Is It Cancer Hepatic Inflammatory Pseudotumor: An Important Hepatic Mass Differential

Introduction: Hepatic inflammatory pseudotumor (HIP), albeit rare, is an important pathology to be included in differentials for hepatic masses. The benign nature and treatment of this disease process should be considered especially in comparison to malignant hepatic processes. Case Description/Methods: A 66-year-old male with pre-existing history of compensated Hepatitis C cirrhosis status post direct-acting antivirals with sustained virologic response presented in shock after a syncopal episode. Initial work up revealed leukocytosis, thrombocytopenia, acute renal injury, elevated liver enzymes, and COVID-19 positive test. Patient underwent initial liver ultrasound revealing intrahepatic and extrahepatic biliary ductal dilation. Subsequent MRCP demonstrated diffuse thickening of intra and extra hepatic bile ducts suggestive of cholangitis and several hepatic masses concerning for abscesses versus possible metastatic cholangiocarcinoma. Patient improved symptomatically with antibiotics and supportive care. A liver biopsy was performed with pathology showing lymphoplasmacytic inflammation and fibroblastic infiltration suggestive of hepatic inflammatory pseudotumor. A repeat MRCP one week later showed interval decrease in size of liver lesions and repeat liver function tests also showed improvement. Patient was discharged on a course of ciprofloxacin and metronidazole. Patient had repeat MRCP 3 months after discharge, with further significant improvement in size of liver lesions. After multi-disciplinary discussion the plan was for further surveillance with imaging and labs in 2 months. Discussion(s): Inflammatory pseudotumors are benign and non-neoplastic lesions that can occur in any organ. They can appear as a malignant lesion when they arise in the liver and an accurate identification can allow for conservative management and prevent unnecessary invasive procedures. Hepatic inflammatory pseudotumors are often seen with concomitant infection or inflammatory processes. Liver biopsies distinguish these tumors from other malignant processes as they demonstrate a characteristic dense inflammatory infiltrate interspersed in stroma of interlacing bundles of myofibroblasts. This case highlights the importance of maintaining HIP on the differential diagnosis. (Figure Presented).

"Long COVID-19" and viral "fibromyalgia-ness": Suggesting a mechanistic role for fascial myofibroblasts (Nineveh, the shadow is in the fascia).

The coronavirus pandemic has led to a wave of chronic disease cases; "Long COVID-19" is recognized as a new medical entity and resembles "fibromyalgia" which, likewise, lacks a clear mechanism. Observational studies indicate that up to 30%-40% of convalescent COVID-19 patients develop chronic widespread pain and fatigue and fulfill the 2016 diagnostic criteria for "fibromyalgia." A recent study suggested a theoretical neuro-biomechanical model (coined "Fascial Armoring") to help explain the pathogenesis and cellular pathway of fibromyalgia, pointing toward mechanical abnormalities in connective tissue and fascia, driven by contractile myo/fibroblasts and altered extracellular matrix remodeling with downstream corresponding neurophysiological aberrations. This may help explain several of fibromyalgia's manifestations such as pain, distribution of pain, trigger points/tender spots, hyperalgesia, chronic fatigue, cardiovascular abnormalities, metabolic abnormalities, autonomic abnormalities, small fiber neuropathy, various psychosomatic symptoms, lack of obvious inflammation, and silent imaging investigations. Pro-inflammatory and pro-fibrotic pathways provide input into this mechanism via stimulation of proto/myofibroblasts. In this hypothesis and theory paper the theoretical model of Fascial Armoring is presented to help explain the pathogenesis and manifestations of "long COVID-19" as a disease of immuno-rheumo-psycho-neurology. The model is also used to make testable experimental predictions on investigations and predict risk and relieving factors.

