Effect of apigetrin in pseudo-SARS-CoV-2-induced inflammatory and pulmonary fibrosis in vitro model (preprint)

SARS-CoV-2 has become a global public health problem. Acute respiratory distress syndrome (ARDS) is the leading cause of death due to the SARS-CoV-2 infection. Pulmonary fibrosis (PF) is a severe and frequently reported COVID-19 sequela. In this study, an in vitro model of ARDS and PF caused by SARS-CoV-2 was established in MH-S, THP-1, and MRC-5 cells using pseudo-SARS-CoV-2 (PSCV). Expression of proinflammatory cytokines (IL-6, IL-1β, and TNF-α) and HIF-1α was increased in PSCV-infected MH-S and THP-1 cells, ARDS model, consistent with other profiling data in SARS-CoV-2-infected patients have been reported. Hypoxia-inducible factor-1 alpha (HIF-1α) siRNA and cobalt chloride were tested using this in vitro model. Furthermore, apigetrin, a glycoside bioactive dietary flavonoid derived from several plants, including Crataegus pinnatifida, which is reported to be a HIF-1α inhibitor, was tested in this in vitro model [1]. Apigetrin significantly reduced the increased inflammatory cytokine (IL-6, IL-1β, and TNF-α) expression and secretion by PSCV in MH-S and THP-1 cells. Apigetrin inhibited the binding of the SARS-CoV-2 spike protein RBD to the ACE2 protein. An in vitro model of PF induced by SARS-CoV-2 was produced using a conditioned medium of THP-1 and MH-S cells that were PSCV-infected (CMPSCV) into MRC-5 cells. In a PF model, CMPSCV treatment of THP-1 and MH-S cells increased cell growth, migration, and collagen synthesis in MRC-5 cells. In contrast, apigetrin suppressed the increase in cell growth, migration, and collagen synthesis induced by CMPSCV in THP-1 and MH-S MRC-5 cells. Also, compared to control, fibrosis-related proteins (CTGF, COLA1, α-SMA, and HIF-1α) levels were over two-fold higher in CMPSV-treated MRC-5 cells. Apigetrin decreased protein levels in CMPSCV-treated MRC-5 cells. Thus, our data suggest that hypoxia-inducible factor-1 alpha (HIF-1α) might be a novel target for SARS-CoV-2 sequela therapies and apigetrin, representative of HIF-1alpha inhibitor, exerts anti-inflammatory and PF effects in PSCV-treated MH-S, THP-1, and CMPVSC-treated MRC-5 cells. These findings indicate that HIF-1α inhibition and apigetrin would have a potential value in controlling SARS-CoV-2-related diseases.

Analysis of Prognostic Factors and Establishment of a Nomogram to Predict Risk for COVID-19 Convalescent Patients Based on Metabolomic and Lipidomic (preprint)

Ethnopharmacological relevance: Qimai Feiluoping Mixture (QM) is a traditional Chinese herbal formulation that has demonstrated efficacy in improving both clinical symptoms and radiological indications of pulmonary fibrosis in patients convalescing from Coronavirus Disease 2019 (COVID-19).Aim of the study: To analyze factors associated with the prognosis of COVID-19 patients. It seeks to develop and validate a nomogram based on metabolomic and lipidomic for predicting improvements in lung imaging in COVID-19 patients. Additionally, the study evaluates the clinical application value of this nomogram.Methods and materials: A retrospective analysis was conducted on the clinical data of COVID-19 recovery patients from January 2020 to April 2022. Non-targeted metabolomic and lipidomic plasma analysis of the patients were performed using LC-MS and normal phase (NP)-HPLC coupled with mass spectrometry. Patients were divided into training and validation sets in a 7:3 ratio based on their omics data. Multivariate logistic regression analysis was conducted to identify independent risk factors associated with the recovery of lung imaging. Based on these factors, a nomogram prediction model was developed. The efficacy of the model was evaluated using receiver operating characteristic (ROC) curves and calibration curves. In addition, decision curve analysis (DCA) was performed to assess the performance of the predictive model in clinical applications.Results The use of QM was found to be associated with the recovery of lung imaging in COVID-19 patients (P < 0.05). Among the 75 metabolites detected in the metabolomic test and 32 lipids identified in the lipidomic test, Pro Ser Ser Val, PC36:1(18:0_18:1), and BMP36:3(18:2_18:1) were utilized for constructing the predictive model. The model demonstrated good discriminative ability, with an Area Under the Curve (AUC) of 0.821 (95% CI: 0.718–0.924) in the training set and 0.808 (95% CI: 0.627–0.989) in the validation set. The calibration curves indicated good agreement between predicted probabilities and actual probabilities in both the training and validation sets. Finally, the DCA curve suggested that the model has good clinical utility.Conclusion The utilization of QM may beneficially influence the recovery of lung imaging in patients with COVID-19. A straightforward nomogram, developed based on metabolomic and lipidomic, could be a valuable tool for clinicians to predict the likelihood of lung imaging recovery in COVID-19 patients.

