Fibrotic Changes In Lungs Research Articles

7242 Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia (DIPNECH) In A Patient With Recurrent Carcinoid

Abstract Disclosure: F. Woron: None. T.L. Anderson: None. P. Madhavan: None. Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare generalized proliferation of pulmonary neuroendocrine cells. It is considered to be a pre-invasive lesion for pulmonary carcinoid, a rare neuroendocrine tumor (NET). DIPNECH is thought to be underdiagnosed, as patients can be asymptomatic or present with nonspecific cough and dyspnea, though it is also associated with fibrotic lung changes. Long-term annual surveillance imaging is recommended for due to the potential for development and metastasis of carcinoid tumors. We present a patient with recurrent pulmonary carcinoid later diagnosed with probable DIPNECH based on CT findings. The patient is a 72-year-old female with a prior 15 pack-year smoking history, who initially had a left lower lobe typical carcinoid tumor diagnosed and resected in 2018, with no evidence of lymph node metastasis. The patient’s medical history also includes pulmonary sarcoidosis, adrenal adenoma, thyroid nodule, hiatal hernia, and prediabetes. She has no family history of neuroendocrine tumors. Physical exam showed stable vitals with blood pressure of 112/70 mmHg in the right upper arm, heart rate of 84 bpm, and a body mass index of 39. Physical exam was unremarkable except for thyroid nodularity and obesity. Extensive biochemical evaluation for markers including chromogranin A and 24-hour urine 5-HIAA levels were within normal limits. In 2022, surveillance CT imaging showed a new 9 mm nodule in the right lobe within the bronchus, which was shown to be carcinoid on FNA. She complained of dyspnea and wheezing at this time, which has been managed with an albuterol inhaler. In 2023, PET/CT copper 64 dotatate scan showed a focal area of activity related to the nodule in the superior segment, also identified on recent CT scan, with the nodule measuring approximately 2.05 cm x 1.8 cm with a maximal SUV of 4.2. Interestingly, somatostatin receptor scintigraphy did not show any pick-up in the lung in 2018 or 2022. In 2023, the patient underwent right lower lobe superior segmentectomy after the nodule was found to have increased in size. Pathology showed G1, well-differentiated 1.1 cm typical carcinoid tumor with margins negative for invasive carcinoma. All 18 regional lymph nodes were negative for tumor. Immunohistochemical tests show that the tumor cells were positive for INSM1 and chromogranin with a low Ki-67 proliferation index (<2%), supporting the diagnosis. The patient is currently being monitored by yearly CT imaging and followed by both endocrinology and pulmonology. Given this case, we propose that DIPNECH should be considered as a differential in cases of pulmonary carcinoid, especially recurrent ones. Given that DIPNECH is thought to be underdiagnosed and a precursor for carcinoid associated with fibrotic lung changes, it is essential for this disease to be identified in order for patients to receive appropriate long-term monitoring. Presentation: 6/1/2024

A Case of End-stage Post-Covid-19 Pulmonary Fibrosis in a Kenyan Hospital

Post-COVID-19 pulmonary fibrosis (PC19-PF) is one of the severe manifestations of the “long COVID syndrome,” with a prevalence of about 7%, and is characterized by the presence of persistent fibrotic lung changes (on a CT scan of the lungs) associated with impairment of pulmonary function. Some of the risk factors for PC19-PF include advanced age, the occurrence of acute respiratory distress syndrome (ARDS), the need for supplemental oxygen, mechanical ventilation, smoking, etc. Antifibrotic agents, e.g., pirfenidone and nintedanib, are increasingly being used in the management of PC19-PF with good outcomes, but larger studies on efficacy and benefit are needed. In this study, we present the case of a young woman in a rural Kenyan hospital found to have end-stage PC19-PF needing long-term oxygen therapy to highlight the reality of PC19-PF in the post-COVID-19 clinical era.

Urea cycle promotion via ammonia-upregulated CPS1 is involved in arsenite-induced pulmonary fibrosis through enhancing collagen synthesis