Developing advanced cell culture models to study COVID19-associated pulmonary fibrosis

Patients with severe COVID-19-associated pneumonia are at risk to develop pulmonary fibrosis. To study the underlying mechanisms, we aim to develop advanced cell culture models that reliably reflect COVID-19-related profibrotic microenvironment. To identify key cellular players, we performed pilot immunohistochemistry analysis on lung tissue from COVID-19 patients with fibrosis collected during autopsy. Results revealed diffuse alveolar damage with macrophage infiltration, and myofibroblast accumulation with enriched collagen deposition surrounding the damaged alveoli. To mimic SARS-CoV-2 infection in alveoli, we infected human primary type II alveolar epithelial cells (AEC2) and found enhanced signaling of profibrotic cytokine transforming growth factor beta (TGFbeta) in some donors. To recreate the early fibrotic niche, an alveolar-macrophage-fibroblast (AMF) tri-culture model was established. After infecting AEC2 with SARS-CoV-2 in this AMF model, gene expression analysis provided evidence for fibroblast-to-myofibroblast transition. Furthermore, we found that overexpression of SARS-CoV-2 papain-like protease (PLpro) can promote TGFbeta signaling in HEK293T and A549 cells. After infecting AEC2 with SARS-CoV-2 PLpro lentivirus in the AMF model, we found signs of epithelial-to-mesenchymal transition and fibroblast-to myofibroblast transition. In future studies, we will use a detailed analysis of COVID-19-associated lung fibrosis with other types of lung fibrosis, to further refine COVID-19-related fibrosis models, including lung-on-chip models.

Involvement of the chemerin-ChemR23 system in severe COVID-19 patients

Background: ChemR23 knock-out mice displays aggravated viral pneumonia, with similar features as observed in severe COVID-19 patients. Aims and objectives: We evaluated the involvement of the chemerin-ChemR23 system in the physiopathology of COVID-19 with a particular focus on its prognostic role. Method(s): Blood samples from confirmed COVID-19 patients were collected at day 1, 5 and 14 from admission to Erasme Hospital (Brussels - Belgium). Chemerin concentrations and inflammatory biomarkers were analyzed in the plasma. Blood cells subtypes and their expression of ChemR23 were determined by flow cytometry. The expression of chemerin and ChemR23 was evaluated on lung tissue from autopsied COVID-19 patients by immunohistochemistry (IHC). Result(s): 21 healthy controls (HC) and 88 COVID-19 patients, including 40 in intensive care unit (ICU) were included. The concentration of chemerin in plasma was significantly higher in ICU patients vs HC at any time-point (p<.0001) and also when comparing deceased patients vs survivors (p=.02). In line with that, chemerin levels correlated with inflammatory biomarkers such as C-reactive protein, interleukin-6 and tumour necrosis factor alpha. Plasmacytoid dendritic cells and natural killers (NK) cells were strongly decreased in hospitalized and ICU COVID 19 patients. On NK cells of all COVID 19 patients, the expression of ChemR23 was reduced regardless its severity. Moreover, IHC analysis showed a strong expression of ChemR23 on smooth muscle cells and chemerin on myofibroblasts during the organizing phase of acute respiratory distress syndrome (ARDS). Conclusion(s): Chemerin is an early marker of severity in COVID-19 patients and could be involved in lung fibrosis post-ARDS.

"Fibromyalgia" and "Long COVID-19" as a chronic compartment-like syndrome of the whole body (Nineveh, the Shadow is in the Fascia)

Background: The Coronavirus pandemic has impact on our community far beyond the acute phase, "Long COVID-19" is recognized as a new medical entity and resembles "fibromyalgia" which, likewise, lacks a clear mechanism. "Fibromyalgia" is a prevalent and misunderstood condition with significant burden and morbidity. "Central sensitization" and biopsychosocial theories describe "fibromyalgia" as the misfortunate neurological fate of traumatized and stressed individuals that have behavioral, cognitive, social, and/or genetic predisposition for an "infinite-positive- feedback of pain with no peripheral organic lesion/injury". Diagnostic criteria seem biologically arbitrary, treatments are insufficient, and physicians are frustrated. This work suggests a theoretical model with an organic mechanical mechanism to help explain "fibromyalgia", "long COVID-19" and "functional psycho/ somatic syndromes", based on cross-disciplinary empirical studies. A practical evidence-based treatment arsenal, which is derived from this model, is discussed briefly. Method(s): Systematically searched multiple phrases in MEDLINE, EMBASE, COCHRANE, PEDro, and medRxiv, majority with no time limit. Inclusion/exclusion based on title and , then full-text inspection. Additional literature added on relevant side topics. Review follows PRISMA-ScR guidelines. Result(s): 831 records included. The theory of "facial-armoring" suggests fibromyalgia-like entities may be a disease of connective-tissue driven by myofibroblast-generated- tensegrity- tension. This mechanism may explain fibromyalgia's pain, distribution of pain, decreased pressure-pain threshold, tender spots, fatigue, cardiovascular and metabolic abnormalities, autonomic abnormalities, absence of clear inflammation, silent imaging investigations, and other phenomena (e.g., complete resolution soon after surgery). "Long-COVID- 19" is predicted to involve fascial armoring. Conclusion(s): "Fibromyalgia" is a mild-moderate- chronic- compartment- like- syndrome- of- the- whole- body. Treatment should focus on lifestyle and non-pharmacological modalities. Early detection is key. The body and the mind are one being.

