Acute Inflammatory Response Research Articles

Modelling lung infection with Klebsiella pneumoniae after murine traumatic brain injury

Pneumonia is a common comorbidity in patients with severe traumatic brain injury (TBI), and is associated with increased morbidity and mortality. In this study, we established a model of intratracheal Klebsiella pneumoniae administration in young adult male and female mice, at 4 days following an experimental TBI, to investigate how K. pneumoniae infection influences acute post-TBI outcomes. A dose-response curve determined the optimal dose of K. pneumoniae for inoculation (1 x 10^6 colony forming units), and administration at 4 days post-TBI resulted in transient body weight loss and sickness behaviors (hypoactivity and acute dyspnea). K. pneumoniae infection led to an increase in pro-inflammatory cytokines in serum and bronchoalveolar lavage fluid at 24 h post-infection, in both TBI and sham (uninjured) mice. By 7 days, when myeloperoxidase + neutrophil numbers had returned to baseline in all groups, lung histopathology was observed with an increase in airspace size in TBI + K. pneumoniae mice compared to TBI + vehicle mice. In the brain, increased neuroinflammatory gene expression was observed acutely in response to TBI, with an exacerbated increase in Ccl2 and Hmox1 in TBI + K. pneumoniae mice compared to either TBI or K. pneumoniae alone. However, the presence of neuroinflammatory immune cells in the injured brain, and the extent of damage to cortical and hippocampal brain tissue, was comparable between K. pneumoniae and vehicle-treated mice by 7 days. Examination of the fecal microbiome across a time course did not reveal any pronounced effects of either injury or K. pneumoniae on bacterial diversity or abundance. Together, these findings demonstrate that K. pneumoniae lung infection after TBI induces an acute and transient inflammatory response, primarily localized to the lungs with some systemic effects. However, this infection had minimal impact on secondary injury processes in the brain following TBI. Future studies are needed to evaluate the potential longer-term consequences of this dual-hit insult.

Exposure to normobaric hypoxia shapes the acute inflammatory response in human whole blood cells in vivo.

Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so-called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signalling pathways. To study the mutual influence of both processes in vivo, we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-h stay in a hypoxic chamber with normobaric hypoxia of 10.5% oxygen. We analysed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in whole blood cells in vivo. Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.

The Effect of Physical Activity and Repeated Whole-Body Cryotherapy on the Expression of Modulators of the Inflammatory Response in Mononuclear Blood Cells among Young Men.

Background: Series of whole-body cryotherapy (WBC) among healthy and physically active individuals can potentially reduce inflammatory response, although exact mechanisms remain unclear. Methods: The impact of whole-body cryotherapy on inflammation modulators among 28 young males, categorized as non-training (NTR, N = 10), non-training with WBC (NTR-WBC, N = 10), and training with WBC (TR-WBC, N = 8), is investigated in this study. Over a period of eight weeks, NTR-WBC and TR-WBC subjects underwent 24 WBC treatments (-130 °C for 3 min, three times a week), examining changes in mRNA expressions of IL-1A, IL-6, IL-10, IFN-G, SIRT1, SIRT3, SOD2, GSS, and ICAM-1. Results: The received data indicate an acute inflammatory response to initial WBC (increased IL-1A, IL-6, and SIRT), with a greater effect in NTR-WBC. Subsequent sessions showed enhanced expressions of antioxidative genes in both WBC groups, particularly non-trained, suggesting improved oxidative stress adaptation. A notable decrease in ICAM-1 mRNA post-24 WBC treatments in NTR-WBC signifies a potential systemic anti-inflammatory effect. Conclusions: The findings of the study suggest that the combination of regular physical activity with WBC administered three times per week can potentially modulate inflammatory and antioxidant responses. This modulation is evidenced by changes in the expression of genes related to these processes.