Arsenic exposure is connected with lung toxicity and is related to lung fibrotic changes. Idiopathic pulmonary fibrosis (IPF) is characterized by extracellular matrix (ECM) deposition. Various genetic mechanisms and environmental factors induce or exacerbate pulmonary fibrosis. Collagen synthesis induced by sodium arsenite (NaAsO2) is closely associated with IPF. Fibroblasts tend to fine-tune their metabolic networks to support their synthetic requirements in response to environmental stimuli. Alterations in metabolism have an influential role in the pathogenesis of IPF. However, it is unclear how arsenic affects the metabolism in IPF. The urea cycle (UC) is needed for collagen formation, which provides adequate levels of proline (Pro) for biosynthesis of collagen. Carbamoyl phosphate synthetase 1 (CPS1) converts the ammonia to carbamoyl phosphate, which controls the first reaction of the UC. We show that, in arsenite-exposed mice, high amounts of ammonia in the lung microenvironment promotes the expression levels of CPS1 and the Pro metabolism. Reduction of ammonia and CPS1 ablation inhibit collagen synthesis and ameliorate IPF phenotypes induced by arsenite. This work takes advantage of multi-omics data to enhance understanding of the underlying pathogenic mechanisms, the key molecules and the complicated cellular responses to this pollutant, which provide a target for the prevention of pulmonary fibrosis caused by arsenic.

The Impact of COVID-19 Infection on Patients with Severe Chronic Pulmonary Hypertension: A Prospective Study from a Single Referral Center.

Background and Objectives. COVID-19 infection has a significant burden on global morbidity and mortality, especially in elderly people and in patients with chronic respiratory and cardiovascular diseases, such as pulmonary hypertension (PH). We aimed to evaluate the impact of COVID-19 infection on patients diagnosed with severe chronic PH. Materials and Methods. A single-center prospective cohort study was performed. Patients were enrolled from 1 November 2020 to 31 December 2022. Follow-up was until 31 December 2023. Data were collected on PH diagnosis, clinical presentation, outcomes, brain natriuretic peptide (BNP) levels, pulmonary function test with lung diffusion capacity for carbon monoxide (DLCO), and computed tomography pulmonary angiography (CTPA) analysis. Results. During the 26 months of our study, 51 PH patients were diagnosed with COVID-19 infection. The majority, 44 (86.3%) of all COVID-19 infected patients, were treated on an outpatient basis, and 7 (13.7%) required hospitalization. During the follow-up period, 8 (15.7%) patients died: 4 (7.8%) due to complications of COVID-19 infection, and the other 4 (7.8%) died in the later stages of the follow-up period after recovery from acute COVID-19 infection. Therefore, the in-hospital mortality in our study was 43% (n = 3). As mentioned above, the overall mortality was 7.8% (n = 4). Higher BNP levels in the third month after COVID-19 were associated with higher mortality rates (p = 0.028). Lung function, including DLCO, did not significantly worsen with COVID-19. In our study, 24 patients (47.1%) were referred for a follow-up CTPA scan and one of them developed typical fibrotic lung changes after COVID-19. Conclusions. The incidence of COVID-19 infection in patients diagnosed with PH was 34%. In our patients with severe chronic PH, the overall mortality rate due to COVID-19 infection was low. Pulmonary fibrosis was a rare complication in our cohort. COVID-19 infection in severe PH may increase the risk of worsening chronic heart failure.

Environmental tobacco smoke exposure exaggerates bleomycin-induced collagen overexpression during pulmonary fibrogenesis.

Environmental tobacco smoke (ETS) is known to cause lung inflammatory and injurious responses. Smoke exposure is associated with the pathobiology related to lung fibrosis, whereas the mechanism that ETS exposure augments pulmonary fibrogenesis is unclear. We hypothesized that ETS exposure could exacerbate fibrotic responses via collagen dynamic dysregulation and complement activation. C57BL/6J and p16-3MR mice were exposed to ETS followed by bleomycin administration. ETS exposure exacerbated bleomycin-induced collagen and lysyl oxidase overexpression in the fibrotic lesion. ETS exposure also led to augmented bleomycin-induced upregulation of C3 and C3AR, which are pro-fibrotic markers. Moreover, overexpressed collagens and C3 levels were highly significant in males than females. The old mice (17 months old) were exposed to ETS and treated with bleomycin to induce fibrogenesiswhich is considered as an aging-associated disease. Fewer gene and protein dysregulations trends were identified between ETS exposure with the bleomycin group and the bleomycin alone group in old mice. Based on our findings, we suggested that ETS exposure increases the risk of developing severe lung fibrotic responses via collagen overexpression and lysyl oxidase-mediated collagen stabilization in the fibrotic lesion,and potentially affected the complement system activation induced by bleomycin. Further, male mice were more susceptible than females during fibrogenesis exacerbation. Thus ETS and bleomycin induced lung fibrotic changes via collagen-lysyl oxidase in anage-dependent mechanism.

