ABSTRACT Background Given the heterogeneity of predisposing factors associated with pulmonary infarction (PI) and the lack of clinically relevant outcomes among patients with acute pulmonary embolism (PE) complicated by PI, further investigation is required. Methods Retrospective study of patients with central PE in an 11-year period. Data were stratified according to the diagnosis of PI. Multivariable logistic regression analysis was used to analyze factors associated with PI development and determine if PI was associated with severe hypoxemic respiratory failure and mechanical ventilation use. Results Of 645 patients with central PE, 24% (n = 156) had PI. After adjusting for demographics, comorbidities, and clinical features on admission, only age (OR 0.98, CI 0.96–0.99; p = 0.008) was independently associated with PI. Regarding outcomes, 35% (n = 55) had severe hypoxemic respiratory failure, and 19% (n = 29) required mechanical ventilation. After adjusting for demographics, PE severity, and right ventricular dysfunction, PI was independently associated with severe hypoxemic respiratory failure (OR 1.78; CI 1.18–2.69, p = 0.005) and mechanical ventilation (OR 1.92; CI 1.14–3.22, p = 0.013). Conclusions Aging is a protective factor against PI. In acute central PE, subjects with PI had higher odds of developing severe hypoxemic respiratory failure and requiring mechanical ventilation.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that primarily affects the elderly. Up to date, the specific pathogenesis of IPF remains unknown. However, it is theorized to be caused by chronic repetitive injuries to the alveolar epithelium, eventually exhausting the stem cell capacity and activating pathological pathways. Heat shock proteins (HSPs), a category of stress response proteins, are also suggested to contribute to IPF pathogenesis. Furthermore, HSPs are key components in the regulation of cell homeostasis and act as chaperones for a multitude of new proteins. This review thoroughly evaluates the roles that specific HSPs, HSP90, HSP70, and HSP47, have in the fibrotic process. A close look into the roles of these HSPs in IPF pathogenesis will give valuable insight into the future of IPF treatment and prevention.

Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.

BACKGROUND:The utility of convalescent coronavirus disease 2019 (COVID-19) plasma (CCP) in the current pandemic is not well defined. We sought to evaluate the safety and efficacy of CCP in severely or life threateningly ill COVID-19 patients when matched with a contemporaneous cohort.METHODS:Patients with severe or life-threatening COVID-19 were treated with CCP according to Food and Drug Administration criteria, prioritization by an interdisciplinary team, and based on CCP availability. Individual-level matched controls (1:1) were identified from patients admitted during the prior month when no CCP was available. The safety outcome was freedom from adverse transfusion reaction, and the efficacy outcome was a composite of death or worsening O2 support. Demographic, clinical, and laboratory data were analyzed by univariate and multivariable regression analyses accounting for matched design.RESULTS:Study patients (n = 94, 47 matched pairs) were 62% male with a mean age of 58, and 98% (90/94) were minorities (53% Hispanic, 45% Black, non-Hispanic) in our inner-city population. Seven-day composite and mortality outcomes suggested a nonsignificant benefit in CCP-treated patients (adjusted hazard ratio [aHR], 0.70; 95% CI, 0.23-2.12; P = .52; aHR, 0.23; 95% CI, 0.04-1.51; P = .13, respectively). Stratification by pretransfusion mechanical ventilation status showed no differences between groups. No serious transfusion reactions occurred.CONCLUSIONS:In this short-term matched cohort study, transfusion with CCP was safe and showed a nonsignificant association with study outcomes. Randomized and larger trials to identify appropriate timing and dosing of CCP in COVID-19 are warranted.TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT04420988.

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease of unknown etiology with limited treatment options. It is characterized by repetitive injury to alveolar epithelial cells and aberrant activation of numerous signaling pathways. Recent evidence suggests that metabolic reprogramming, metabolic dysregulation, and mitochondria dysfunction are distinctive features of the IPF lungs. Through numerous mechanisms, metabolomic abnormalities in alveolar epithelial cells, myofibroblast, macrophages, and fibroblasts contribute to the abnormal collagen synthesis and dysregulated airway remodeling described in lung fibrosis. This review summarizes the metabolomic changes in amino acids, lipids, glucose, and heme seen in IPF lungs. Simultaneously, we provide new insights into potential therapeutic strategies by targeting a variety of metabolites.