Dynamic molecular signatures of acute myocardial infarction based on transcriptomics and metabolomics

Acute myocardial infarction (AMI) commonly precedes ventricular remodeling, heart failure. Few dynamic molecular signatures have gained widespread acceptance in mainstream clinical testing despite the discovery of many potential candidates. These unmet needs with respect to biomarker and drug discovery of AMI necessitate a prioritization. We enrolled patients with AMI aged between 30 and 70. RNA-seq analysis was performed on the peripheral blood mononuclear cells collected from the patients at three time points: 1 day, 7 days, and 3 months after AMI. PLC/LC–MS analysis was conducted on the peripheral blood plasma collected from these patients at the same three time points. Differential genes and metabolites between groups were screened by bio-informatics methods to understand the dynamic changes of AMI in different periods. We obtained 15 transcriptional and 95 metabolite expression profiles at three time points after AMI through high-throughput sequencing. AMI-1d: enrichment analysis revealed the biological features of 1 day after AMI primarily included acute inflammatory response, elevated glycerophospholipid metabolism, and decreased protein synthesis capacity. Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) might stand promising biomarkers to differentiate post-AMI stage. Anti-inflammatory therapy during the acute phase is an important direction for preventing related pathology. AMI-7d: the biological features of this stage primarily involved the initiation of cardiac fibrosis response and activation of platelet adhesion pathways. Accompanied by upregulated TGF-beta signaling pathway and ECM receptor interaction, GP5 help assess platelet activation, a potential therapeutic target to improve haemostasis. AMI-3m: the biological features of 3 months after AMI primarily showed a vascular regeneration response with VEGF signaling pathway, NOS3 and SHC2 widely activated, which holds promise for providing new therapeutic approaches for AMI. Our analysis highlights transcriptional and metabolomics signatures at different time points after MI, which deepens our understanding of the dynamic biological responses and associated molecular mechanisms that occur during cardiac repair.

Postimplantation Syndrome after Traumatic Internal Carotid Artery Pseudoaneurysm Repair with Stent

AbstractEndovascular repair of traumatic internal carotid artery pseudoaneurysm (TICAP) with covered stents represents a safe treatment with few complications. However, the presence of foreign material used to treat TICAP and blood clots in the excluded pseudoaneurysms can trigger an acute systemic inflammatory response syndrome called postimplantation syndrome (PIS). To the best of our knowledge, PIS is described only after abdominal aortic endovascular aneurysm repair. Here, we report the case of PIS in a young, healthy, polytraumatized female patient with TICAP treated with endovascular covered stent.

A nox2/cybb zebrafish mutant with defective myeloid cell reactive oxygen species production displays normal initial neutrophil recruitment to sterile tail injuries.

Reactive oxygen species are important effectors and modifiers of the acute inflammatory response, recruiting phagocytes including neutrophils to sites of tissue injury. In turn, phagocytes such as neutrophils are both consumers and producers of reactive oxygen species. Phagocytes including neutrophils generate reactive oxygen species in an oxidative burst through the activity of a multimeric phagocytic nicotinamide adenine dinucleotide phosphate oxidase complex. Mutations in the NOX2/CYBB (previously gp91phox) nicotinamide adenine dinucleotide phosphate oxidase subunit are the commonest cause of chronic granulomatous disease, a disease characterized by infection susceptibility and an inflammatory phenotype. To model chronic granulomatous disease, we made a nox2/cybb zebrafish (Danio rerio) mutant and demonstrated it to have severely impaired myeloid cell reactive oxygen species production. Reduced early survival of nox2 mutant embryos indicated an essential requirement for nox2 during early development. In nox2/cybb zebrafish mutants, the dynamics of initial neutrophil recruitment to both mild and severe surgical tailfin wounds was normal, suggesting that excessive neutrophil recruitment at the initiation of inflammation is not the primary cause of the "sterile" inflammatory phenotype of chronic granulomatous disease patients. This nox2 zebrafish mutant adds to existing in vivo models for studying reactive oxygen species function in myeloid cells including neutrophils in development and disease.

Acute response to pathogens in the early human placenta at single-cell resolution

The placenta is a selective maternal-fetal barrier that provides nourishment and protection from infections. However, certain pathogens can attach to and even cross the placenta, causing pregnancy complications with potential lifelong impacts on the child's health. Here, we profiled at the single-cell level the placental responses to three pathogens associated with intrauterine complications-Plasmodium falciparum, Listeria monocytogenes, and Toxoplasma gondii. We found that upon exposure to the pathogens, all placental lineages trigger inflammatory responses that may compromise placental function. Additionally, we characterized the responses of fetal macrophages known as Hofbauer cells (HBCs) to each pathogen and propose that they are the probable niche for T.gondii. Finally, we revealed how P.falciparum adapts to the placental microenvironment by modulating protein export into the host erythrocyte and nutrient uptake pathways. Altogether, we have defined the cellular networks and signaling pathways mediating acute placental inflammatory responses that could contribute to pregnancy complications.