Significance of serum Krebs von den Lungen-6 in systemic sclerosis

BackgroundSystemic sclerosis (SSc) is a well-known multi-system connective tissue disease, it has an unidentified aetiology that is characterised by abnormal immune system activation, vascular injury, which may progress to faulty neovascularization and inadequate vessel remodelling, and tissue scarring of the skin, lungs, and other internal viscera. Krebs von den Lungen-6 is a kind of transmembrane glycoprotein of type II alveolar epithelial cells and is specific for determining its damage. Regardless of the cause, serum Krebs von den Lungen-6 levels have been investigated in interstitial lung disease (ILD) of several etiologies and have been found to be a significant serum marker for ILD. The current research aims to look into the relationship between serum Krebs von den Lungen-6 levels and disease severity and clinical manifestations, specifically interstitial pulmonary fibrosis, in patients with SSc. In this study, 30 patients with systemic sclerosis and 30 control subjects—15 dermatomyositis patients and 15 healthy volunteers— were also incorporated to see if the change in serum Krebs von den Lungen-6 levels is specific for SSc as dermatomyositis is another connective tissue disorder with lung affection.ResultsA statistically significant difference (P < 0.001) in the median value of Krebs von den Lungen-6 when compared to the control groups was observed, which was 447.95 (145.68–817.98) in the SSc patients group, 158.80 (130.00–730.70) in the dermatomyositis group, and 48.10 (39.50–103.90) in the healthy control group. A significantly higher median value of Krebs von den Lungen-6 in ground glass, honeycombing, and nodular HRCT was established, with P-value (P < 0.001). There was a highly statistically significant discrepancy in the median Krebs von den Lungen-6 value between patients with ILD (717.7) and patients without ILD (145.7) with P-value (P < 0.001). A statistically significant positive correlation was found between Krebs von den Lungen-6 (U/ml) and Disease duration (years), Medsger severity scale, Digital ulceration, modified Rodnan skin score (MRSS), and P-value (P < 0.05).ConclusionKrebs von den Lungen-6 could be a scleroderma biomarker. It has been linked to the development and severity of interstitial lung disease in systemic sclerosis patients and may shed light on the pathophysiology of some fibrotic lung changes.

Arsenic exposure was associated with lung fibrotic changes in individuals living near a petrochemical complex.

Individuals residing near petrochemical complexes have been found to have increasing the risk of respiratory distress and diseases. On visit 1 in 2016, all participants underwent urinary arsenic measurement and low-dose computed tomography (LDCT). The same participants had LDCT performed at visit 2 in 2018. Our study revealed that individuals with lung fibrotic changes had significantly higher levels of urinary arsenic compared to the non-lung fibrotic changes group. Moreover, we found that participants with urinary arsenic levels in the highest sextile (> 209.7 μg/g creatinine) had a significantly increased risk of lung fibrotic changes in both visit 1 (OR = 1.87; 95% CI= 1.16-3.02; P = 0.010) and visit 2 (OR = 1.74; 95% CI = 1.06-2.84; P = 0.028) compared to those in the lowest sextile (≤ 41.4 μg/g creatinine). We also observed a significantly increasing trend across urinary arsenic sextile in both visits (Ptrend = 0.015 in visit 1 and Ptrend = 0.026 in visit 2). Furthermore, participants with urinary arsenic levels in the highest sextile had a significantly increased risk of lung fibrotic positive to positive (OR = 2.18; 95% CI: 1.24, 3.82; P = 0.007) compared to the lowest sextile (reference category: lung fibrotic negative to negative). Our findings provide support for the hypothesis that arsenic exposure is significantly associated with an increased risk of lung fibrotic changes. It is advisable to reduce the levels of arsenic exposure for those residing near such petrochemical complexes.

Arsenic exposure and lung fibrotic changes-evidence from a longitudinal cohort study and experimental models.

