Lipid-laden Macrophages Research Articles

Xanthogranulomatous Orchitis Mimicking a Testicular Malignancy: A Rare Case with Brief Review of Literature

Xanthogranulomatous orchitis (XGO) is a rare, distinct type of chronic inflammation causing destruction of the tissue by infiltrate of lipid laden macrophages. It is commonly seen in the gall bladder, kidney and is rarely reported in the testis. Authors hereby, report report a case of a 32-year-old man who presented with a swelling in the right testis since 3 weeks. On clinical examination, ultrasound findings, a provisional diagnosis of testicular neoplasm was made. Simple right orchidectomy was performed and on histopathological examination the testis was found to be replaced with large lipid laden macrophages (Xanthoma cells) along with lymphocytes, foci of necrosis and hemorrhage, a diagnosis of XGO was rendered. The preoperative diagnosis of XGO is very challenging as the condition often mimics a testicular neoplasm, thus the final diagnosis relies on the histopathological examination. Extensive sampling of the tissue should be done to rule out any concurrent testicular neoplasm

Epilepsy in Stroke as De Novo Independent Nosology Unit – Physiology, Pathogenesis, Histology, Clinical Picture, Diagnosis, and Treatment – A Systematic Review

INTRODUCTION: Early seizures are considered complications of stroke, and late seizures are a type of structural epilepsy. If they are separated as a new independent nosology unit, the problem in the diagnostic – treatment approach will be solved. PHYSIOLOGY: Cerebral blood flow is regulated by local factors such as carbon dioxide and oxygen content. Brain activity is also an important factor in the regulation of the volume speed of the blood – with locally increased neuronal activity, the local blood flow increases. Neurons in the CNS are subject to a variety of effects mediated by membrane receptors of two types – ionotropic and metabotropic. PATHOGENESIS: Early seizures are due to transient biochemical dysfunctions, while late seizures are due to gliosis changes affecting neuronal excitability. HISTOLOGY: The highlighted histopathological aspects confirm and support the results of clinical and radiological studies with dead nervous tissue, replaced by numerous newly formed capillaries, and surrounded by lipid-laden macrophages. CLINICAL PICTURE: This is represented by a complex combination of excitatory epileptic manifestations and residual focal symptoms depending on the localization of the lesion. LABORATORY DIAGNOSTICS: A very typical group of patients with post-stroke seizures have a high risk of recurrence when some of the studied biomarkers for this are available in the blood. In summary, the additional expanded package of studies of stroke patients should include screening diagnostics for the risk of epileptic seizures, namely: IL-6, IL-1β, TNF, Mg2+, Ca2+, CD40L, and Hsc70. IMAGING: Transient periodic MRI abnormalities have been demonstrated, possibly as a result of cerebral edema induced by seizure activity. Routine MRI in stroke patients is recommended. TREATMENT: It is possible that rt-PA may increase the risk of early seizures after stroke. Levetiracetam (LEV) as a neuroprotective agent in stroke has been proposed as the drug of first choice, based on safety and efficacy profiles. The usual practice is to treat recurrent early-onset seizures with short-term (3–6 months) treatment with antiepileptic drugs. CONCLUSIONS: Separation of stroke-epilepsy as a new independent nosology entity will solve the diagnostic-treatment problems in this area by changing the minimum package for laboratory tests, as well as routine MRI in patients with clinical evidence of stroke. LEV is the first-line agent for the treatment of these patients, in combination with correction of registered laboratory parameters.

Lipid-Laden Macrophage Index as a Diagnostic Tool for Pediatric Aspiration: A Systematic Review.