Cepharanthine Ameliorates Pulmonary Fibrosis by Inhibiting the NF-κB/NLRP3 Pathway, Fibroblast-to-Myofibroblast Transition and Inflammation.

Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-ß1 (TGF-ß1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.

CRYPTOGENIC ORGANIZING PNEUMONIA: A DIAGNOSTIC DILEMMA IN A WORLD DOMINATED BY COVID-19 PNEUMONIA

SESSION TITLE: Pulmonary Involvement in Critical Care Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Cryptogenic organizing pneumonia (COP), also known as bronchiolitis obliterans organizing pneumonia (BOOP), is one of the idiopathic interstitial lung diseases that affects the alveolar epithelium and surrounding interstitium. Its diagnosis is usually delayed due to similar clinical presentation as other illnesses (e.g. pneumonia) [1]. CASE PRESENTATION: A 65-year-old male presented with rapidly progressive respiratory failure. Computed tomography (CT) of chest showed multifocal ground glass opacities. He had suboptimal response to antibiotics and had to be intubated on day 9 due to worsening respiratory failure. Bronchoscopy with bronchoalveolar lavage was performed, cytology of which revealed severe acute inflammation and mononuclear infiltration. Decision was made to perform open lung biopsy which showed polypoid plugs of organizing fibroblasts and myofibroblasts in the distal airways and alveoli with focal hyaline membrane and alveolar damage, consistent with acute onset fulminant COP. As expected, the patient responded fairly well to high-dose corticosteroids and was extubated on day 9 of intubation. DISCUSSION: Even though it is very rare, COP should be kept in differentials especially when initial interventions fail (as in our patient). There is no single laboratory study or intervention to diagnose this condition. Hence it is imperative to rule out other causes of similar presentation like pneumonia (using cultures, urine antigen testing, and viral polymerase chain reaction tests). The clinical picture is combined with supportive evidence like elevated erythrocyte sedimentation rate, leukocytosis, imaging findings, and bronchoscopic and histopathology evaluation [2]. Once diagnosed, it is important to rule out any associated CTD, for it can change management and prevent additional complications. The majority of patients with COP exhibit rapid response to glucocorticoid treatment. For fulminant disease, intravenous glucocorticoids (e.g. methylprednisolone 125-250 mg every six hours) should be initiated based on the clinical experience and case reports [3]. CONCLUSIONS: Diagnoses of interstitial lung diseases should be pursued in a systemic fashion from more common to less common. However, anchoring to common diagnoses should be avoided to negate delay in diagnoses and allow timely management. If initial workup is unrevealing, bronchoscopy and open lung biopsies should be performed while the patient is stable enough to undergo the interventions to avoid antibiotic resistance, morbidity and mortality associated with rapidly progressive noninfectious illnesses like fulminant COP. Reference #1: Drakopanagiotakis F, Polychronopoulos V, Judson MA. Organizing pneumonia. The American journal of the medical sciences. 2008 Jan 1;335(1):34-9. Reference #2: Cordier JF. Cryptogenic organising pneumonia. European Respiratory Journal. 2006 Aug 1;28(2):422-46. Reference #3: Nizami IY, Kissner DG, Visscher DW, Dubaybo BA. Idiopathic bronchiolitis obliterans with organizing pneumonia: an acute and life-threatening syndrome. Chest. 1995 Jul 1;108(1):271-7 DISCLOSURES: No relevant relationships by Fareeha Abid No relevant relationships by Vipin Garg No relevant relationships by Qirat Jawed No relevant relationships by Asnia Latif No relevant relationships by Ahmed Mowafy No relevant relationships by Muniba Naqi No relevant relationships by Muhammad Atif Masood Noori No relevant relationships by Hasham Saeed

Targeting Histone Deacetylases in Idiopathic Pulmonary Fibrosis: A Future Therapeutic Option.

