Complement MASP-1 Modifies Endothelial Wound Healing.

Endothelial wound-healing processes are fundamental for the maintenance and restoration of the circulatory system and are greatly affected by the factors present in the blood. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) induces the proinflammatory activation of endothelial cells and is able to cooperate with other proinflammatory activators. Our aim was to investigate the combined effect of mechanical wounding and MASP-1 on endothelial cells. Transcriptomic analysis showed that MASP-1 alters the expression of wound-healing-related and angiogenesis-related genes. Both wounding and MASP-1 induced Ca2+ mobilization when applied individually. However, MASP-1-induced Ca2+ mobilization was inhibited when the treatment was preceded by wounding. Mechanical wounding promoted CREB phosphorylation, and the presence of MASP-1 enhanced this effect. Wounding induced ICAM-1 and VCAM-1 expression on endothelial cells, and MASP-1 pretreatment further increased VCAM-1 levels. MASP-1 played a role in the subsequent stages of angiogenesis, facilitating the breakdown of the endothelial capillary network on Matrigel®. Our findings extend our general understanding of endothelial wound healing and highlight the importance of complement MASP-1 activation in wound-healing processes.

Absorption and pharmacokinetics of bupivacaine after bilateral topical administration in tonsillar fossae for posttonsillectomy pain relief.

No previous studies have investigated the systemic absorption of bupivacaine when used topically for posttonsillectomy pain. The present study was undertaken to investigate the pharmacokinetics of bupivacaine after administration by a swab in the tonsillar fossae over 4 min after tonsillectomy. Eleven adult patients undergoing elective tonsillectomy were recruited. After removal of both tonsils, each of the two tonsillar fossae was covered with a swab moistened with 2 mL of bupivacaine 5 mg/mL, that is, a total of 20 mg bupivacaine. Blood samples were drawn after 0, 5, 10, 20, 30, 45, and 60 min. Bupivacaine was analyzed with an ultra-high-performance liquid chromatography-tandem mass spectrometry method. The highest single measured bupivacaine serum concentration was 23.2 ng/mL and took place 10 min after drug administration. Mean (±SD) Cmax was 11.4 ± 6.0 ng/mL and mean tmax was 11.3 ± 4.7 min. Mean t1/2 was 31.6 ± 9.3 min. As the toxic concentration threshold has been reported to be in the interval 1500-4500 ng/mL, the concentrations measured were well below 2% of the lowest cited toxic threshold. In conclusion, this study shows that applying 4 mL of bupivacaine 5 mg/mL by a swab in the tonsillar fossae posttonsillectomy yields very low plasma concentrations, suggesting its safe application without any risk of systemic toxic effects.

The Lectin Pathway of the Complement System-Activation, Regulation, Disease Connections and Interplay with Other (Proteolytic) Systems.

The complement system is the other major proteolytic cascade in the blood of vertebrates besides the coagulation-fibrinolytic system. Among the three main activation routes of complement, the lectin pathway (LP) has been discovered the latest, and it is still the subject of intense research. Mannose-binding lectin (MBL), other collectins, and ficolins are collectively termed as the pattern recognition molecules (PRMs) of the LP, and they are responsible for targeting LP activation to molecular patterns, e.g., on bacteria. MBL-associated serine proteases (MASPs) are the effectors, while MBL-associated proteins (MAps) have regulatory functions. Two serine protease components, MASP-1 and MASP-2, trigger the LP activation, while the third component, MASP-3, is involved in the function of the alternative pathway (AP) of complement. Besides their functions within the complement system, certain LP components have secondary ("moonlighting") functions, e.g., in embryonic development. They also contribute to blood coagulation, and some might have tumor suppressing roles. Uncontrolled complement activation can contribute to the progression of many diseases (e.g., stroke, kidney diseases, thrombotic complications, and COVID-19). In most cases, the lectin pathway has also been implicated. In this review, we summarize the history of the lectin pathway, introduce their components, describe its activation and regulation, its roles within the complement cascade, its connections to blood coagulation, and its direct cellular effects. Special emphasis is placed on disease connections and the non-canonical functions of LP components.

Current Approaches to Wound Repair in Burns: How far Have we Come From Cover to Close? A Narrative Review.

Burn injuries are a significant global health concern, with more than 11 million people requiring medical intervention each year and approximately 180,000 deaths annually. Despite progress in health and social care, burn injuries continue to result in socioeconomic burdens for victims and their families. The management of severe burn injuries involves preventing and treating burn shock and promoting skin repair through a two-step procedure of covering and closing the wound. Currently, split-thickness/full-thickness skin autografts are the gold standard for permanent skin substitution. However, deep burns treated with split-thickness skin autografts may contract, leading to functional and appearance issues. Conversely, defects treated with full-thickness skin autografts often result in more satisfactory function and appearance. The development of tissue-engineered dermal templates has further expanded the scope of wound repair, providing scar reductive and regenerative properties that have extended their use to reconstructive surgical interventions. Although their interactions with the wound microenvironment are not fully understood, these templates have shown potential in local infection control. This narrative review discusses the current state of wound repair in burn injuries, focusing on the progress made from wound cover to wound closure and local infection control. Advancements in technology and therapies hold promise for improving the outcomes for burn injury patients. Understanding the underlying mechanisms of wound repair and tissue regeneration may provide new insights for developing more effective treatments in the future.