Lipid-laden macrophage index (LLMI) has been proposed as a marker for aspiration on bronchoalveolar lavage. It has also been studied as a marker for gastroesophageal reflux and other pulmonary diseases. This review aims to determine the clinical correlation between LLMI and pediatric aspiration. PubMed (MeSH search), Scopus, and Cochrane Central Register of Controlled Trials (CENTRAL) portals through December 17th, 2020. Preferred Reporting Items for Systematic Review and Meta-Analysis criteria were followed, and a quality assessment of included studies was performed using the Methodological Index for Non-Randomized Studies. Search criteria included all occurrences in the title or abstract of the terms "pulmonary aspiration" and "alveolar macrophages." Five studies describing 720 patients met inclusion, 3 retrospective case-control studies, and 2prospective observational studies. Four studies suggested a link between elevated LLMI and aspiration, and 1 found no association. Control groups varied and included healthy nonaspirators to nonaspirators with other pulmonary diseases. Diagnosis of aspiration was not standardized across the studies. Three papers proposed cutoff values for LLMI, all different. The existing literature indicates that LLMI is not a sensitive or specific marker for aspiration. Further study is needed to define the utility of LLMI in pediatric aspiration.

A green-inspired method to prepare non-split high-density lipoprotein (HDL) carrier with anti-dysfunctional activities superior to reconstituted HDL

Numerous studies have demonstrated that dysfunctional high-density lipoprotein (HDL), especially oxidized HDL (OxHDL), could generate multifaceted in vivo proatherogenic effects that run counter to the antiatherogenic activities of HDL. It thereby reminded us that the in vitro reconstituted HDL (rHDL) might encountered with oxidation-induced dysfunction. Accordingly, a green-inspired method was employed to recycle non-split HDL from human plasma fraction IV. Then it was compared with rHDL formulated by an ethanol-injection method in terms of physicochemical properties and anti-dysfunctional activities. Results exhibited that rHDL oxidation extent exceeded that of non-split HDL evidenced by higher malondialdehy content, weaker inhibition on low-density lipoprotein (LDL) oxidation and more superoxide anion. The reserved paraoxonase-1 activity on non-split HDL could partially explain for above experimental results. In the targeted transport mechanism experiment, upon SR-BI receptor inhibition and/or CD36 receptor blockage, the almost unchanged non-split HDL uptake in lipid-laden macrophage indicated its negligible oxidation modification profile with regard to rHDL again. Furthermore, compared to rHDL, better macrophage biofunctions were observed for non-split HDL as illustrated by accelerated cholesterol efflux, inhibited oxidized LDL uptake and lessened cellular lipid accumulation. Along with decreased ROS secretion, obviously weakened oxidative stress damage was also detected under treatment with non-split HDL. More importantly, foam cells with non-split HDL-intervention inspired an enhanced inflammation repression and apoptosis inhibition effect. Collectively, the anti-dysfunctional activities of non-split HDL make it suitable as a potential nanocarrier platform for cardiovascular drug payload and delivery.

Differential Expression of Inflammarafts in Macrophage Foam Cells and in Nonfoamy Macrophages in Atherosclerotic Lesions-Brief Report.

Reprogramming of monocytes and macrophage manifests in hyperinflammatory responses and chronification of inflammation in atherosclerosis. Recent studies focused on epigenetic, transcriptional, and metabolic alterations that characterize trained immunity. However, the underlying effector mechanisms driving the hyperinflammatory response of reprogrammed macrophages remain unclear. We hypothesized that the plasma membrane of atherosclerotic lesion macrophages undergoes reprogramming to maintain inflammarafts, enlarged lipid rafts (LR) serving as a platform for assembly of inflammatory receptor complexes. Single-cell suspensions from the aortae of Western diet-fed Ldlr-/- mice were gated for BODIPY-high foamy and BODIPY-low nonfoamy F4/80 macrophages by flow cytometry. Inflammarafts were characterized by increased levels of LR, TLR4 (toll-like receptor-4) localization to LR, TLR4 dimers, and the proximity between TLR2, TLR1, and CD36. In a cellular model of trained immunity, LR, TLR4 dimers, and the inflammatory response were measured in bone marrow-derived macrophages subjected to a 24-hour treatment with LPS (lipopolysaccharide) or OxLDL (oxidized low-density lipoprotein), followed by a 6-day wash-out period. Nonfoamy macrophages, which constituted ≈40% of macrophages in atherosclerotic lesions, expressed significantly higher levels of LR and TLR4 dimers, as well as proximity ligation signals for TLR4-LR, TLR2-CD36, and TLR2-TLR1 complexes, compared with foamy macrophages. These inflammaraft measures associated, to a different degree, with plasma cholesterol and inflammatory cytokines, as well as the size of the atherosclerotic lesions and necrotic cores. The bone marrow-derived macrophages trained with LPS simulated nonfoamy atherosclerotic lesion macrophages and continued to express inflammarafts and inflammatory genes for 6 days after LPS removal and displayed a hyperinflammatory response to Pam3CSK4, a TLR2/TLR1 agonist. OxLDL-exposed, lipid-laden macrophages did not express inflammarafts. Our data support the hypothesis that persistent inflammarafts in nonfoamy macrophages in atherosclerotic lesions serve as effectors of macrophage reprogramming into a hyperinflammatory phenotype.

Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling.

Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear. The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of CH25H in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or Ch25h-/- mice to lethally irradiated Ldlr-/- mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from Ldlr-/- or Ch25h-/-;Ldlr-/- mice. The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, Myh11ERT2CREmT/mG;Ldlr-/-, adoptively transferred with wild-type or Ch25h-/- mice bone marrow followed by 12 weeks of Western diet feeding. We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity. Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.

Surfactant protein D inhibits lipid-laden foamy macrophages and lung inflammation in chronic obstructive pulmonary disease.

Increased levels of surfactant protein D (SP-D) and lipid-laden foamy macrophages (FMs) are frequently found under oxidative stress conditions and/or in patients with chronic obstructive pulmonary disease (COPD) who are also chronically exposed to cigarette smoke (CS). However, the roles and molecular mechanisms of SP-D and FMs in COPD have not yet been determined. In this study, increased levels of SP-D were found in the bronchoalveolar lavage fluid (BALF) and sera of ozone- and CS-exposed mice. Furthermore, SP-D-knockout mice showed increased lipid-laden FMs and airway inflammation caused by ozone and CS exposure, similar to that exhibited by our study cohort of chronic smokers and COPD patients. We also showed that an exogenous recombinant fragment of human SP-D (rfhSP-D) prevented the formation of oxidized low-density lipoprotein (oxLDL)-induced FMs in vitro and reversed the airway inflammation and emphysematous changes caused by oxidative stress and CS exposure in vivo. SP-D upregulated bone marrow-derived macrophage (BMDM) expression of genes involved in countering the oxidative stress and lipid metabolism perturbations induced by CS and oxLDL. Our study demonstrates the crucial roles of SP-D in the lipid homeostasis of dysfunctional alveolar macrophages caused by ozone and CS exposure in experimental mouse emphysema, which may provide a novel opportunity for the clinical application of SP-D in patients with COPD.

Pseudotumor Xanthogranulomatous Pyelonephritis: Dignaostic and Therapeutic Difficulties (Two Cases)

Introduction: Xanthogranulomatous pyelonephritis is a rare and unusual form of chronic pyelonephritis, characterized by the destruction of the renal parenchyma and its replacement by granulomas, abscesses and lipid-laden macrophage collections. Despite clinical and radiological knowledge, it remains a surprise for the surgeon. We are reporting through these two observations the diagnostic difficulties of this condition would lead to an inappropriate treatment as well as to a more severe disease. Observations: Two patients (52 and 57 years old), one of whom is followed fortype 2 diabetes mellitus , were hospitalized for pyonephrosis due to obstructive pyelic and ureteral lithiasis. The pyonephrosis was revealed by a chronic loin pain in a febrile context and confirmed by urogramme showing a destruction of the renal parenchyma, dilated pyelocaliceal cavities with rounded formations of pseudo-tumoral appearance on the lithiasis obstacles. Our initialtreatment consisted of percutaneous nephrostomy under antibiotic covering and secondarily of nephro-ureterectomy without bladder flange performed six weeks later. Histopathology studies showed diffuse xanthogranulomatous pyelonephritis. The postoperative follow up was simple in both cases. Conclusion: Xantogranulomatous pyelonephritis is a rare, severe and chronic form of pyelonephritis whose diagnosis is always histological. Its clinical picture is no specific, hence the problem is that it poses achalleng of differential diagnosis with renal tumors and urogenital tuberculosis. Its treatment is based on nephrectomy.