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with limited therapeutic options, and there is a huge unmet need for new therapies. A growing body of evidence suggests that the histone deacetylase (HDAC) family of transcriptional corepressors has emerged as crucial mediators of IPF pathogenesis. HDACs deacetylate histones and result in chromatin condensation and epigenetic repression of gene transcription. HDACs also catalyse the deacetylation of many non-histone proteins, including transcription factors, thus also leading to changes in the transcriptome and cellular signalling. Increased HDAC expression is associated with cell proliferation, cell growth and anti-apoptosis and is, thus, a salient feature of many cancers. In IPF, induction and abnormal upregulation of Class I and Class II HDAC enzymes in myofibroblast foci, as well as aberrant bronchiolar epithelium, is an eminent observation, whereas type-II alveolar epithelial cells (AECII) of IPF lungs indicate a significant depletion of many HDACs. We thus suggest that the significant imbalance of HDAC activity in IPF lungs, with a "cancer-like" increase in fibroblastic and bronchial cells versus a lack in AECII, promotes and perpetuates fibrosis. This review focuses on the mechanisms by which Class I and Class II HDACs mediate fibrogenesis and on the mechanisms by which various HDAC inhibitors reverse the deregulated epigenetic responses in IPF, supporting HDAC inhibition as promising IPF therapy.

Autoimmunity, cancer and COVID-19 abnormally activate wound healing pathways: critical role of inflammation.

Recent evidence indicates that targeting IL-6 provides broad therapeutic approaches to several diseases. In patients with cancer, autoimmune diseases, severe respiratory infections [e.g. coronavirus disease 2019 (COVID-19)] and wound healing, IL-6 plays a critical role in modulating the systemic and local microenvironment. Elevated serum levels of IL-6 interfere with the systemic immune response and are associated with disease progression and prognosis. As already noted, monoclonal antibodies blocking either IL-6 or binding of IL-6 to receptors have been used/tested successfully in the treatment of rheumatoid arthritis, many cancer types, and COVID-19. Therefore, in the present review, we compare the impact of IL-6 and anti-IL-6 therapy to demonstrate common (pathological) features of the studied diseases such as formation of granulation tissue with the presence of myofibroblasts and deposition of new extracellular matrix. We also discuss abnormal activation of other wound-healing-related pathways that have been implicated in autoimmune disorders, cancer or COVID-19.

The Roles of Immune Cells in the Pathogenesis of Fibrosis.

Tissue injury and inflammatory response trigger the development of fibrosis in various diseases. It has been recognized that both innate and adaptive immune cells are important players with multifaceted functions in fibrogenesis. The activated immune cells produce various cytokines, modulate the differentiation and functions of myofibroblasts via diverse molecular mechanisms, and regulate fibrotic development. The immune cells exhibit differential functions during different stages of fibrotic diseases. In this review, we summarized recent advances in understanding the roles of immune cells in regulating fibrotic development and immune-based therapies in different disorders and discuss the underlying molecular mechanisms with a focus on mTOR and JAK-STAT signaling pathways.

Lung Fibrosis and Fibrosis in the Lungs: Is It All about Myofibroblasts?

In the lungs, fibrosis is a growing clinical problem that results in shortness of breath and can end up in respiratory failure. Even though the main fibrotic disease affecting the lung is idiopathic pulmonary fibrosis (IPF), which affects the interstitial space, there are many fibrotic events that have high and dangerous consequences for the lungs. Asthma, chronic obstructive pulmonary disease (COPD), excessive allergies, clearance of infection or COVID-19, all are frequent diseases that show lung fibrosis. In this review, we describe the different kinds of fibrosis and analyse the main types of cells involved-myofibroblasts and other cells, like macrophages-and review the main fibrotic mechanisms. Finally, we analyse present treatments for fibrosis in the lungs and highlight potential targets for anti-fibrotic therapies.

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

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

Latent Transforming Growth Factor-ß Binding Protein-2 Regulates Lung Fibroblast-to-Myofibroblast Differentiation in Pulmonary Fibrosis via NF-κB Signaling.