An elevated gamma gap as diagnostic tool for acute systemic inflammatory response syndromes in Hospitalized patients

An elevated gamma gap as diagnostic tool for acute systemic inflammatory response syndromes in Hospitalized patients

Naïve Inflammatory Proteome Profiles of Glucocorticoid Responsive Polymyalgia Rheumatica and Rheumatic Arthritis Patients—Links to Triggers and Proteomic Manifestations

Polymyalgia rheumatica (PMR) is an inflammatory disorder of unknown etiology, sharing symptoms with giant cell arthritis (GCA) and rheumatoid arthritis (RA). The pathogenic inflammatory roots are still not well understood, and there is a lack of extensive biomarker studies to explain the disease debut and post-acute phase. This study aimed to deeply analyze the serum proteome and inflammatory response of PMR patients before and after glucocorticoid treatment. We included treatment-naïve PMR patients, collecting samples before and after 3 months of treatment. For comparison, disease-modifying antirheumatic drug (DMARD)-naïve RA patients were included and matched to healthy controls (CTL). The serum proteome was examined using label-free quantitative mass spectrometry, while inflammation levels were assessed using multiplex inflammatory cytokine and cell-free DNA assays. The serum proteomes of the four groups comprised acute phase reactants, coagulation factors, complement proteins, immunoglobulins, and apolipoproteins. Serum amyloid A (SAA1) was significantly reduced by active PMR treatment. Cell-free DNA levels in PMR and RA groups were significantly higher than in healthy controls due to acute inflammation. Complement factors had minimal changes post-treatment. The individual serum proteome in PMR patients showed over 100 abundantly variable proteins, emphasizing the systemic impact of PMR disease debut and the effect of treatment. Interleukin (IL)-6 and interferon-gamma (IFN-γ) were significantly impacted by glucocorticoid treatment. Our study defines the PMR serum proteome during glucocorticoid treatment and highlights the role of SAA1, IL-6, and IFN-γ in treatment responses. An involvement of PGLYRP2 in acute PMR could indicate a response to bacterial infection, highlighting its role in the acute phase of the immune response. The results suggest that PMR may be an aberrant response to a bacterial infection with an exacerbated IL-6 and acute phase inflammatory response and molecular attempts to limit the inflammation.

Structural studies of a serum amyloid A octamer that is primed to scaffold lipid nanodiscs.

Serum amyloid A (SAA) is a highly conserved acute-phase protein that plays roles in activating multiple pro-inflammatory pathways during the acute inflammatory response and is commonly used as a biomarker of inflammation. It has been linked to beneficial roles in tissue repair through improved clearance of lipids and cholesterol from sites of damage. In patients with chronic inflammatory diseases, elevated levels of SAA may contribute to increased severity of the underlying condition. The majority of circulating SAA is bound to lipoproteins, primarily high-density lipoprotein (HDL). Interaction with HDL not only stabilizes SAA but also alters its functional properties, likely through altered accessibility of protein-protein interaction sites on SAA. While high-resolution structures for lipid-free, or apo-, forms of SAA have been reported, their relationship with the HDL-bound form of the protein, and with other possible mechanisms of SAA binding to lipids, has not been established. Here, we have used multiple biophysical techniques, including SAXS, TEM, SEC-MALS, native gel electrophoresis, glutaraldehyde crosslinking, and trypsin digestion to characterize the lipid-free and lipid-bound forms of SAA. The SAXS and TEM data show the presence of soluble octamers of SAA with structural similarity to the ring-like structures reported for lipid-free ApoA-I. These SAA octamers represent a previously uncharacterized structure for lipid-free SAA and are capable of scaffolding lipid nanodiscs with similar morphology to those formed by ApoA-I. The SAA-lipid nanodiscs contain four SAA molecules and have similar exterior dimensions as the lipid-free SAA octamer, suggesting that relatively few conformational rearrangements may be required to allow SAA interactions with lipid-containing particles such as HDL. This study suggests a new model for SAA-lipid interactions and provides new insight into how SAA might stabilize protein-lipid nanodiscs or even replace ApoA-I as a scaffold for HDL particles during inflammation.