E-cigarette or vaping product use-associated lung injury: A review of clinico-radio-pathological characteristics.

Aggressive, albeit false marketing of electronic nicotine delivery systems (ENDS) or vaping devices as safer alternatives to cigarette smoking, combined with lack of regulations, has led to its mass adoption, especially among youth. A sudden increase in acute lung injuries was noted in 2019 which was linked to ENDS. It was termed by the Centers for Disease Control and Prevention (CDC) as electronic cigarette or vaping product use-associated lung injury (EVALI). Analysis of bronchoalveolar lavage fluid samples linked EVALI to vitamin E acetate (VEA), which is used as a diluting agent for marijuana oils. Patients with EVALI present with a combination of non-specific respiratory, gastrointestinal, and systemic symptoms. Laboratory results may show elevated inflammatory biomarkers. EVALI is a diagnosis of exclusion and must meet the following criteria: i) history of vaping within last 90 days, ii) abnormal chest imaging, iii) negative evaluation for infection, and iv) no other plausible diagnosis. A spectrum of computed tomography (CT) chest findings has been reported in EVALI, ranging from diffuse alveolar damage to organizing pneumonia, characterized by bilateral ground-glass opacities, consolidation, and septal thickening. A similar spectrum is seen on histopathology, characterized by lipid-laden alveolar macrophages, with varying degrees of infiltrative inflammatory cells and fibrin deposition. Early and accurate identification of the EVALI pattern can help optimize patient care. For example, in diffuse alveolar damage (DAD), a lower threshold for ventilation support and corticosteroid may improve outcomes. Here, we review the etiopathogenesis, clinical management, histopathology, and imaging features of EVALI.

Oil Red O Staining of Pulmonary Macrophages in Bronchoalveolar Lavage Specimens Is Not Specific for Vaping-Associated Lung Injury.

Oil Red O (ORO) positivity in bronchoalveolar lavage (BAL) fluid macrophages in the setting of e-cigarette, or vaping, product use-associated acute lung injury (EVALI) has been frequently requested by clinicians based on rare reports and subsequent US Centers for Disease Control and Prevention guidelines. The aim of this study was to determine the specificity of ORO staining in BAL specimens with disease states other than EVALI. Consecutive BAL specimens (October-December 2019) were stained with ORO. The lipid-laden macrophage index (LLMI) was calculated for each case. We studied BAL samples from 50 patients. Indications for BAL were surveillance bronchoscopy for lung transplantation (27/50), suspected infection (12/50), sarcoidosis/suspected sarcoidosis (3/50), nodules or ground-glass opacities (3/50), hemoptysis (2/50), asthma or eosinophilic pneumonia (2/50), and idiopathic pulmonary fibrosis (1/50). ORO staining was seen in BAL fluid macrophages in 45 of 50 cases (focal in 18, moderate in 23, diffuse in 4); LLMI ranged from 0 to 218. Using a threshold of LLMI of 85 or higher as positive, ORO was positive in 7 of 50 (14%) cases (range, 85-218). ORO staining in BAL fluid macrophages is not specific for EVALI. Even when an LLMI of 85 or higher is used as a threshold for positivity, ORO positivity occurs in a significant subset of non-vaping-related cases.