Could SP-A and SP-D Serum Levels Predict COVID-19 Severity? (preprint)

Given the various clinical manifestations that characterize COVID-19, the scientific community is constantly searching for biomarkers with prognostic value. SP-A and SP-D collectins play a crucial role in ensuring proper alveolar function and an alteration of their serum levels have been reported in several pulmonary diseases characterized by ARDS and pulmonary fibrosis. Considering that such clinical manifestations can also occur during SARS-CoV-2 infection, we wondered if these collectins could act as prognostic markers. In this regard, serum levels of SP-A and SP-D were measured by enzyme immunoassay in patients with SARS-CoV-2 infection (n=51) at admission (T0) and after 7 days (T1) and compared with healthy donors (n=11). SP-D increased in COVID-19 patients compared to healthy controls during the early phases of infection, while a significant reduction was observed at T1. Stratifying SARS-CoV-2 patients according to disease severity, increased serum SP-D levels were observed in severe compared to mild patients. In the light of these results SP-D, but not SP-A, seems to be an eligible marker of COVID-19 pneumonia and the early detection of SP-D serum levels could be crucial for a preventive clinical management

Pulmonary fibrosis in critically ill patients with COVID-19: A multi-center retrospective cohort study in South Korea (preprint)

Background: Pulmonary fibrosis persists long after recovering from coronavirus disease 2019 (COVID-19) infection, thereby reducing quality of life and lung function. We aimed to evaluate the prevalence and risk factors for pulmonary fibrosis in patients with severe COVID-19 pneumonia requiring mechanical ventilation, a high-risk group for developing pulmonary fibrosis. Methods: Clinical data and chest computed tomography (CT) scans of patients with severe COVID-19 pneumonia requiring mechanical ventilation were retrospectively collected from nine hospitals in South Korea. Fibrotic-like changes on chest CT were visually assessed. Results: We included 125 patients with a mean age of 68.5 years, 60.8% men and 7.2% having underlying lung disease. Based on follow-up chest CT (the median interval: 38.0 days, interquartile range: 24.0–68.0 days), 94 (75.2%) patients exhibited fibrotic-like changes, with traction bronchiectasis and/or bronchiolectasis being the most common change (60.8%). Adjusted Cox regression analysis revealed as association between hemoglobin levels ≤9 g/dL and an increased risk of pulmonary fibrosis development (HR: 3.182, 95% Cl: 1.203–8.415, P=0.025). Among all patients, 17.6% died during hospitalization and 71.2% experienced complications, including intubation-related airway injury (12.8%), ventilator-associated pneumonia (44.8%), lung injury (11.2%), and hemodynamic disturbance (33.4%). In-hospital mortality (16.1% vs. 18.1%) and complications (67.7% vs. 72.3%) were similar between patients with and without fibrotic-like changes. Conclusion: Our study demonstrated that in patients with severe COVID-19 pneumonia requiring mechanical ventilation, chest CT revealed fibrotic-like changes in approximately three-fourths of patients. Low hemoglobin levels might be associated with pulmonary fibrosis in severe COVID-19 pneumonia.