The post-septic peripheral myeloid compartment reveals unexpected diversity in myeloid-derived suppressor cells.

Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness. Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering. We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome. The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity.

Deregulation in adult IgA vasculitis skin as the basis for the discovery of novel serum biomarkers

IntroductionImmunoglobulin A vasculitis (IgAV) in adults has a variable disease course, with patients often developing gastrointestinal and renal involvement and thus contributing to higher mortality. Due to understudied molecular mechanisms in IgAV currently used biomarkers for IgAV visceral involvement are largely lacking. Our aim was to search for potential serum biomarkers based on the skin transcriptomic signature.MethodsRNA sequencing analysis was conducted on skin biopsies collected from 6 treatment-naïve patients (3 skin only and 3 renal involvement) and 3 healthy controls (HC) to get insight into deregulated processes at the transcriptomic level. 15 analytes were selected and measured based on the transcriptome analysis (adiponectin, lipopolysaccharide binding protein (LBP), matrix metalloproteinase-1 (MMP1), C-C motif chemokine ligand (CCL) 19, kallikrein-5, CCL3, leptin, C-X-C motif chemokine ligand (CXCL) 5, osteopontin, interleukin (IL)-15, CXCL10, angiopoietin-like 4 (ANGPTL4), SERPIN A12/vaspin, IL-18 and fatty acid-binding protein 4 (FABP4)) in sera of 59 IgAV and 22 HC. Machine learning was used to assess the ability of the analytes to predict IgAV and its organ involvement.ResultsBased on the gene expression levels in the skin, we were able to differentiate between IgAV patients and HC using principal component analysis (PCA) and a sample-to-sample distance matrix. Differential expression analysis revealed 49 differentially expressed genes (DEGs) in all IgAV patient’s vs. HC. Patients with renal involvement had more DEGs than patients with skin involvement only (507 vs. 46 DEGs) as compared to HC, suggesting different skin signatures. Major dysregulated processes in patients with renal involvement were lipid metabolism, acute inflammatory response, and extracellular matrix (ECM)-related processes. 11 of 15 analytes selected based on affected processes in IgAV skin (osteopontin, LBP, ANGPTL4, IL-15, FABP4, CCL19, kallikrein-5, CCL3, leptin, IL-18 and MMP1) were significantly higher (p-adj < 0.05) in IgAV serum as compared to HC. Prediction models utilizing measured analytes showed high potential for predicting adult IgAV.ConclusionSkin transcriptomic data revealed deregulations in lipid metabolism and acute inflammatory response, reflected also in serum analyte measurements. LBP, among others, could serve as a potential biomarker of renal complications, while adiponectin and CXCL10 could indicate gastrointestinal involvement.

The emerging importance of skull-brain interactions in traumatic brain injury.

The recent identification of skull bone marrow as a reactive hematopoietic niche that can contribute to and direct leukocyte trafficking into the meninges and brain has transformed our view of this bone structure from a solid, protective casing to a living, dynamic tissue poised to modulate brain homeostasis and neuroinflammation. This emerging concept may be highly relevant to injuries that directly impact the skull such as in traumatic brain injury (TBI). From mild concussion to severe contusion with skull fracturing, the bone marrow response of this local myeloid cell reservoir has the potential to impact not just the acute inflammatory response in the brain, but also the remodeling of the calvarium itself, influencing its response to future head impacts. If we borrow understanding from recent discoveries in other CNS immunological niches and extend them to this nascent, but growing, subfield of neuroimmunology, it is not unreasonable to consider the hematopoietic compartment in the skull may similarly play an important role in health, aging, and neurodegenerative disease following TBI. This literature review briefly summarizes the traditional role of the skull in TBI and offers some additional insights into skull-brain interactions and their potential role in affecting secondary neuroinflammation and injury outcomes.