Background Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood. Methods We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 ( Ap3b1 ) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2). Results We observed widespread changes in mitochondrial homeostasis in HPS-2 cells, including the acquisition of abnormally shaped mitochondria, with reduced number of cristae, and markedly reduced activity of the electron transport chain and the tricarboxylic acid cycle. We also found that mitochondrial redox imbalance and activity of the mitochondrial unfolded protein response were dysregulated in HPS-2 cells and this associated with various other changes that appeared to be compensatory to mitochondrial dysfunction. This included an increase in glycolytic activity, an upregulation in the expression of mitochondrial biogenesis factors and enhanced activation of the energy-conserving enzyme AMP-activated protein kinase. Conclusion In summary, our findings indicate that mitochondrial function is dramatically altered in HPS-2 lung tissues, suggesting dysfunction of this organelle might be a driver of HPS lung disease.

The pathogenesis of chronic obstructive pulmonary disease (COPD) involves aberrant responses to cellular stress caused by chronic cigarette smoke (CS) exposure. However, not all smokers develop COPD and the critical mechanisms that regulate cellular stress responses to increase COPD susceptibility are not understood. Because microRNAs are well-known regulators of cellular stress responses, we evaluated microRNA expression arrays performed on distal parenchymal lung tissue samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA that best correlated with radiographic emphysema and validated this finding in multiple cohorts. In a CS exposure mouse model, inhibition of miR-24-3p increased susceptibility to apoptosis, including alveolar type II epithelial cell apoptosis, and emphysema severity. In lung epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue, and BIM and BRCA1 expression inversely correlated with miR-24-3p. We concluded that miR-24-3p, a regulator of the cellular response to DNA damage, is decreased in COPD, and decreased miR-24-3p increases susceptibility to emphysema through increased BIM and apoptosis.

Lung fibrosis is a lung disease that primarily affects older adults and makes it hard to breathe. The lungs get scarred and thick from inflammation, so exchange of oxygen and carbon dioxide is impaired. In this article, you will first learn how the lungs allow us to breathe and why we must breathe in the first place. You will also learn what causes lung fibrosis, its symptoms, how doctors diagnose it, and the ways to treat it. You will learn that there is no cure, but that means that maybe 1 day you can discover the cure!

TOPIC: Sleep Disorders TYPE: Original Investigations PURPOSE: Heart failure (HF) affects approximately 6 million adults in the United States. Among those, 45-76% have comorbid obstructive sleep apnea (OSA). OSA leads to intermittent hypoxia and hypertension, resulting in an increased incidence of myocardial ischemia and accelerating the progression of HF.OSA is believed to be underdiagnosed in 85% of the patients. There is currently no guideline for screening for comorbid OSA in HF patients. Because of the potential adverse effects of untreated OSA, it is crucial to use a screening tool to identify HF patients who may have comorbid OSA early on. We chose STOP BANG Questionnaire to evaluate the likelihood of OSA based on symptoms, blood pressure, BMI, neck circumference, age and gender.Our Internal Medicine Resident Clinic provides care to a medically underserved population with above national average illiteracy rate (52%), poverty rate (27.4%), and uninsured rate (19.1%). Medical conditions are often diagnosed at later stages, poorly controlled and often progress to end stage disease. This progression is costly in terms of quality of life, financial burden, and mortality. Identifying heart failure patients with OSA is a critical step in alleviating some of the burden. METHODS: We generated a random list of 91 adult patients who were seen in the Internal Medicine Resident Clinic in 2020 who had diagnosis of systolic heart failure or diastolic heart failure. No exclusion criteria were used. Data was manually extracted from each of the 91 patients’ charts with respect to age, gender, ethnicity, neck circumference, medication regimen, answers to the STOP BANG questionnaire if they were asked, HF classification, and history of OSA screening and referral. RESULTS: Among 91 patients, 19 (21%) patients were screened for OSA, 67 (74%) patients were not screened, and 5 patients were previously diagnosed with OSA. Among those screened for OSA, all (100%) patients had high risk of OSA based on STOP BANG questionnaire. Among eight patients referred to sleep study, four patients were later diagnosed with OSA and 4 patients did not proceed with sleep study. CONCLUSIONS: No studies yet have been done to evaluate the screening rate of comorbid OSA in HF patients in primary care setting. Studies done on evaluating screening rate of OSA in HTN and epileptic patients in primary care academic clinics show a screening rate between 1-3.3%. Our clinic has a higher rate of screening at 21%. With all patients screened having high risk of OSA, we are likely only screening for patients for whom we already have a high suspicion. However, there is a potential of underscreening symptomatic patients and delaying their diagnosis and treatment. CLINICAL IMPLICATIONS: Raise awareness of OSA screening in HF patients in primary care setting DISCLOSURES: No relevant relationships by Sung Choi, source=Web Response No relevant relationships by DANIEL MATASSA, source=Web Response No relevant relationships by amanda meredith, source=Web Response No relevant relationships by Willy Roque, source=Web Response No relevant relationships by Kajol Shah, source=Web Response No relevant relationships by Phoenix Xu, source=Web Response