Unravelling heterogeneous effects of cancer­associated fibroblasts on poor prognosis markers in breast cancer EM­G3 cell line: In vitro­targeted treatment (anti­IL-6, anti­VEGF-A, anti­MFGE8) based on transcriptomic profiling.

Breast cancer is the most frequently diagnosed cancer in women worldwide. Although dramatically increased survival rates of early diagnosed cases have been observed, late diagnosed patients and metastatic cancer may still be considered fatal. The present study's main focus was on cancer­associated fibroblasts (CAFs) which is an active component of the tumor microenvironment (TME) regulating the breast cancer ecosystem. Transcriptomic profiling and analysis of CAFs isolated from breast cancer skin metastasis, cutaneous basal cell carcinoma, and squamous cell carcinoma unravelled major gene candidates such as IL6, VEGFA and MFGE8 that induced co­expression of keratins­8/­14 in the EM­G3 cell line derived from infiltrating ductal breast carcinoma. Western blot analysis of selected keratins (keratin­8, ­14, ­18, ­19) and epithelial­mesenchymal transition­associated markers (SLUG, SNAIL, ZEB1, E­/N­cadherin, vimentin) revealed specific responses pointing to certain heterogeneity of the studied CAF populations. Experimental in vitro treatment using neutralizing antibodies against IL-6, VEGF­A and MFGE8 attenuated the modulatory effect of CAFs on EM­G3 cells. The present study provided novel data in characterizing and understanding the interactions between CAFs and EM­G3 cells in vitro. CAFs of different origins support the pro­inflammatory microenvironment and influence the biology of breast cancer cells. This observation potentially holds significant interest for the development of novel, clinically relevant approaches targeting the TME in breast cancer. Furthermore, its implications extend beyond breast cancer and have the potential to impact a wide range of other cancer types.

Heterogeneous response to TGF-ß1/3 isoforms in fibroblasts of different origins: implications for wound healing and tumorigenesis.

Identification of therapeutic targets for treating fibrotic diseases and cancer remains challenging. Our study aimed to investigate the effects of TGF-ß1 and TGF-ß3 on myofibroblast differentiation and extracellular matrix deposition in different types of fibroblasts, including normal/dermal, cancer-associated, and scar-derived fibroblasts. When comparing the phenotype and signaling pathways activation we observed extreme heterogeneity of studied markers across different fibroblast populations, even within those isolated from the same tissue. Specifically, the presence of myofibroblast and deposition of extracellular matrix were dependent on the origin of the fibroblasts and the type of treatment they received (TGF-ß1 vs. TGF-ß3). In parallel, we detected activation of canonical signaling (pSMAD2/3) across all studied fibroblasts, albeit to various extents. Treatment with TGF-ß1 and TGF-ß3 resulted in the activation of canonical and several non-canonical pathways, including AKT, ERK, and ROCK. Among studied cells, cancer-associated fibroblasts displayed the most heterogenic response to TGF-ß1/3 treatments. In general, TGF-ß1 demonstrated a more potent activation of signaling pathways compared to TGF-ß3, whereas TGF-ß3 exhibited rather an inhibitory effect in keloid- and hypertrophic scar-derived fibroblasts suggesting its clinical potential for scar treatment. In summary, our study has implications for comprehending the role of TGF-ß signaling in fibroblast biology, fibrotic diseases, and cancer. Future research should focus on unraveling the mechanisms beyond differential fibroblast responses to TGF-ß isomers considering inherent fibroblast heterogeneity.

Complement inhibition can decrease the haemostatic response in a microvascular bleeding model at multiple levels.