Infrared Thermographic Imaging as a Tool to Assess Inflammatory and Ischemic Response With Rubber Ring Tail Docking in Suffolk and Hampshire Lambs (Ovis Aries)

ABSTRACT Tail docking in lambs is associated with an acute inflammatory and ischemic response correlated to pain. The present study sought to quantify these responses by utilizing infrared thermographic imaging (IRT) after tail docking lambs. Images were taken for each lamb before tail docking (T0), within a minute after the band was placed (T1), at 5 minutes (T5), and 15 minutes (T15) respectively and analyzed for pixel intensity in areas on the lamb’s rump, tail base, and two locations below the docking band. The pixel intensity at 2 cm below the docking band did significantly decrease (p < 0.05) over the course of the study at 15 minutes, indicating the presence of ischemia, and a significant decrease in the pixel intensity of the rump and tail base was observed. The closest location to the rubber ring showed the presence of inflammation as an indirect indicator of acute pain . IRT is a valuable tool in the detection of inflammation and ischemic areas and has the potential to be used to quantify and measure the experience of inflammation and pain after tail docking.

The Effects of Ultrasound-Guided Percutaneous Tenotomy on Patients' Pain and Satisfaction Levels.

Tendinopathy is a common pathology with numerous treatment options. Ultrasound-guided percutaneous tenotomy is a newer procedure to treat chronic tendinopathy. It reduces costs and riskscompared to other treatments, such as open surgery and platelet-rich plasma (PRP) injections. The goal of percutaneous tenotomy is to induce an acute inflammatory response that recruits clotting and growth factors, induces bleeding, and transforms scar tissue and diseased tendons into a healing state. A tenotomy was performed in 57 patients for elbow epicondylitis (13), supraspinatus tendonitis (4), gluteal tendinopathy (34), and patellar tendinopathy (5). The survey was created and sent electronically to all 57 patients, yielding 46 respondents. Each patient was surveyed postoperatively to determine their pain levels on a numeric scale from 1 to 10 prior to and following the procedure. We also asked patients about their satisfaction with the procedure, whether they would recommend it to a friend, and how long it took them to recover completely. Forty-six of 57 patients responded to the survey. The average healing time was 58 days, and no patients required further surgery. Pain scores significantly improved after tenotomies in the shoulder, elbow, and hip. About 74% of patients were completely satisfied with the procedure, and 80% received enough benefit to recommend it to a friend. Ultrasonic tenotomy provides significant relief for tendinopathy in the shoulder, elbow, and hip for the majority of patients. The knee pain scores were not significantly reduced, likely due to the small sample size of four patients. Some patients did not experience complete relief and benefited from a PRP injection after tenotomy. Some patients did not benefit, likely due to additional pathology, arthritis, and referred pain. Some limitations to our study include the lack of a control group and each procedure was performed by the same physician, which limits its generalizability. The survey responses were subjective, and the sample size was variable between each body region. More high-quality research is needed to establish the efficacy of tenotomy between different tendons and compare it to other treatment methods.

Propofol and Dexmedetomidine Ameliorate Endotoxemia-Associated Encephalopathy via Inhibiting Ferroptosis.

Sepsis is recognized as a multiorgan and systemic damage caused by dysregulated host response to infection. Its acute systemic inflammatory response highly resembles that of lipopolysaccharide (LPS)-induced endotoxemia. Propofol and dexmedetomidine are two commonly used sedatives for mechanical ventilation in critically ill patients and have been reported to alleviate cognitive impairment in many diseases. In this study, we aimed to explore and compare the effects of propofol and dexmedetomidine on the encephalopathy induced by endotoxemia and to investigate whether ferroptosis is involved, finally providing experimental evidence for multi-drug combination in septic sedation. A total of 218 C57BL/6J male mice (20-25 g, 6-8 weeks) were used. Morris water maze (MWM) tests were performed to evaluate whether propofol and dexmedetomidine attenuated LPS-induced cognitive deficits. Brain injury was evaluated using Nissl and Fluoro-Jade C (FJC) staining. Neuroinflammation was assessed by dihydroethidium (DHE) and DCFH-DA staining and by measuring the levels of three cytokines. The number of Iba1+ and GFAP+ cells was used to detect the activation of microglia and astrocytes. To explore the involvement of ferroptosis, the levels of ptgs2 and chac1; the content of iron, malondialdehyde (MDA), and glutathione (GSH); and the expression of ferroptosis-related proteins were investigated. The single use of propofol and dexmedetomidine mitigated LPS-induced cognitive impairment, while the combination showed poor performance. In alleviating endotoxemic neural loss and degeneration, the united sedative group exhibited the most potent capability. Both propofol and dexmedetomidine inhibited neuroinflammation, while propofol's effect was slightly weaker. All sedative groups reduced the neural apoptosis, inhibited the activation of microglia and astrocytes, and relieved neurologic ferroptosis. The combined group was most prominent in combating genetic and biochemical alterations of ferroptosis. Fpn1 may be at the core of endotoxemia-related ferroptosis activation.