Arsenic (As) exposure is associated with lung toxicity and we aim to investigate the effects of arsenic exposure on lung fibrotic changes. Participants (n= 976) enrolled via a general health survey underwent chest low-dose computed tomography (LDCT), spirometry forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and urinary arsenic examination during 2016 and 2018. Lung fibrotic changes from LDCT were defined. AsLtoL, low arsenic levels in both 2016 and 2018; AsLtoH, low arsenic in 2016 but high levels in 2018; AsHtoL, high arsenic in 2016 but low levels in 2018; AsHtoH, high arsenic levels in both 2016 and 2018. Mice exposed to 0. 0.2mg/L, 2 mg/L, 50 mg/L of sodium arsenite (NaAsO2) through drinking water for 12 weeks and 24 weeks were applied for histological analysis. Cultured lung epithelial cells were exposed to NaAsO2 and the mesenchymal changes were examined. AsHtoH increased the risk (OR= 1.65, 95% CI 1.10, 2.49) of Lung fibrotic positive to positive (reference: Lung fibrotic negative to negative) compared with AsLtoL. Moreover, the predicted mean of FVC and FEV1 in AsHtoH (-0.09 units, 95% CI: -0.27, -0.09; -0.09 units, 95% CI: -0.17, -0.01) and AsLtoH (-0.13 units, 95% CI: -0.30, -0.10; -0.13 units, 95% CI: -0.22, -0.04) was significantly lower than ASLtoL. Significant lung fibrotic changes including the increase of the alveolar septum thickness and collagen fiber deposition were observed upon 2 mg/L NaAsO2 treatment for 12 weeks, and the damage was dose- and time-dependent. In vitro, sodium arsenite treatment promotes the epithelial-mesenchymal transition (EMT)-like changes of the normal human bronchial epithelial cells, including upregulation of several fibrotic and mesenchymal markers (fibronectin, MMP-2, and Snail) and cell migration. Inhibition of reactive oxygen species (ROS) and MMP-2 impaired the arsenic-induced EMT changes. Administration of a flavonoid, apigenin, inhibited EMT in vitro and pulmonary damages in vivo with the reduction of mesenchymal markers. we demonstrated that continued exposure to arsenic causes lung fibrosis in humans and mice. Targeting lung epithelial cells EMT is effective on the development of therapeutic strategy. Apigenin is effective in the inhibition of arsenic-induced pulmonary fibrosis and EMT.

Arsenic exposure associated with lung interstitial changes in non-smoking individuals living near a petrochemical complex: A repeated cross-sectional study

Arsenic exposure is associated with airway inflammation and decreased lung function tests. Whether arsenic exposure associated with lung interstitial changes remains unknown. We conducted this population-based study in southern Taiwan during 2016 and 2018. Our study recruited individuals aged over 20 years, residing in the vicinity of a petrochemical complex and with no history of cigarette smoking. In both the 2016 and 2018 cross-sectional studies, we conducted chest low-dose computed tomography (LDCT) scans, as well as urinary arsenic and blood biochemistry analyses. Lung interstitial changes included lung fibrotic changes that were defined as the presence of curvilinear or linear densities, fine lines, or plate opacity in specific lobes; additionally, other interstitial changes were defined as the presence of ground-glass opacity (GGO) or bronchiectasis on the LDCT images. In both cross-sectional studies conducted in 2016 and 2018, participants with lung fibrotic changes exhibited a statistically significant increase in the mean urinary arsenic concentrations compared to those without fibrotic changes (geometric mean = 100.1 vs. 82.8 μg/g creatinine, p < 0.001 for cross-sectional study 2016, and geometric mean = 105.6 vs. 71.0 μg/g creatinine, p < 0.001 for cross-sectional study 2018). After controlling for age, gender, body mass index, platelet counts, hypertension, aspartate aminotransferase, cholesterol, HbA1c, and educational levels, we observed a significant positive association between a unit increase in log urinary arsenic concentrations and the risk of lung fibrotic changes in both cross-sectional study 2016 (odds ratio [OR] = 1.40, 95% confidence interval [CI] = 1.04–1.90, p = 0.028) and cross-sectional study 2018 (OR = 3.03, 95% CI = 1.38–6.63, p = 0.006). Our study did not find a significant association between arsenic exposure and bronchiectasis or GGO. It is imperative for the government to take significant measures to reduce arsenic exposure levels among individuals living near petrochemical complexes.

Blood lead (Pb) is associated with lung fibrotic changes in non-smokers living in the vicinity of petrochemical complex: a population-based study.

Lead (Pb) is a toxic metal that has been extensively used in various industrial processes, and it persists in the environment, posing a continuous risk of exposure to humans. This study investigated blood lead levels in participants aged 20 years and older, who resided in Dalinpu for more than two years between 2016 to 2018, at Kaohsiung Municipal Siaogang Hospital. Graphite furnace atomic absorption spectrometry was used to analyze the blood samples for lead levels, and the LDCT (Low-Dose computed tomography) scans were interpreted by experienced radiologists. The blood lead levels were divided into quartiles, with Q1 representing levels of ≤1.10 μg/dL, Q2 representing levels of >1.11 and ≤1.60 μg/dL, Q3 representing levels of >1.61 and ≤2.30 μg/dL, and Q4 representing levels of >2.31 μg/dL. Individuals with lung fibrotic changes had significantly higher (mean ± SD) blood lead levels (1.88±1.27vs. 1.72±1.53 μg/dl, p< 0.001) than those with non-lung fibrotic changes. In multivariate analysis, we found that the highest quartile (Q4: >2.31 μg/dL) lead levels (OR: 1.36, 95% CI: 1.01-1.82; p= 0.043) and the higher quartile (Q3: >1.61 and ≤2.30 μg/dL) (OR: 1.33, 95% CI: 1.01-1.75; p= 0.041) was significantly associated with lung fibrotic changes compared with the lowest quartile (Q1: ≤1.10 μg/dL) (Cox and Snell R2, 6.1 %; Nagelkerke R2, 8.5 %). The dose-response trend was significant (Ptrend= 0.030). Blood lead exposure was significantly associated lung fibrotic change. To prevent lung toxicity, it is recommended to maintain blood lead levels lower than the current reference value.