ATYPICAL PRESENTATION OF FAT EMBOLISM SYNDROME IN AN IMMUNOCOMPROMISED PATIENT

ATYPICAL PRESENTATION OF FAT EMBOLISM SYNDROME IN AN IMMUNOCOMPROMISED PATIENT

XANTHOGRANULOMATOUS CHOLECYSTITIS: DIFFICULTY IN DIFFERENTIATING FROM GALLBLADDER CANCER

Xanthogranulomatous cholecystitis (XGC) is a benign, rare form of chronic cholecystitis characterized by focal or diffuse inammation of the gallbladder. Its incidence varies in different subjects from 1.2% to 8.9%. It is often misdiagnosed as a carcinoma GB in many cases in clinical and radiological diagnoses, and sometimes even in histopathological tests. XGC was rst described by Christensen and Ishak, as Fibroxanthogranulomatous inammation in the 1970s. This condition was later described as ceroid as histiocytic granuloma of the gall bladder (GB) and biliary granulomatous cholecystitis. It is characterized by focal or diffuse destructive inammatory process that mainly involves endothelial cells, brous tissues and lipid-laden macrophages. In particular it shows brownish-yellow spots with unusual irregular and asymmetrical thickening of the bladder wall. Its pathogenesis is unclear. It is thought to begin as biliary obstruction with severe or chronic cholelithiasis and an increase in intragallbladder pressure.

S2130 Rectal Xanthoma: A Rare Clinical Finding

Introduction: Xanthomas are localized lipid deposits within an organ system. They are more commonly found as cutaneous lesions and less likely to appear in the gastrointestinal tract. The incidence of gastrointestinal xanthomas is not well documented, but the vast majority of authors agree they occur more frequently in the stomach. Colonic xanthomas are rare and usually incidental endoscopic findings. There are several case reports that present gastrointestinal xanthomas, however a small subset of these cases are located in the rectum. Here we present a case of rectal xanthoma and discuss its macroscopic and microscopic features. Case Description/Methods: A 55-year-old female with a recent diagnosis of atrophic metaplastic autoimmune gastritis presents for colonoscopy. Per chart review, patient had a normal colonoscopy in 2012. During the colonoscopy in 2022, one 10 mm sessile polyp was resected in the cecum; pathology returned as hyperplastic polyp. In the rectum was an area concerning for a submucosal lesion, encompassing about one quarter of the rectal circumference. Overlying it was an area of mucosa with hues of yellow which was biopsied. Pathology showed fragments of colonic mucosa with mild chronic inactive inflammation with histiocytic aggregate and focal surface glandular hyperplasia suggestive of xanthoma. Lipid panel available from 2019 showed LDL 100 with other levels within normal range (Figure). Discussion: Colorectal xanthomas are intestinal lesions with aggregates of lipid laden macrophages called foamy histiocytes. These cells are distributed in the lamina propria, between the colonic glands and muscularis mucosa. Unlike cutaneous xanthomas, gastrointestinal xanthomas are not associated with dyslipidemia. There has been a reported case of colonic xanthomas presenting as submucosal masses in the rectum and sigmoid. In a case series of 28 patients with colorectal xanthomas, 23 were sessile and 5 were pedunculated. Twelve xanthomas appeared reddish in color, 5 were white, and 2 were of a yellow hue. The relationship between colorectal xanthomas and malignancy is unclear. Of the 28 colorectal xanthomas, 4 hyperplastic lesions were found within the xanthoma, while 4 adenomas and 2 adenocarcinomas were found adjacent to xanthomas. Chronic injury is believed to be associated with the cause of colorectal xanthomas. In our case, a sigmoidoscopy with EUS is planned to rule out a submucosal mass. Adding case reports to the literature will help assess potential correlation with polyps and malignancies.Figure 1.: (Top) Rectum with appearance of submucosal lesion and localized area of yellow hue in mucosa (bottom) Foamy histiocytes confined to the lamina propria.

