syndrome, a primary cause of lung damage/fibrosis in patients with Coronavirus Disease-2019 (COVID-19). Currently, there is no efficacious therapy available to alleviate lung fibrosis in COVID-19 cases. In this proof-of-concept study, we evaluated the effect of CC-11050, a small molecule phosphodiesterase-4 inhibitor, in dampening lung inflammation and fibrosis in a hamster model of SARS-CoV-2 infection. Methods: Following intranasal inoculation with SARS-CoV-2/WA- 1/2000 strain, hamsters were treated with CC-11050 or placebo by gavage from day-1 until day-16 post-infection (dpi). Animals were monitored for body weight changes, virus titers, histopathology, fibrotic remodeling, cellular composition in the lungs between 2 and 16 dpi. Results: We observed significant reduction in lung viral titer with concomitant reduction in inflammation and fibrotic remodeling in CC-11050 treated hamsters compared to untreated animals. The reductions in immunopathologic manifestations were associated with significant downregulation of inflammatory and fibrotic remodeling gene expression, reduced infiltration of activated monocytes, granulocytes, and reticular fibroblasts in CC-11050 treated animals. Cellular studies indicate a link between TNF-α and fibrotic remodeling during CC-11050 therapy. Discussion: These findings suggest that CC-11050 may be a potential host-directed therapy to dampen inflammation and fibrosis in COVID-19 cases.

Diagnosis of interstitial lung disease (ILD) secondary to systemic sclerosis (SSc) and rheumatoid arthritis (RA) and identification of 'progressive pulmonary fibrosis' using chest CT: a narrative review.

Interstitial lung disease (ILD) is a frequent manifestation of connective tissue diseases (CTDs), with incidence and prevalence variously assessed in the literature but reported in up to 30% of patients, with higher frequency in rheumatoid arthritis (RA) and systemic sclerosis (SSc). Recent years have seen a growing interest in the pulmonary manifestations of ILD-CTDs, mainly due to the widening of the use of anti-fibrotic drugs initially introduced exclusively for IPF, and radiologists play a key role because the lung biopsy is very rarely used in these patients where the morphological assessment is essentially left to imaging and especially HRCT. In this narrative review we will discuss, from the radiologist's point of view, the most recent findings in the field of ILD secondary to SSc and RA, with a special focus about the progression of disease and in particular about the 'progressive pulmonary fibrosis' (PPF) phenotype, and we will try to address two main issues: How to predict a possible evolution and therefore a worse prognosis when diagnosing a new case of ILD-CTDs and how to assess the progression of an already diagnosed ILD-CTDs.

Neutrophil extracellular traps and long COVID.

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan. In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID. Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can drive NET formation through their pro-inflammatory secretome in long COVID. Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.