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.

Berberine attenuates epithelial mesenchymal transition in bleomycin-induced pulmonary fibrosis in mice via activating A2aR and mitigating the SDF-1/CXCR4 signaling

AimsBerberine is endowed with anti-oxidant, anti-inflammatory and anti-fibrotic effects. This study explored the role of adenosine A2a receptor (A2aR) activation and SDF-1/CXCR4 signaling suppression in the protective effects of berberine in bleomycin-induced pulmonary fibrosis in mice. Main methodsPulmonary fibrosis was generated in mice by injecting bleomycin (40 U/kg, i.p.) on days 0, 3, 7, 10 and 14. Mice were treated with berberine (5 mg/kg, i.p.) from day 15 to day 28. Key findingsSevere lung fibrosis and increased collagen content were observed in the bleomycin-challenged mice. Pulmonary A2aR downregulation was documented in bleomycin-induced pulmonary fibrosis animals and was accompanied by enhanced expression of SDF-1/CXCR4. Moreover, TGF-β1elevation and pSmad2/3 overexpression were reported in parallel with enhanced epithelial mesenchymal transition (EMT) markers expression, vimentin and α-SMA. Besides, bleomycin significantly elevated the inflammatory and pro-fibrogenic mediator NF-κB p65, TNF-α and IL-6. Furthermore, bleomycin administration induced oxidative stress as depicted by decreased Nrf2, SOD, GSH and catalase levels. Interestingly, berberine administration markedly ameliorated the fibrotic changes in lungs by modulating the purinergic system through the inhibition of A2aR downregulation, mitigating EMT and effectively suppressing inflammation and oxidative stress. Strikingly, A2aR blockade by SCH 58261, impeded the pulmonary protective effect of berberine. SignificanceThese findings indicated that berberine could attenuate the pathological processes of bleomycin-induced pulmonary fibrosis at least partially via upregulating A2aR and mitigating the SDF-1/CXCR4 related pathway, suggesting A2aR as a potential therapeutic target for the management of pulmonary fibrosis.

Copper Exposure Induces Epithelial-Mesenchymal Transition-Related Fibrotic Change via Autophagy and Increase Risk of Lung Fibrosis in Human

Copper is an essential trace element involved in several vital biological processes of the human body. However, excess exposure to copper caused by occupational hazards and environmental contamination, such as food, water, and air, damages human health. In this study, in vitro cell culture model and epidemiologic studies were conducted to evaluate the effect of copper on lung fibrosis. In vitro, treatment of CuSO4 in lung epithelial cells at 100 μM consistently decreases cell viability in alveolar type (A549) and human bronchial epithelial (HBE) cells. CuSO4 promotes epithelial-mesenchymal transition (EMT) as shown by increased cell migration and increased EMT marker and fibrotic gene expressions. Besides, CuSO4 induced cell autophagy, with an increased LC3, PINK, and decreased p62 expression. Inhibition of ROS by N-acetylcysteine reversed the CuSO4-induced PINK1, LC3, and Snail expressions. Inhibition of autophagy by chloroquine reverses the CuSO4-induced EMT changes. Nature flavonoids, especially kaempferol, and fustin, were shown to inhibit Copper-induced EMT. In humans, a unit increase in urinary copper concentration was significantly associated with an increased risk of lung fibrotic changes (odds ratio [OR] = 1.17, 95% confidence interval [CI] = 1.01-1.36, p = 0.038). These results indicated that Copper is a risk factor for lung fibrosis through activation of the ROS-autophagy-EMT pathway, which can be reversed by flavonoids.

Association of Lung Fibrotic Changes and Cardiological Dysfunction with Comorbidities in Long COVID-19 Cohort.