SESSION TITLE: Medical Student/Resident Lung Cancer Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Small cell lung cancer (SCLC) is an aggressive entity that represents about 20% of all lung malignancies and is often diagnosed after there have been metastases (1). We present a case of a patient that was properly diagnosed using a metastatic liver lesion CASE PRESENTATION: A 61-year-old actively smoking male with PMHx of hypothyroidism, coronary artery disease, paroxysmal VT with AICD, and hypertension who presented to the ED after being referred from the ENT clinic with the complaint of sore throat for 2 months. He denied weight loss, fatigue, weakness, hemoptysis, fever, and chills. Vitals, blood-work, and physical examination were unremarkable. Chest X-ray showed extensive right lower lobe infiltrate. CT-chest showed extensive mediastinal, carinal, and paratracheal lympho-adenopathy without calcification and large lobulated poorly demarcated right hilar mass lesion. Bronchoscopy with lavage (BAL) of right lower lobe and subcarinal lymph node was performed. Sample specimens were sent to outside hospital for consultation. Subcarinal lymph node biopsy was unsatisfactory for evaluation, while BAL reported a final diagnosis of degenerated hyperchromatic cells of carcinoma with features of squamous cell carcinoma. PET-scan showed cervical, mediastinal, right hilar, and abdominal adenopathy, right lower lobe malignancy, and hepatic and osseous metastases. On multidisciplinary tumor boards (MTB), it was decided that additional tissue biopsy was needed for definitive diagnosis given pathology slides not entirely characteristic of squamous cell carcinoma. Biopsy of the right liver lobe lesion seen on PET-scan reported immune-stains strongly positive for CD56, TTF-1, 90% for Ki-67, negative for p63 and LCA. Findings consistent with neuroendocrine malignancy, compatible with small cell carcinoma. DISCUSSION: Small cell lung carcinoma is a high grade neuroendocrine tumor with poor prognosis, located centrally, and associated with smoking. Typically presents with cough, dyspnea, and weight loss. BAL has a sensitivity of 47.6% and specificity of 44.7% (2). Cytological sampling by BAL relies mainly on exfoliated cells that can lose their morphological details. In addition, SCLC may have intermediate sized cells with distinct nucleoli and lack definitive neuroendocrine features cytologically, leading to misclassification as non-small cell lung carcinoma (3). CONCLUSIONS: Multidisciplinary management of patients with cancer using MTB is recommended for the modern practice of oncology to establish accurate diagnosis of malignancies, ensure appropriate therapy, and potentially improve survival. Reference #1: Open Biol. 2017 Sep; 7(9): 170070. Reference #2: J Cytol. 2014 Apr-Jun; 31(2): 63–67. Reference #3: Int J Clin Exp Pathol. 2010; 3(4): 367–385. DISCLOSURES: No relevant relationships by Willy Roque, source=Web Response

ABSTRACT Activation of the DNA damage response (DDR) due to chronic exposure to cigarette smoke (CS) is implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). However, not all smokers develop COPD and the pathologic consequences of CS exposure are heterogenous. Cellular mechanisms that regulate the DDR and contribute to disease progression in susceptible individuals are poorly understood. Because microRNAs are well known regulators of the DDR, we evaluated microRNA expression arrays performed on lung samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA best correlated with radiographic emphysema (ρ=-0.353, P=1.3e-04) and validated this finding in multiple cohorts. In a CS-exposure mouse model, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue and inversely correlated with miR-24-3p expression. We concluded that decreased miR-24-3p expression increases COPD susceptibility and potentiates the DDR through BIM and BRCA1.