S-RBD-modified and miR-486-5p-engineered exosomes derived from mesenchymal stem cells alleviate radiation-induced lung injury and long-term pulmonary fibrosis via suppression of ferroptosis (preprint)

Background Radiation-induced pulmonary fibrosis (RIPF) is a late-stage complication of therapeutic radiation, associated with poor prognosis and limited therapeutic options. Radiation-induced lung injury (RILI) is an early manifestation of RIPF, and intervention of RILI is an effective method for preventing long-term RIPF. Mesenchymal stem cell (MSC)-derived exosomes exhibit regenerative activity in injured lungs and are effective drug-delivery nanoparticles. SARS-CoV-2-S-RBD enables ACE2+ cell targeting of MSC extracellular vesicles. miR-486-5p is a multifunctional miRNA with angiogenic and anti-fibrotic activities and is enriched in MSC-derived exosomes. In this study, we investigated the therapeutic effects of miR-486-5p and SARS-COV-2-S-RBD-engineered MSC exosomes on RIPF in vitro and in vivo.Results Adenovirus-mediated gene modification led to the overexpression of miR-486-5p in umbilical cord MSCs (UC-MSCs), which further enriched miR-486-5p in UC-MSCs-derived exosomes. MiR-486-5p-engineered MSC exosomes (miR-486-MSC-Exo) promoted the proliferation and migration of irradiated MLE-12 cells in vitro and inhibited RILI in vivo. An in vitro assay revealed the occurrence of ferroptosis, a major form of cell death during radiation injury, indicated by the upregulated expression of fibrosis-related genes. miR-486-MSC-Exo effectively reversed these changes. MiR-486-MSC-Exo strongly reversed the upregulated expression of MLE-12 fibrosis-related genes induced by TGF in vitro and improved pathological fibrosis in the RIPF model in vivo. The distribution of RBD-VSVG-MSC exosomes labeled with DiR dye in hACE2CKI/CKI Sftpc-Cre+ mice demonstrated that the fluorescence of RBD-VSVG exosomes remained in the lungs for a long time. miR-486-RBD-MSC-exosomes significantly improved the survival rate and pathological changes in hACE2CKI/CKI Sftpc-Cre+ RIPF mice. Furthermore, miR-486-MSC-Exo exerted anti-fibrotic effects through targeted inhibition of SMAD2 and activation of Akt phosphorylation.Conclusions Here, miR-486-MSC-Exo inhibited lung injury and alleviated fibrosis in vivo and in vitro. Surface modification with COVID-S-RBD conferred engineered exosomes with the ability to target the lungs of animal models. The therapeutic effects of miR-486-5p and COVID-S-RBD-engineered MSC exosomes on RIPF were significantly enhanced. MSC-derived exosomes modified with recombinant COVID-S-RBD enabled targeted delivery of miR-486-5p, which is an effective approach for the treatment of RIPF.

The Interleukin 6 (IL-6) blockade for coronavirus disease 2019 (COVID-19) In Lung (preprint)

COVID-19 has caused global pandemics since the emergent outbreak and resulted in a large number of deaths. IL-6, as an important autoimmune cytokine, had been suggested for the treatment of acute respiratory distress syndrome (ARDS) patients in COVID-19. A review of the relevant literature revealed more than one role for IL-6 in the lung infection because of its diverse biological effects. It may have a variety of different physiological functions in the development of lung infection. We have summarized its role in different progress of COVID-19, including lung infection, pneumonia, ALI, pulmonary fibrosis, and lung translation and even lung cancer. This will facilitate a deeper understanding of the role of IL-6 in the treatment of COVID-19.

SOX9-regulated matrix proteins predict poor outcomes in patients with COVID-19 and pulmonary fibrosis (preprint)

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.

Pulmonary Fibrosis Followed by Severe Pneumonia in Patients with COVID- 19 infection: A Prospective Multicentre Study (preprint)

Backgrounds : The management of lung complications, especially fibrosis, after coronavirus disease (COVID-19) pneumonia, is an important issue in the COVID-19 post-pandemic era. We aimed to investigate risk factors for pulmonary fibrosis development in patients with severe COVID-19 pneumonia.Methods Clinical and radiologic data were prospectively collected from 64 patients who required mechanical ventilation due to COVID-19 pneumonia and were enrolled from eight hospitals in South Korea. Fibrotic changes on chest computed tomography (CT) was evaluated by visual assessment, and extent of fibrosis (mixed disease score) was measured using automatic quantification system.Results Sixty-four patients were enrolled, and their mean age was 58.2 years (64.1% were males). On chest CT (median interval: 60 days [interquartile range, IQR; 41–78 days] from enrolment), 35 (54.7%) patients showed ≥ 3 fibrotic lesions. The most frequent fibrotic change was traction bronchiectasis (47 patients, 73.4%). Median extent of fibrosis measured by automatic quantification was 10.6% (IQR, 3.8–40.7%). In a multivariable Cox proportional hazard model, which included nine variables with a p-value of < 0.10 in an unadjusted analysis as well as age, sex, and body mass index, male sex (hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.27–7.11) and higher initial sequential organ failure assessment (SOFA) score (HR, 1.18; 95% CI, 1.02–1.37) were independently associated with pulmonary fibrosis (≥ 3 fibrotic lesions).Conclusion Our data suggests that male gender and higher SOFA score at intensive care unit admission were associated with pulmonary fibrosis in patients with severe COVID-19 pneumonia requiring mechanical ventilation.