Background. Long COVID-19 symptoms appeared in many COVID-19 survivors. However, the prevalence and symptoms associated with long COVID-19 and its comorbidities have not been established. Methods. In total, 312 patients with long COVID-19 from 21 primary care centers were included in the study. At the six-month follow-up, their lung function was assessed by computerized tomography (CT) and spirometry, whereas cardiac function was assessed by elec-trocardiogram (ECG), Holter ECG, echocardiography, 24 h blood pressure monitoring, and a six-minute walk test (6MWT). Results. Of the 312 persons investigated, significantly higher sys-tolic and diastolic blood pressure, left ventricular hypertrophy, and elevated NT-proBNP were revealed in participants with hypertension or type 2 diabetes. Left ventricular diastolic dysfunc-tion was more frequently present in patients with hypertension. The most common registered CT abnormalities were fibrotic changes (83, 36.6%) and mediastinal lymphadenopathy (23, 10.1%). Among the tested biochemical parameters, three associations were found in long COVID-19 patients with hypertension but not diabetes: increased hemoglobin, fibrinogen, and ferritin. Nine patients had persisting IgM antibodies to SARS-CoV-2. Conclusions. We demon-strated a strong association between signs of cardiac dysfunction and lung fibrotic changes with comorbidities in a cohort of long COVID-19 subjects.

Inhibition of CEMIP potentiates the effect of sorafenib on metastatic hepatocellular carcinoma by reducing the stiffness of lung metastases

Hepatocellular carcinoma (HCC) with lung metastasis is associated with poor prognosis and poor therapeutic outcomes. Studies have demonstrated that stiffened stroma can promote metastasis in various tumors. However, how the lung mechanical microenvironment favors circulating tumor cells remains unclear in metastatic HCC. Here, we found that the expression of cell migration-inducing hyaluronan-binding protein (CEMIP) was closely associated with lung metastasis and can promote pre-metastatic niche formation by increasing lung matrix stiffness. Furthermore, upregulated serum CEMIP was indicative of lung fibrotic changes severity in patients with HCC lung metastasis. By directly targeting CEMIP, pirfenidone can inhibit CEMIP/TGF-β1/Smad signaling pathway and reduce lung metastases stiffening, demonstrating promising antitumor activity. Pirfenidone in combination with sorafenib can more effectively suppress the incidence of lung metastasis compared with sorafenib alone. This study is the first attempt to modulate the mechanical microenvironment for HCC therapy and highlights CEMIP as a potential target for the prevention and treatment of HCC lung metastasis.CEMIP mediating an HCC-permissive microenvironment through controlling matrix stiffness. Meanwhile, Pirfenidone could reduce metastasis stiffness and increases the anti-angiogenic effect of Sorafenib by directly targeting CEMIP.

Matrix metalloproteinase-7 is increased in lung bases but not apices in idiopathic pulmonary fibrosis.

IntroductionIdiopathic pulmonary fibrosis (IPF) is a progressively fibrotic lung condition with poor prognosis. Matrix metalloproteinase-7 (MMP7) is a protein secreted by epithelial cells in IPF lungs. It is not known if MMP7 expression correlates with fibrotic changes in lung tissue.MethodsTissue samples from lung apices and bases were obtained from 20 IPF patients and 14 non-diseased control (NDC) donors. In formalin-fixed paraffin-embedded sections, histological assessment of fibrosis was performed; overall MMP7 positivity was assessed by immunohistochemistry and MMP7+ cells were quantified using multiplex immunohistochemistry. Protein expression of MMP7 in whole lung lysates was quantified by Western blotting. Bulk tissue transcriptomic profiles of 101 samples were analysed using RNA sequencing technologies.ResultsLung tissue from IPF bases was more fibrotic than in apices. MMP7 protein is elevated in IPF lung base tissue. In IPF whole lung lysates, MMP7 protein levels are increased compared to NDC donors and was increased in IPF lung bases compared to apices. MMP7 protein levels correlated with MMP7 gene expression levels in lung tissue. MMP7 transcript levels were increased in IPF base compared to NDC base lung tissue and increased in IPF base tissue compared to IPF apex tissue.ConclusionsOur cross-sectional study suggests that lung epithelial MMP7 expression increases as the tissue becomes more fibrotic and identifies a potentially nonepithelial or immune-cell source. Mechanisms of disease progression in IPF are still unclear, and our study suggests aberrant MMP7 production may be a histological starting point of lung tissue fibrosis.