The current hypothesis suggests that Idiopathic pulmonary fibrosis (IPF) arises as a result of chronic injury to alveolar epithelial cells and aberrant activation of multiple signaling pathways. Dysfunctional IPF lung epithelium manifests many hallmarks of aging tissues, including cellular senescence, mitochondrial dysfunction, metabolic dysregulation, and loss of proteostasis. Unfortunately, this disease is often fatal within 3-5 years from diagnosis, and there is no effective treatment. One of the major limitations to the development of novel treatments in IPF is that current models of the disease fail to resemble several features seen in elderly IPF patients. In this study, we sought to develop an in vitro epithelial injury model using repeated low levels of bleomycin to mimic the phenotypic and functional characteristics of the IPF lung epithelium. Consistent with the hallmarks of the aging lung epithelium, we found that chronic-injured epithelial cells exhibited features of senescence cells, including an increase in β-galactosidase staining, induction of p53 and p21, mitochondrial dysfunction, excessive ROS production, and proteostasis alteration. Next, combined RNA sequencing, untargeted metabolomics, and lipidomics were performed to investigate the dynamic transcriptional, metabolic, and lipidomic profiling of our in vitro model. We identified that a total of 8,484 genes with different expression variations between the exposed group and the control group. According to our GO enrichment analysis, the down-regulated genes are involved in multiple biosynthetic and metabolic processes. In contrast, the up-regulated genes in our treated cells are responsible for epithelial cell migration and regulation of epithelial proliferation. Furthermore, metabolomics and lipidomics data revealed that overrepresented pathways were amino acid, fatty acid, and glycosphingolipid metabolism. This result suggests that by using our in vitro model, we were able to mimic the transcriptomic and metabolic alterations of those seen in the lung epithelium of IPF patients. We believe this model will be ideally suited for use in uncovering novel insights into the gene expression and molecular pathways of the IPF lung epithelium and performing screening of pharmaceutical compounds.

We are presenting a case of patient with type 2 diabetes mellitus that was diagnosed with a soft tissue infection in the lower extremity. This was initially treated as cellulitis and antibiotic treatment was initiated. Due to a poor clinical response, the diagnosis of pyoderma gangrenosum was proposed as part of the differential diagnosis. Skin biopsies and pathology confirmed the diagnosis of pyoderma gangrenosum that had a satisfactory response to steroid treatment

SESSION TITLE: Medical Student/Resident Chest Infections Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: A diagnosis of non-tuberculous mycobacteria (NTM) does not necessarily imply that treatment is required, e.g. Mycobacterium xenopi is often considered a commensal pathogen (1). However, NTM including M. xenopi can cause chronic pulmonary infection, although it usually requires host immune impairment. CASE PRESENTATION: A 75-year-old man presented with a 6-month history of weight loss of 20 pounds despite adequate appetite; he otherwise felt well. He reported no fever, fatigue, night sweats, or hemoptysis, although reported non-productive chronic cough of unknown duration. He had a history of diabetes mellitus, mild chronic obstructive pulmonary disease, coronary artery disease and obstructive sleep apnea. He was an active smoker, having smoked 2 packs per day for 13 years, but later decreasing to 3 cigarettes daily during the last 5 years. He was retired; had served in the military and later worked in the housing/roofing industry. He reported exposure to asbestos but always wore protective equipment while working and denied exposure to mycobacterium tuberculosis. On physical exam, T was 98.8°F, HR was 66 per minute, BP was 123/68 mmHg, RR was 17 per minute, and O2 saturation was 95% while breathing ambient air. Weight was 68 kg, height was 170 cm and BMI was 24 (28 six months ago). The patient appeared well and had no diaphoresis. Examination of skin, heart, and lungs was normal, and there was no lymphadenopathy. Laboratory tests were only significant for mild normocytic anemia; tuberculosis skin testing, HIV and quantiferon gold were negative. CT chest-abdomen-pelvis showed extensive scarring and cavitation in the lung apices with minimal fluid in some cavities. Sputum showed acid-fast bacilli on smear, and a M. tuberculosis PCR was negative. The patient was discharged from the hospital and the patient remained in his usual state of health. Mycobacterium xenopi grew on multiple cultures after 3-4 weeks. Although colonization of the cavitary lesions by M. xenopi was considered, therapy with isoniazid, rifampin, ethambutol and clarithromycin for at least 1 year was started. The patient adhered to treatment and at 4 months reported increased weight. He was lost to follow-up after 7 months and stopped receiving the medications after 11 months of therapy when he was diagnosed with dementia. No repeat cultures were obtained since the start of therapy. DISCUSSION: Our patient had significant weight loss and met clinical and microbiological criteria for NTM lung disease, which suggested the need for treatment. The treatment of M. xenopi has a success rate of 8-73% and its all-cause-mortality in HIV-negative patients can be as high as 69% (2). CONCLUSIONS: Host factors reportedly associated with M. xenopi disease include COPD. Increased awareness of the presence of this organism is necessary given manifestations can be confused with tuberculosis. Reference #1: 1.Haworth CS, Floto RA. Introducing the new BTS Guideline: Management of non-tuberculous mycobacterial pulmonary disease (NTM-PD). Thorax. 2017;72(11):969-970. Reference #2: 2.Andrejak C, Lescure F-X, Pukenyte E, et al. Mycobacterium xenopi pulmonary infections: a multicentric retrospective study of 136 cases in north-east France. Thorax. 2009;64(4):291-296. DISCLOSURES: No relevant relationships by Willy Roque, source=Web Response