Hunting imaging biomarkers in pulmonary fibrosis: Benchmarks of the AIIB23 challenge (preprint)

Airway-related quantitative imaging biomarkers are crucial for examination, diagnosis, and prognosis in pulmonary diseases. However, the manual delineation of airway trees remains prohibitively time-consuming. While significant efforts have been made towards enhancing airway modelling, current public-available datasets concentrate on lung diseases with moderate morphological variations. The intricate honeycombing patterns present in the lung tissues of fibrotic lung disease patients exacerbate the challenges, often leading to various prediction errors. To address this issue, the 'Airway-Informed Quantitative CT Imaging Biomarker for Fibrotic Lung Disease 2023' (AIIB23) competition was organized in conjunction with the official 2023 International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI). The airway structures were meticulously annotated by three experienced radiologists. Competitors were encouraged to develop automatic airway segmentation models with high robustness and generalization abilities, followed by exploring the most correlated QIB of mortality prediction. A training set of 120 high-resolution computerised tomography (HRCT) scans were publicly released with expert annotations and mortality status. The online validation set incorporated 52 HRCT scans from patients with fibrotic lung disease and the offline test set included 140 cases from fibrosis and COVID-19 patients. The results have shown that the capacity of extracting airway trees from patients with fibrotic lung disease could be enhanced by introducing voxel-wise weighted general union loss and continuity loss. In addition to the competitive image biomarkers for prognosis, a strong airway-derived biomarker (Hazard ratio>1.5, p<0.0001) was revealed for survival prognostication compared with existing clinical measurements, clinician assessment and AI-based biomarkers.

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19 (preprint)

The long-term health effects of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are quickly evolving into a major public health concern, but the underlying cellular and molecular etiology remain poorly defined. There is growing evidence that PASC is linked to abnormal immune responses and/or poor organ recovery post-infection. However, the exact processes linking non-resolving inflammation, impaired tissue repair, and PASC are still unclear. In this report, we utilized a cohort of respiratory PASC patients with viral infection-mediated pulmonary fibrosis and a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. Using a combination of imaging and spatial transcriptomics, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, and the development of fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors in fibrotic areas. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC and identify potential therapeutic targets to dampen chronic pulmonary sequelae post respiratory viral infections including SARS-CoV-2.

Deep spatial proteomic exploration of severe COVID-19-related pulmonary injury in post-mortem specimens (preprint)

The lung, as a primary target of SARS-CoV-2, exhibits heterogeneous microenvironment accompanied by various histopathological changes following virus infection. However, comprehensive insight into the protein basis of COVID-19-related pulmonary injury with spatial resolution is currently deficient. Here, we generated a region-resolved quantitative proteomic atlas of seven major pathological structures within the lungs of COVID-19 victims by integrating histological examination, laser microdissection, and ultrasensitive proteomic technologies. Over 10,000 proteins were quantified across 71 dissected FFPE post-mortem specimens. By comparison with control samples, we identified a spectrum of COVID-19-induced protein and pathway dysregulations in alveolar epithelium, bronchial epithelium, and pulmonary blood vessels, providing evidence for the proliferation of transitional-state pneumocytes. Additionally, we profiled the region-specific proteomes of hallmark COVID-19 pulmonary injuries, including bronchiole mucus plug, pulmonary fibrosis, airspace inflammation, and hyperplastic alveolar type 2 cells. Bioinformatic analysis revealed the enrichment of cell-type and functional markers in these regions (e.g. enriched TGFBI in fibrotic region). Furthermore, we identified the up-regulation of proteins associated with viral entry, host restriction, and inflammatory response in COVID-19 lungs, such as FURIN and HGF. Collectively, this study provides spatial proteomic insights for understanding COVID-19-caused pulmonary injury, and may serve as a valuable reference for improving therapeutic intervention for severe pneumonia.