S2743 Mesalamine-Induced Interstitial Lung Disease in a Crohn’s Patient With COVID-19

Introduction: Extraintestinal manifestations of Crohn’s disease (CD) generally correlate to the disease activity and may be seen in 1 of 4 patients with CD. Though the prevalence of bronchopulmonary manifestations in CD is 0.4%, subclinical pulmonary changes may be seen in up to half of adults with CD, with involvement of the tracheobronchial tree, lung parenchyma or the pleura. Case Description/Methods: A 61-year-old man, with a history of CD diagnosed 2 years ago, currently in remission with mesalamine, was admitted to the ICU with acute hypoxic respiratory failure due to COVID-19. Inflammatory markers were elevated and he needed high-flow nasal cannula. He was started on a 5-day course of dexamethasone. By HOD-9 O2 requirement and inflammatory markers had trended down. However, around HOD-10 his O2 requirement increased to 6-10 L at rest. CT-chest showed peripherally distributed ground-glass opacities and superimposed early diffuse fibrotic lung changes. Superadded bacterial infection was ruled out. Mesalamine was discontinued and the patient was started on a course of iv methylprednisolone, after which oxygen requirements dramatically declined. He was discharged on HOD 24 with 2L O2 at rest and 4L on ambulation and a prednisone taper. Chest x-ray in 8 weeks showed improving infiltrates. On follow-up 5 months later, he was not on O2 anymore and was doing well. Discussion: Latent interstitial pulmonary involvement is seen in around 20%-55% of patients with IBD, with the most common manifestation being drug-induced lung disease, due to sulfasalazine, mesalamine, methotrexate, or anti-TNF agents. Pulmonary function tests can help in early identification of lung injury since respiratory involvement is latent many times. Onset of drug reaction can occur from 5 days to 44 months after initiation of mesalamine therapy and has been reported in the form of eosinophilic pneumonia, organizing pneumonia, nonspecific interstitial pneumonia and hypersensitivity pneumonitis. The absence of other extra-intestinal manifestations, and the remission of CD itself, can be helpful in excluding other pulmonary manifestations of CD from drug-induced lung disease. Discontinuation of the causative drug, along with a course of steroids, can help in reversing the symptoms. Though the differential of mesalamine-induced lung injury, cannot be confirmed nor excluded here, this patient probably had underlying lung pathology from his CD or its treatment, making his recovery from COVID-19 more complicated (Figure).Figure 1.: A: Portable Chest X-ray showing multifocal pneumonia, low lung volumes with bilateral patchy airspace disease; B, C: CT-Chest showing peripherally distributed ground-glass opacities, distributed in upper and lower lobes. There were superimposed early diffuse lung fibrotic changes, without any evidence of pulmonary thromboembolism; D: CT Chest, 5 months post-discharge, showing improvement in opacities.

Asthma and Post-Asthmatic Fibrosis: A Search for New Promising Molecular Markers of Transition from Acute Inflammation to Pulmonary Fibrosis.

Asthma is a heterogeneous pulmonary disorder, the progression and chronization of which leads to airway remodeling and fibrogenesis. To understand the molecular mechanisms of pulmonary fibrosis development, key genes forming the asthma-specific regulome and involved in lung fibrosis formation were revealed using a comprehensive bioinformatics analysis. The bioinformatics data were validated using a murine model of ovalbumin (OVA)-induced asthma and post-asthmatic fibrosis. The performed analysis revealed a range of well-known pro-fibrotic markers (Cat, Ccl2, Ccl4, Ccr2, Col1a1, Cxcl12, Igf1, Muc5ac/Muc5b, Spp1, Timp1) and a set of novel genes (C3, C3ar1, Col4a1, Col4a2, Cyp2e1, Fn1, Thbs1, Tyrobp) mediating fibrotic changes in lungs already at the stage of acute/subacute asthma-driven inflammation. The validation of genes related to non-allergic bleomycin-induced pulmonary fibrosis on asthmatic/fibrotic lungs allowed us to identify new universal genes (Col4a1 and Col4a2) associated with the development of lung fibrosis regardless of its etiology. The similarities revealed in the expression profiles of nodal fibrotic genes between asthma-driven fibrosis in mice and nascent idiopathic pulmonary fibrosis in humans suggest a tight association of identified genes with the early stages of airway remodeling and can be considered as promising predictors and early markers of pulmonary fibrosis.

Diagnostic Accuracy of Chest Digital Tomosynthesis in Patients Recovering after COVID-19 Pneumonia.