Impaired autophagy following ex vivo cooling of simulated hypothermic temperatures in peripheral blood mononuclear cells from young and older adults

Hypothermia is a critical consequence of extreme cold exposure that increases the risk of cold-related injury and death in humans. While the initiation of cytoprotective mechanisms including the process of autophagy and the heat shock response (HSR) is crucial to cellular survival during periods of stress, age-related decrements in these systems may underlie cold-induced cellular vulnerability in older adults. Moreover, whether potential sex-related differences in autophagic regulation influence the human cold stress response remain unknown. We evaluated the effect of age and sex on mechanisms of cytoprotection (autophagy and the HSR) and cellular stress (apoptotic signaling and the acute inflammatory response) during ex vivo hypothermic cooling. Venous blood samples from 20 healthy young (10 females; mean [SD]: 22 [2] years) and 20 healthy older (10 females; 66 [5] years) adults were either isolated immediately (baseline) for peripheral blood mononuclear cells (PBMCs) or exposed to water bath temperatures maintained at 37, 35, 33, 31, or 4 °C for 90 min before PBMC isolation. Proteins associated with autophagy, apoptosis, the HSR, and inflammation were analyzed via Western blotting. Indicators of autophagic initiation and signaling (LC3, ULK1, and beclin-2) and the HSR (HSP90 and HSP70) increased when exposed to hypothermic temperatures in young and older adults (all p ≤ 0.007). Sex-related differences were only observed with autophagic initiation (ULK1; p = 0.015). However, despite increases in autophagic initiators ULK1 and beclin-2 (all p < 0.001), this was paralleled by autophagic dysfunction (increased p62) in all groups (all p < 0.001). Further, apoptotic (cleaved-caspase-3) and inflammatory (IL-6 and TNF-α) signaling increased in all groups (all p < 0.001). We demonstrated that exposure to hypothermic conditions is associated with autophagic dysfunction, irrespective of age or sex, although there may exist innate sex-related differences in cytoprotection in response to cold exposure as evidenced through altered autophagic initiation.

The clinical relevance of heme detoxification by the macrophage heme oxygenase system.

Heme degradation by the heme oxygenase (HMOX) family of enzymes is critical for maintaining homeostasis and limiting heme-induced tissue damage. Macrophages express HMOX1 and 2 and are critical sites of heme degradation in healthy and diseased states. Here we review the functions of the macrophage heme oxygenase system and its clinical relevance in discrete groups of pathologies where heme has been demonstrated to play a driving role. HMOX1 function in macrophages is essential for limiting oxidative tissue damage in both acute and chronic hemolytic disorders. By degrading pro-inflammatory heme and releasing anti-inflammatory molecules such as carbon monoxide, HMOX1 fine-tunes the acute inflammatory response with consequences for disorders of hyperinflammation such as sepsis. We then discuss divergent beneficial and pathological roles for HMOX1 in disorders such as atherosclerosis and metabolic syndrome, where activation of the HMOX system sits at the crossroads of chronic low-grade inflammation and oxidative stress. Finally, we highlight the emerging role for HMOX1 in regulating macrophage cell death via the iron- and oxidation-dependent form of cell death, ferroptosis. In summary, the importance of heme clearance by macrophages is an active area of investigation with relevance for therapeutic intervention in a diverse array of human diseases.