LEFT SIDE PREDOMINANT E-CIGARETTE OR VAPING USE-ASSOCIATED LUNG INJURY (EVALI): A CHALLENGING DIAGNOSIS OF EXCLUSION

LEFT SIDE PREDOMINANT E-CIGARETTE OR VAPING USE-ASSOCIATED LUNG INJURY (EVALI): A CHALLENGING DIAGNOSIS OF EXCLUSION

Xanthogranulomatous Pyelonephritis, a Great Imitator: Case Report

Xanthogranulomatous pyelonephritis (XPN) is an atypical form of chronic pyelonephritis, characterized by the destruction of the renal parenchyma and its replacement with a chronic infiltrate of lipid-laden macrophages [1]. The clinical presentation is nonspecific and variable. Consider clear cell carcinoma, sarcomatoid renal cell carcinoma, renal tuberculosis, renal lymphoma, renal or psoas abscess, actinomycosis, renal cystic disease, and emphysematous pyelonephritis [2,3]. We present the case of a 59-year-old female patient, with a history of recurrent urinary tract infections, who came to our center due to severe anemia (5gr/dl), weight loss of 10 kg in 2 months, night sweats and weakness, concomitant sudden-onset lumbar pain and hematuria, after multiple studies, a diagnosis of PNX was made, which was confirmed by anatomopathological study.

Clinicopathological Correlations in Enucleated Globes of Late-Stage Coats Disease with a Review of the Literature

BackgroundCoats disease may cause diagnostic dilemma because of its variable clinical presentation that can be suspicious of retinoblastoma. Late sequelae of the disease are blinding with possible enucleation. We demonstrate the main histopathological findings of Coats enucleated eyes with literature review.MethodsThis was a retrospective study of all enucleated globes diagnosed as Coats disease over 30 years and were reviewed by two pathologists. The corresponding demographic data, clinical presentation, pre-operative clinical impression, and indication for enucleation were collected. Descriptive analysis of our own series data was performed. Our findings were then correlated to published data that were collected from 1983 to 2021 from the PUBMED database in English-written language. Shields classification was used as an inclusion criterion for the published reports to be analyzed.ResultsWe had seven enucleated globes with Coats disease. Mean age at presentation was 3.2 years (range 3 months to 9 years). Male predominance was observed in 6 and all cases were unilateral. Strabismus was the most common initial presentation (57%, n = 4), followed by leukocoria (43%, n = 3). Indication for enucleation was mostly suspected retinoblastoma (57%, n = 4). Four eyes were classified as stage 4, and 2 had advanced stage 5 changes. Histopathologically, subretinal fluid with lipid-laden macrophages was seen in all cases, the anterior chamber was shallow in 5/7 with angle neovascularization in 2/7. Telangiectatic vessels were clearly observed in 4/7. ConclusionCoats disease is a potentially visually disabling disease that is mostly unilateral in 95%, has male predominance of 81%, and wide age range with a mean of 17 years. In Saudi Arabia, the disease seems to present at younger age, tends to be more advanced, and may be indistinguishable from retinoblastoma at the time of diagnosis. Shields staging of Coats is highly recommended to be followed clinically to unify the pathways for treatment and to correlate the concluded outcomes.

Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis.

Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2fl/fl/ApoE−/−, TM6 mKO) with littermate LysM Cre−/Tm6sf2fl/fl/ApoE−/− (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.

Dysregulation of miR-103a Mediates Cigarette Smoking-induced Lipid-laden Macrophage Formation.

Cigarette smoke (CS) is considered a major risk factor for chronic obstructive pulmonary disease (COPD) that is currently the third leading cause of death in the United States. Studies have indicated that patients with COPD have elevated blood low-density lipoprotein levels, which may contribute to the dysregulation of lipid metabolism. Accumulating data show that microRNAs (miRNAs) are involved in various human diseases. However, the role of microRNAs in the pathogenesis of COPD remains poorly defined. In this study, we found that miR-103a expression was significantly reduced in alveolar macrophages from smokers and patients with COPD versus that in alveolar macrophages from nonsmokers. Our data indicated that reactive oxygen species negatively regulate miR-103a in macrophages. Functionally, miR-103a modulates the expressions of genes involved in lipid metabolism and directly targets low-density lipoprotein receptors in macrophages. Furthermore, overexpression of miR-103a suppressed the accumulation of lipid droplets and reduced the reactive oxygen species, both invitro and invivo. Taken together, our findings indicate that downregulation of miR-103a contributes to cigarette smoke-induced lipid-laden macrophage formation and plays a critical role in lipid homeostasis in lung macrophages in the pathogenesis of COPD.

Intratracheal Administration of Acyl Coenzyme A Acyltransferase-1 Inhibitor K-604 Reduces Pulmonary Inflammation Following Bleomycin-Induced Lung Injury.