An integrated cell atlas of the lung in health and disease.

Single-cell technologies have transformed our understanding of human tissues. Yet, studies typically capture only a limited number of donors and disagree on cell type definitions. Integrating many single-cell datasets can address these limitations of individual studies and capture the variability present in the population. Here we present the integrated Human Lung Cell Atlas (HLCA), combining 49 datasets of the human respiratory system into a single atlas spanning over 2.4 million cells from 486 individuals. The HLCA presents a consensus cell type re-annotation with matching marker genes, including annotations of rare and previously undescribed cell types. Leveraging the number and diversity of individuals in the HLCA, we identify gene modules that are associated with demographic covariates such as age, sex and body mass index, as well as gene modules changing expression along the proximal-to-distal axis of the bronchial tree. Mapping new data to the HLCA enables rapid data annotation and interpretation. Using the HLCA as a reference for the study of disease, we identify shared cell states across multiple lung diseases, including SPP1+ profibrotic monocyte-derived macrophages in COVID-19, pulmonary fibrosis and lung carcinoma. Overall, the HLCA serves as an example for the development and use of large-scale, cross-dataset organ atlases within the Human Cell Atlas.

Short telomeres in alveolar type II cells associate with lung fibrosis in post COVID-19 patients with cancer.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic. The severity of COVID-19 increases with each decade of life, a phenomenon that suggest that organismal aging contributes to the fatality of the disease. In this regard, we and others have previously shown that COVID-19 severity correlates with shorter telomeres, a molecular determinant of aging, in patient's leukocytes. Lung injury is a predominant feature of acute SARS-CoV-2 infection that can further progress to lung fibrosis in post-COVID-19 patients. Short or dysfunctional telomeres in Alveolar type II (ATII) cells are sufficient to induce pulmonary fibrosis in mouse and humans. Here, we analyze telomere length and the histopathology of lung biopsies from a cohort of alive post-COVID-19 patients and a cohort of age-matched controls with lung cancer. We found loss of ATII cellularity and shorter telomeres in ATII cells concomitant with a marked increase in fibrotic lung parenchyma remodeling in post- COVID-19 patients compared to controls. These findings reveal a link between presence of short telomeres in ATII cells and long-term lung fibrosis sequel in Post-COVID-19 patients.

[Pulmonary fibrosis in patients with COVID-19: A review].

The viral infectious disease pandemic caused by SARS-CoV-2 has affected over 500 million people and killed over 6 million. This is the official data provided by the WHO as of the end of May 2022. Among people who have recovered from COVID-19, post-COVID syndrome is quite common. Scattered epidemiological studies on post-COVID syndrome, however, indicate its high relevance. One of the manifestations of post-COVID syndrome is the development of pulmonary fibrosis (PF). This article is devoted to the analysis of literature data on epidemiology, immunomorphology, as well as X-ray morphological and functional characteristics of PF in patients with post-COVID syndrome. Attention is drawn to the various phenotypes of the post-COVID syndrome and the incidence of PF, which, as clinical practice shows, is most common in people who have had severe COVID-19. This article discusses in detail the molecular biological and immunological mechanisms of PF development. The fibrotic process of the lung parenchyma is not an early manifestation of the disease; as a rule, radiomorphological signs of this pathological process develop after four weeks from the onset of acute manifestations of a viral infection. The characteristic signs of PF include those that indicate the process of remodulation of the lung tissue: volumetric decrease in the lungs, "cellular" degeneration of the lung parenchyma, bronchiectasis and traction bronchiolectasis. The process of remodulating the lung tissue, in the process of fibrosis, is accompanied by a violation of the lung function; a particularly sensitive test of functional disorders is a decrease in the diffusion capacity of the lung tissue. Therefore, in the process of monitoring patients with post-COVID syndrome, a dynamic study of the ventilation function of the lungs is recommended. The main clinical manifestation of PF is dyspnea that occurs with minimal exertion. Shortness of breath also reflects another important aspect of fibrous remodulation of the lung parenchyma - oxygen dissociation is disturbed, which reflects a violation of the gas exchange function of the lungs. There are no generally accepted treatments for PF in post-COVID syndrome. The literature considers such approaches as the possibility of prescribing antifibrotic therapy, hyaluronidase, and medical gases: thermal helium, nitric oxide, and atomic hydrogen. The article draws attention to the unresolved issues of post-covid PF in people who have had COVID-19.