Despite past extensive studies, the mechanisms underlying pulmonary fibrosis (PF) still remain poorly understood. The aberrantly activated lung myofibroblasts, predominantly emerging through fibroblast-to-myofibroblast differentiation, are considered to be the key cells in PF, resulting in excessive accumulation of extracellular matrix (ECM). Latent transforming growth factor-ß (TGFß) binding protein-2 (LTBP2) has been suggested as playing a critical role in modulating the structural integrity of the ECM. However, its function in PF remains unclear. Here, we demonstrated that lungs originating from different types of patients with PF, including idiopathic PF and rheumatoid arthritis-associated interstitial lung disease, and from mice following bleomycin (BLM)-induced PF were characterized by increased LTBP2 expression in activated lung fibroblasts/myofibroblasts. Moreover, serum LTBP2 was also elevated in patients with COVID-19-related PF. LTBP2 silencing by lentiviral shRNA transfection protected against BLM-induced PF and suppressed fibroblast-to-myofibroblast differentiation in vivo and in vitro. More importantly, LTBP2 overexpression was able to induce differentiation of lung fibroblasts to myofibroblasts in vitro, even in the absence of TGFß1. By further mechanistic analysis, we demonstrated that LTBP2 silencing prevented fibroblast-to-myofibroblast differentiation and subsequent PF by suppressing the phosphorylation and nuclear translocation of NF-κB signaling. LTBP2 overexpression-induced fibroblast-to-myofibroblast differentiation depended on the activation of NF-κB signaling in vitro. Therefore, our data indicate that intervention to silence LTBP2 may represent a promising therapy for PF.

Pulmonary fibrosis from molecular mechanisms to therapeutic interventions: lessons from post-COVID-19 patients.

Pulmonary fibrosis (PF) is characterised by several grades of chronic inflammation and collagen deposition in the interalveolar space and is a hallmark of interstitial lung diseases (ILDs). Recently, infectious agents have emerged as driving causes for PF development; however, the role of viral/bacterial infections in the initiation and propagation of PF is still debated. In this context, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for the current coronavirus disease 2019 (COVID-19) pandemic, has been associated with acute respiratory distress syndrome (ARDS) and PF development. Although the infection by SARS-CoV-2 can be eradicated in most cases, the development of fibrotic lesions cannot be precluded; furthermore, whether these lesions are stable or progressive fibrotic events is still unknown. Herein, an overview of the main molecular mechanisms driving the fibrotic process together with the currently approved and newly proposed therapeutic solutions was given. Then, the most recent data that emerged from post-COVID-19 patients was discussed, in order to compare PF and COVID-19-dependent PF, highlighting shared and specific mechanisms. A better understanding of PF aetiology is certainly needed, also to develop effective therapeutic strategies and COVID-19 pathology is offering one more chance to do it. Overall, the work reported here could help to define new approaches for therapeutic intervention in the diversity of the ILD spectrum.

Potential Impact of Diabetes and Obesity on Alveolar Type 2 (AT2)-Lipofibroblast (LIF) Interactions After COVID-19 Infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a new emerging respiratory virus, caused evolving pneumonia outbreak around the world. In SARS-Cov-2 infected patients, diabetes mellitus (DM) and obesity are two metabolic diseases associated with higher severity of SARS-CoV-2 related complications, characterized by acute lung injury requiring assisted ventilation as well as fibrosis development in surviving patients. Different factors are potentially responsible for this exacerbated response to SARS-CoV-2 infection. In patients with DM, base-line increase in inflammation and oxidative stress represent preexisting risk factors for virus-induced damages. Such factors are also likely to be found in obese patients. In addition, it has been proposed that massive injury to the alveolar epithelial type 2 (AT2) cells, which express the SARS-CoV-2 receptor angiotensin-converting enzyme 2 (ACE2), leads to the activation of their stromal niches represented by the Lipofibroblasts (LIF). LIF are instrumental in maintaining the self-renewal of AT2 stem cells. LIF have been proposed to transdifferentiate into Myofibroblast (MYF) following injury to AT2 cells, thereby contributing to fibrosis. We hypothesized that LIF's activity could be impacted by DM or obesity in an age- and gender-dependent manner, rendering them more prone to transition toward the profibrotic MYF status in the context of severe COVID-19 pneumonia. Understanding the cumulative effects of DM and/or obesity in the context of SARS-CoV-2 infection at the cellular level will be crucial for efficient therapeutic solutions.