Abstract 5392: Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis

Abstract Introduction: The Matrix metalloproteinases (MMPs) family are a collection of zinc and calcium-dependent endopeptidases. MMP-9 is instrumental in modifying the extracellular matrix (ECM) and generating bioactive molecules which influence a range of physiological functions. Cellular TNF-a, IL-8, VEGF, and FGF-2 can stimulate the production of MMP-9 in endothelial cells (EC), a process that controls healthy and disease-related angiogenesis. MMP-9 facilitates tumor metastasis and also is involved with wound healing. MMP-9 is generated by white blood cells, ECs, and several other cells. There’s a significant increase in plasma MMP-9 levels in patients suffering from colorectal cancer (CRC). The aim of this study was to assess plasma MMP-9 levels before and during the first month following MICR for CRC. Method: CRC patients enrolled in an IRB approved data/plasma bank who had undergone MICR for whom plasma samples were available from the following time points were deemed eligible for this study; preoperatively (PreOp) and on Postoperative Day (POD) 1, POD 3 and at least 1 later postop timepoint (POD 7-41). The demographic, clinical operative and pathology reports were reviewed. Blood specimens were collected, processed, and frozen. MMP-9 levels were measured in duplicate via ELISA. The Wilcoxon paired t-test was used for analysis and significance set at p&amp;lt;0.05. Results: 86 CRC MICR patients (69% colon,31% rectal; laparoscopic 69%, hand-assisted 31%; 47 males, 39 females; mean age 63.9± 14.3 years), met the entry criteria. The mean hospital stay was 6.5±3.0 days. The cancer stages were distributed as follows: stage I; (n=26), II; (n=25), III; (n=30), and IV; (n=4). Compared to the mean preop MMP-9 plasma levels (155.3±132.1,n=86; ng/ml), there was a significant increase on postoperative day (POD) 1 (292.6± 213.0; n=86, p&amp;lt;0.001), POD3 (232.1±205.9,n=78, p&amp;lt;0.01), POD7-13 (217.8±171.2, n=63, p&amp;lt;0.01), POD14-20 (228.7± 109.1,n=24,p=03). No difference was found at the POD 21-41 time points vs preop results. Non-significant increases in plasma MMP-9 levels were noted in the hand-assisted surgery group during the POD 3-27 period compared to the laparoscopic group. Conclusion: Postop plasma MMP-9 levels were significantly elevated (20% - 88%) vs preop levels for 3 weeks after MICR for CRC. The increased MMP-9 levels in the early postoperative period may be due to the acute inflammatory response, including increases in IL-1 and TNF mediated activation of neutrophils and macrophages. However, the spike during weeks 2-3 may be related to wound healing given MMP-9’s role in angiogenesis. This persistent elevation for 3 weeks after surgery may also enhance angiogenesis in residual cancer deposits postoperatively. Further studies are needed. Citation Format: Chandana S. K. Herath Mudiyanselage, Anuj R. Sharma, Neil Mitra, Aashutosh Sah, Xiaohong Yan, Pablo Palacios, Vesna Cekic, Richard L. Whelan. Plasma levels of Matrix metalloproteinases 9, an angiogenic promoting protein, are persistently elevated three weeks after minimally invasive colorectal resection (MICR) for cancer which may support residual tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5392.

Silicone implant surface microtopography modulates inflammation and tissue repair in capsular fibrosis.

Excessive fibrous capsule formation around silicone mammary implants (SMI) involves immune reactions to silicone. Capsular fibrosis, a common SMI complication linked to host responses, worsens with specific implant topographies. Our study with 10 patients investigated intra- and inter-individually, reduced surface roughness effects on disease progression, wound responses, chronic inflammation, and capsular composition. The results illuminate the significant impact of surface roughness on acute inflammatory responses, fibrinogen accumulation, and the subsequent fibrotic cascade. The reduction of surface roughness to an average roughness of 4 μm emerges as a promising approach for mitigating detrimental immune reactions, promoting healthy wound healing, and curbing excessive fibrosis. The identified proteins adhering to rougher surfaces shed light on potential mediators of pro-inflammatory and pro-fibrotic processes, further emphasizing the need for meticulous consideration of surface design. The composition of the implant capsule and the discovery of intracapsular HSP60 expression highlight the intricate web of stress responses and immune activation that can impact long-term tissue outcomes.