Acute lung injury (ALI) is characterized by epithelial damage, barrier dysfunction, and pulmonary edema. Macrophage activation and failure to resolve play a role in ALI; thus, macrophage phenotype modulation is a rational target for therapeutic intervention. Large, lipid-laden macrophages have been observed in various injury models, including intratracheal bleomycin (ITB), suggesting that lipid storage may play a role in ALI severity. The endoplasmic reticulum-associated enzyme acyl coenzyme A acyltransferase-1 (Acat-1/Soat1) is highly expressed in macrophages, where it catalyzes the esterification of cholesterol, leading to intracellular lipid accumulation. We hypothesize that inhibition of Acat-1 will reduce macrophage activation and improve outcomes of lung injury in ITB. K-604, a selective inhibitor of Acat-1, was used to reduce cholesterol esterification and hence lipid accumulation in response to ITB. Male and female C57BL6/J mice (n = 16-21/group) were administered control, control + K-604, ITB, or ITB + K-604 on d0, control or K-604 on d3, and were sacrificed on day 7. ITB caused significant body weight loss and an increase in cholesterol accumulation in bronchoalveolar lavage cells. These changes were mitigated by Acat-1 inhibition. K-604 also significantly reduced ITB-induced alveolar thickening. Surfactant composition was normalized as indicated by a significant decrease in phospholipid: SP-B ratio in ITB+K-604 compared with ITB. K-604 administration preserved mature alveolar macrophages, decreased activation in response to ITB, and decreased the percentage mature and pro-fibrotic interstitial macrophages. These results show that inhibition of Acat-1 in the lung is associated with reduced inflammatory response to ITB-mediated lung injury.SIGNIFICANCE STATEMENTAcyl coenzyme A acyltransferase-1 (Acat-1) is critical to lipid droplet formation, and thus inhibition of Acat-1 presents as a pharmacological target. Intratracheal administration of K-604, an Acat-1 inhibitor, reduces intracellular cholesterol ester accumulation in lung macrophages, attenuates inflammation and macrophage activation, and normalizes mediators of surface-active function after intratracheal bleomycin administration in a rodent model. The data presented within suggest that inhibition of Acat-1 in the lung improves acute lung injury outcomes.

Utilization of Oil Red O staining for assessing aspiration risk in lung transplant patients: A multidisciplinary prospective study with clinical practice insights.

Gastroesophageal reflux disease with microaspiration has been associated with graft dysfunction in lung transplant patients. Identifying patients with aspiration is clinically important because it enables implementation of appropriate interventions like antireflux therapy. Oil Red O (ORO) staining with determination of the lipid-laden macrophage index (LLMI) has been proposed as a noninvasive surrogate marker in the detection of aspiration. The aim of this study was to prospectively evaluate clinical utilization of ORO staining in the assessment of aspiration risk. All transbronchial surgical pathology biopsies obtained in lung transplant patients undergoing routine surveillance from August 2020 through November 2021 were included in this study. Clinical team members prospectively ascertained the aspiration risk category (ARC) of each patient both before and after biopsy findings and recorded reasons for change in ARC. A total of 132 transbronchial biopsies with concurrent LLMI were included in the study. LLMI was low in 51 cases (38.6%), including 21 of the 54 cases (38.9%) where aspiration was suggested based on the transbronchial biopsy findings. In total, 19 cases (14.4%) underwent a change in ARC post-biopsy including 10 that were upgraded and nine cases that were downgraded. Transbronchial biopsy findings were noted as the reason for change in ARC in the majority (15/19; 79%) of cases; only a minority (2/19; 10.5%) were due to the LLMI. Notably, 16 cases (12.1%) had a low LLMI with high-risk post-biopsy ARC and nine cases (6.8%) had a high LLMI with low-risk post-biopsy ARC. This study observed that clinical evaluation for aspiration relied more heavily on transbronchial biopsy findings. Although LLMI may retain clinical utility in some scenarios, reevaluation of the clinical value of ORO testing would be prudent.