SESSION TITLE: Sleep Disorders Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Obstructive Sleep Apnea (OSA) sleep-related breathing disorder characterized by repetitive interruptions during sleep. The importance of OSA and its associated health risks have increased considerably in recent years because of its rising prevalence. We aimed to observe the effect OSA has on inpatient mortality in patients with various pulmonary and cardiovascular comorbidities. METHODS: Data from the National Inpatient Sample database for 2010-2014 was used to assess the major causes of inpatient mortality in patients with prior diagnosis of OSA. All hospitalizations with OSA (ICD-9-CM 327.23) were analyzed. Univariate and multivariate logistic regression analyses were performed. The multivariate model was adjusted for age, sex, race, and selected respiratory and cardiac co-morbidities. SPSS was used for data analysis. RESULTS: There were 7,542,841 hospital admissions (mean age 60.4; 44 % women) among individuals with OSA from 2010 to 2014, with mortality of 1.2%. Of those with poor outcomes, 84.1% were between the ages of 40 and 80 years of age. The following co-morbidities with correspondent prevalence were tested (Table 1): asthma (15.0%), bronchitis (11.0%), heart failure (26.1%), interstitial lung disease (ILD) (2.1%), and atrial fibrillation (19.1%). In the multivariate analysis, higher mortality was associated with concomitant ILD (OR 1.088; 95% CI 1.037-1.140), bacterial pneumonia (OR 6.231; 95% CI 6.103-6.361), pulmonary embolism (OR 2.550, 95% CI 2.468-2.635), and heart failure (OR 1.620; 95% CI 1.596-1.643), but not with asthma (OR 0.564; 95% CI 0.549-0.579) or bronchitis (OR 0.910; 95% CI 0.892-0.929). CONCLUSIONS: Current data shows that OSA is an independent risk factor for many comorbidities and contributes to patient outcomes. There was an increased in-hospital mortality in those with prior diagnosed of OSA with ILD, bacterial pneumonia, heart failure, and pulmonary embolism. Those with underlying asthma or bronchitis had lower risk of mortality. This may be because OSA, asthma, and bronchitis involve airway obstruction and can be relieved with the help of bronchodilators and positive air pressure ventilation. CLINICAL IMPLICATIONS: Although OSA is widely recognized as a risk factor for other pulmonary and cardiovascular diseases, there is limited data regarding the clinical outcomes of these comorbidities in conjunction with OSA. Our findings add to the growing evidence that OSA represents a major risk factor for mortality in hospitalized patients. DISCLOSURES: No relevant relationships by Thomas Ng, source=Web Response No relevant relationships by Willy Roque, source=Web Response No relevant relationships by Kyrollos Saad, source=Web Response

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the activation of fibroblasts and the irreversible deposition of connective tissue matrices that leads to altered pulmonary architecture and physiology. Multiple factors have been implicated in the pathogenesis of lung fibrosis, including genetic and environmental factors that cause abnormal activation of alveolar epithelial cells, leading to the development of complex profibrotic cascade activation and extracellular matrix (ECM) deposition. One class of proteinases that is thought to be important in the regulation of the ECM are the matrix metalloproteinases (MMPs). MMPs can be up- and down- regulated in idiopathic pulmonary fibrosis (IPF) lungs and their role depends upon their location and function. Furthermore, alterations in the ubiquitin-proteosome system (UPS), a major intracellular protein degradation complex, have been described in aging and IPF lungs. UPS alterations could potentially lead to the abnormal accumulation and deposition of ECM. A better understanding of the specific roles MMPs and UPS play in the pathophysiology of pulmonary fibrosis could potentially drive to the development of novel biomarkers that can be as diagnostic and therapeutic targets. In this review, we describe how MMPs and UPS alter ECM composition in IPF lungs and mouse models of pulmonary fibrosis, thereby influencing the alveolar epithelial and mesenchymal cell behavior. Finally, we discuss recent findings that associate MMPs and UPS interplay with the development of pulmonary fibrosis.