New therapeutic approaches against pulmonary fibrosis.

Pulmonary fibrosis is the end-stage change of a large class of lung diseases characterized by the proliferation of fibroblasts and the accumulation of a large amount of extracellular matrix, accompanied by inflammatory damage and tissue structure destruction, which also shows the normal alveolar tissue is damaged and then abnormally repaired resulting in structural abnormalities (scarring). Pulmonary fibrosis has a serious impact on the respiratory function of the human body, and the clinical manifestation is progressive dyspnea. The incidence of pulmonary fibrosis-related diseases is increasing year by year, and no curative drugs have appeared so far. Nevertheless, research on pulmonary fibrosis have also increased in recent years, but there are no breakthrough results. Pathological changes of pulmonary fibrosis appear in the lungs of patients with coronavirus disease 2019 (COVID-19) that have not yet ended, and whether to improve the condition of patients with COVID-19 by means of the anti-fibrosis therapy, which are the questions we need to address now. This review systematically sheds light on the current state of research on fibrosis from multiple perspectives, hoping to provide some references for design and optimization of subsequent drugs and the selection of anti-fibrosis treatment plans and strategies.

Post-intensive care syndrome and pulmonary fibrosis in patients surviving ARDS-pneumonia of COVID-19 and non-COVID-19 etiologies.

The purpose was to examine patient-centered outcomes and the occurrence of lung fibrotic changes on Chest computed tomography (CT) imaging following pneumonia-related acute respiratory distress syndrome (ARDS). We sought to investigate outpatient clinic chest CT imaging in survivors of COVID19-related ARDS and non-COVID-related ARDS, to determine group differences and explore relationships between lung fibrotic changes and functional outcomes. A retrospective practice analysis of electronic health records at an ICU Recovery Clinic in a tertiary academic medical center was performed in adult patients surviving ARDS due to COVID-19 and non-COVID etiologies. Ninety-four patients with mean age 53 ± 13 and 51% male were included (n = 64 COVID-19 and n = 30 non-COVID groups). There were no differences for age, sex, hospital length of stay, ICU length of stay, mechanical ventilation duration, or sequential organ failure assessment (SOFA) scores between the two groups. Fibrotic changes visualized on CT imaging occurred in a higher proportion of COVID-19 survivors (70%) compared to the non-COVID group (43%, p < 0.001). Across both groups, patients with fibrotic changes (n = 58) were older, had a lower BMI, longer hospital and ICU LOS, lower mean RASS scores, longer total duration of supplemental oxygen. While not statistically different, patients with fibrotic changes did have reduced respiratory function, worse performance on the six-minute walk test, and had high occurrences of anxiety, depression, emotional distress, and mild cognitive impairment regardless of initial presenting diagnosis. Patients surviving pneumonia-ARDS are at high risk of impairments in physical, emotional, and cognitive health related to Post-Intensive Care Syndrome. Of clinical importance, pulmonary fibrotic changes on chest CT occurred in a higher proportion in COVID-ARDS group; however, no functional differences were measured in spirometry or physical assessments at ICU follow-up. Whether COVID infection imparts a unique recovery is not evident from these data but suggest that long-term follow up is necessary for all survivors of ARDS.

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.

Pathology Outlines of Post-COVID-19 Pulmonary Fibrosis Comparative with Idiopathic Pulmonary Fibrosis (preprint)

This review brings together the current knowledge regarding the risk factors, and the clinical, radiologic and histological features of both post-COVID-19 interstitial pul-monary fibrosis (PCPF) and Idiopathic Pulmonary Fibrosis (IPF) with a particular fo-cus on describing the similarities and the disparities between the fibrotic changes in these two diseases. It is important to highlight the common points of PCPF and IPF to observe if they are some targetable changes to improve patient outcomes. The litera-ture review was performed using numerous databases to identify relevant articles published in English through October 2022. This review would help clinicians, pathologists and researchers to make an accurate diagnosis, which can be useful in identifying the group of patients who can be selected for antifibrotic therapies, and future therapeutic perspectives.