Purpose: To assess the diagnostic accuracy of traditional chest X-ray (CXR) and digital tomosynthesis (DTS) compared to computed tomography (CT) in detecting pulmonary interstitial changes in patients having recovered from severe COVID-19. Materials and Methods: This was a retrospective observational study, and received local ethics committee approval. Patients suspected of having COVID-19 pneumonia upon emergency department admission between 1 March and 31 August 2020, and who underwent CXR followed by DTS and CT, were considered. Inclusion criteria were as follows: (1) patients with previous SARS-CoV-2 infection proven by a positive RT-PCR on nasopharyngeal swabs performed upon admission to the hospital, and with complete clinical recovery; (2) a diagnosis of SARS-CoV-2-related ARDS, according to the Berlin criteria, during hospitalization; (3) no recent history of other lung disease; and (4) complete imaging follow-up by CXR, DTS, and CT for at least 6 months and up to one year. Analysis of DTS images was carried out independently by two radiologists with 16 and 10 years of experience in chest imaging, respectively. The following findings were evaluated: (1) ground-glass opacities (GGOs); (2) air-space consolidations with or without air bronchogram; (3) reticulations; and (4) linear consolidation. Indicators of diagnostic performance of RX and digital tomosynthesis were calculated using CT as a reference. All data were analyzed using R statistical software (version 4.0.2, 2020). Results: Out of 44 patients initially included, 25 patients (17 M/8 F), with a mean age of 64 years (standard deviation (SD): 12), met the criteria and were included. The overall average numbers of findings confirmed by CT were GGOs in 11 patients, lung consolidations in 8 patients, 7 lung interstitial reticulations, and linear consolidation in 20 patients. DTS showed a significantly higher diagnostic accuracy compared to CXR in recognizing interstitial lung abnormalities—especially GGOs (p = 0.0412) and linear consolidations (p = 0.0009). The average dose for chest X-ray was 0.10 mSv (0.07–0.32), for DTS was 1.03 mSv (0.74–2.00), and for CT scan was 3 mSv. Conclusions: According to our results, DTS possesses a high diagnostic accuracy, compared with CXR, in revealing lung fibrotic changes in patients who have recovered from COVID-19 pneumonia.

Quercetin-3-Rutinoside alleviates radiation-induced lung inflammation and fibrosis via regulation of NF-κB/TGF-β1 signaling

BackgroundRadiation exposure to lungs during nuclear catastrophes or radiotherapy poses long-term side effects and can induce pulmonary injury sufficient for causing death. The strategies for preventing or reversing radiation-induced lung injuries have not been yet developed. Quercetin-3-Rutinoside (Q-3-R), a polyphenolic bioflavonoid, has shown multifaceted pharmacological applications due to its high antioxidant and anti-inflammatory properties. PurposeIn the current study, the potential of Q-3-R against radiation-induced lung pneumonitis/fibrosis and the possible underlying mechanism was investigated. Study designTo evaluate the effect of Q-3-R against lung damage, C57Bl/6 mice were administered with Q-3-R (10 mg/kg b.wt.) and irradiated with a single dose of gamma radiation (12 Gy) at thoracic region. Methods16 weeks after irradiation lung damage was seen by histopathological studies and staining for collagen deposition. Expression of Nuclear factor kappa-B (NF-κB), transforming growth factor-β1 (TGF-β1), Smad3, intercellular adhesion molecule 1 (ICAM-1), α-smooth muscle actin protein (α-SMA), Aquaporin 5 (AQP 5), Interleukins (IL-6, IL-18, IL-1β), tumor necrosis factor-α (TNF-α) and caspase-3 was evaluated by immunohistochemistry/western blot/Elisa. Reactive oxygen species (ROS)/ Nitric oxide (NO) scavenging potential of Q-3-R and inhibition of cell death in irradiated lungs were also assessed. ResultsMice showed signs of pneumonitis and fibrotic changes in lungs following radiation treatment. A dramatic increase in inflammatory cells and cytokines contributing to lung disease pathogenesis was observed. Furthermore, expression of NF-κB, TGF-β1, Smad3, ICAM-1, AQP5and α-SMA was found markedly up-regulated. However, pretreatment of Q-3-R significantly attenuated radiation-induced pneumonitis and fibrosis. Histological examination revealed less structural and fibrotic changes with down-regulation of AQP 5, ICAM-1, α-SMA and caspase-3 in Q-3-R pretreated irradiated groups. The formulation significantly relieved lung injury by suppressing inflammatory and pro-fibrotic cytokines such as IL-6, IL-18, IL-1β, TNF-α and TGF-β1 via inhibition of NF-κB. Q-3-R also curtailed radiation-induced ROS/NO generation and minimized DNA damage in the irradiated lungs. ConclusionThe findings from the current study clearly demonstrate that Q-3-R provides radioprotection to the lungs by regulating NF-κB/TGF-β1 signaling, scavenging free radicals, preventing perivascular infiltration and prolonged inflammatory cascade which could otherwise lead to chronic radiation fibrosis. Q-3-R can be proved as a potential therapeutic agent for alleviating radiation-induced lung injury in case of planned or unplanned radiation exposure scenario.