ABSTRACT Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β-galactosidase activity (SA-β-gal) staining, the DNA damage marker γH2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1 ser307 and HSF1 K298 sumo , downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H 2 O 2 showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.

SESSION TITLE: Monday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: Active tuberculosis (TB) is a known complication of anti-tumor necrosis factor (TNF) therapy. TB in the anti-TNF treated population may present atypically, including extrapulmonary and disseminated manifestations. We report a case of a disseminated TB with peritoneal involvement in a patient on adalimumab for rheumatoid arthritis (RA). CASE PRESENTATION: A 62 year-old Asian female with RA on adalimumab and methotrexate presented with dyspnea, nonproductive cough, fever, and abdominal pain after recent treatment with azithromycin for suspected pneumonia on outpatient chest radiograph. Lung and abdominal exams were unremarkable. Laboratory studies were significant for AST 63 IU/L, ALT 69 IU/L, and CA-125 314 units/mL. Chest and abdominopelvic CT demonstrated bilateral lung nodules, peritoneal enhancement with diffuse mesenteric infiltration, ascites, and multiple splenic lesions. Fungal serologies were negative. Sputum cultures were obtained, with negative acid-fast bacilli (AFB) staining. QuantiFERON-TB Gold assay was negative (two assays prior to adalimumab initiation were indeterminate). Paracentesis yielded amber ascites with 711 WBCs/mm3 with 76% lymphocytes, LDH 1,486 IU/L, protein 2.9g/dL, glucose 76mg/dL, amylase < 30U/L, adenosine deaminase 13.3U/L. Bronchoscopic exam was grossly unremarkable. Bacterial and fungal cultures, AFB stain, and cytology of bronchoalveolar lavage (BAL) and ascites were negative. Laparoscopic peritoneal biopsy was pursued, with gross inflammation of the peritoneum and mesentery noted. Intraoperative frozen section demonstrated granulomatous inflammatory material suspicious for TB, prompting empiric therapy with rifampin, isoniazid, pyrazinamide, and ethambutol. Subsequent histopathology demonstrated TB-positive necrotizing granulomas. Due to hepatotoxicity with empiric therapy, a combination of linezolid, amikacin, ethambutol, and moxifloxacin was substituted. Approximately 20 days after sputum, BAL, and ascites collection, cultures grew TB. The patient was discharged on rifampin, linezolid, ethambutol, and moxifloxacin. DISCUSSION: In comparison to the general population, extrapulmonary and disseminated TB occur with greater frequency in patients treated with anti-TNF agents.1 There has only been one report of disseminated TB with peritoneal involvement in association with adalimumab.2 Given the complex, atypical presentation of extrapulmonary TB and overlap with entities such as advanced ovarian carcinoma3, it is imperative to recognize the risk for development of disseminated TB associated with anti-TNF agents. Atypical presentations such as described in our case can delay diagnosis and treatment. CONCLUSIONS: Atypical TB infection should remain high on the differential in adalimumab-treated patients presenting with peritoneal infiltration. Reference #1: Rychly et al. Infections Associated with Tumor Necrosis Factor-α Antagonists. Pharmacotherapy. 2005 Sep;25(9):1181-92. Reference #2: Yoo WH. Multiple organ tuberculosis of lung, pleura, and peritoneum in ankylosing spondylitis during adalimumab therapy. Rheumatology international. 2012 Mar 1;32(3):787-90. Reference #3: Gosein et al. Peritoneal tuberculosis mimicking advanced ovarian carcinoma: an important differential diagnosis to consider. BMC research notes. 2013 Dec;6(1):88. DISCLOSURES: No relevant relationships by Jonathan Packer, source=Web Response No relevant relationships by Eman Rashed, source=Web Response No relevant relationships by Willy Roque, source=Web Response No relevant relationships by Omry Zuckerman, source=Web Response