Background: Haemostasis is a crucial process by which the body stops bleeding. It is achieved by the formation of a platelet plug, which is strengthened by formation of a fibrin mesh mediated by the coagulation cascade. In proinflammatory and prothrombotic conditions, multiple interactions of the complement system and the coagulation cascade are known to aggravate thromboinflammatory processes and increase the risk of arterial and venous thrombosis. Whether those interactions also play a relevant role during the physiological process of haemostasis is not yet completely understood. The aim of this study was to investigate the potential role of complement components and activation during the haemostatic response to mechanical vessel injury. Methods: We used a microvascular bleeding model that simulates a blood vessel, featuring human endothelial cells, perfusion with fresh human whole blood, and an inducible mechanical injury to the vessel. We studied the effects of complement inhibitors against components of the lectin (MASP-1, MASP-2), classical (C1s), alternative (FD) and common pathways (C3, C5), as well as a novel triple fusion inhibitor of all three complement pathways (TriFu). Effects on clot formation were analysed by recording of fibrin deposition and the platelet activation marker CD62P at the injury site in real time using a confocal microscope. Results: With the inhibitors targeting MASP-2 or C1s, no significant reduction of fibrin formation was observed, while platelet activation was significantly reduced in the presence of the FD inhibitor. Both common pathway inhibitors targeting C3 or C5, respectively, were associated with a substantial reduction of fibrin formation, and platelet activation was also reduced in the presence of the C3 inhibitor. Triple inhibition of all three activation pathways at the C3-convertase level by TriFu reduced both fibrin formation and platelet activation. When several complement inhibitors were directly compared in two individual donors, TriFu and the inhibitors of MASP-1 and C3 had the strongest effects on clot formation. Conclusion: The observed impact of complement inhibition on reducing fibrin clot formation and platelet activation suggests a role of the complement system in haemostasis, with modulators of complement initiation, amplification or effector functions showing distinct profiles. While the interactions between complement and coagulation might have evolved to support haemostasis and protect against bleeding in case of vessel injury, they can turn harmful in pathological conditions when aggravating thromboinflammation and promoting thrombosis.

De Novo Cost-Effectiveness Model Framework for Nonalcoholic Steatohepatitis-Modeling Approach and Validation.

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease associated with hepatic morbidity and mortality and extra-hepatic comorbidities. Published NASH cost-effectiveness models (CEMs) are heterogeneous and consistently omit comorbid conditions that frequently co-exist alongside NASH. We aimed to develop a de novo CEM framework that incorporates extra-hepatic disease states and outcomes alongside hepatic components to enable future estimation of the cost-effectiveness of NASH interventions. METHODS: Patient-level simulation and cohort-level Markov models were implemented in the same framework. Model inputs included fibrosis progression; late-stage liver disease outcomes; comorbidity outcomes for cardiovascular disease, type 2 diabetes, and obesity; mortality; health-related quality of life; and direct medical costs. The prototype analysis assessed the cost-effectiveness of obeticholic acid versus standard of care from a US payer perspective over a lifetime horizon with costs and effects discounted at 3% per annum. However, the CEM was designed for easy adaptation to other countries, time horizons, and other considerations. Efficacy and adverse event parameters were obtained from the 18-month interim analysis of the REGENERATE trial. Outputs include total and incremental costs, total life years, and quality-adjusted life years. RESULTS: In this model, total costs, total life years, and quality-adjusted life years were all higher with obeticholic acid compared with standard of care. Cross-validation of this model with the 2016 and 2020 Institute for Clinical and Economic Review models revealed marked differences, mainly driven by mortality inputs, transition probability estimates, and incorporation of the effect of treatment and comorbidities. CONCLUSION: This is the first CEM in NASH to incorporate the clinical consequences of several comorbidities. The flexible yet standardized framework permits estimation of the cost-effectiveness of NASH interventions in a variety of settings. The model currently includes several assumptions and will be further developed as more relevant data become available.

Quantification of the zymogenicity and the substrate-induced activity enhancement of complement factor D.

Complement factor D (FD) is a serine protease present predominantly in the active form in circulation. It is synthesized as a zymogen (pro-FD), but it is continuously converted to FD by circulating active MASP-3. FD is a unique, self-inhibited protease. It has an extremely low activity toward free factor B (FB), while it is a highly efficient enzyme toward FB complexed with C3b (C3bB). The structural basis of this phenomenon is known; however, the rate enhancement was not yet quantified. It has also been unknown whether pro-FD has any enzymatic activity. In this study, we aimed to measure the activity of human FD and pro-FD toward uncomplexed FB and C3bB in order to quantitatively characterize the substrate-induced activity enhancement and zymogenicity of FD. Pro-FD was stabilized in the proenzyme form by replacing Arg25 (precursor numbering) with Gln (pro-FD-R/Q). Activated MASP-1 and MASP-3 catalytic fragments were also included in the study for comparison. We found that the complex formation with C3b enhanced the cleavage rate of FB by FD approximately 20 million-fold. C3bB was also a better substrate for MASP-1, approximately 100-fold, than free FB, showing that binding to C3b renders the scissile Arg-Lys bond in FB to become more accessible for proteolysis. Though easily measurable, this cleavage by MASP-1 is not relevant physiologically. Our approach provides quantitative data for the two-step mechanism characterized by the enhanced susceptibility of FB for cleavage upon complex formation with C3b and the substrate-induced activity enhancement of FD upon its binding to C3bB. Earlier MASP-3 was also implicated as a potential FB activator; however, MASP-3 does not cleave C3bB (or FB) at an appreciable rate. Finally, pro-FD cleaves C3bB at a rate that could be physiologically significant. The zymogenicity of FD is approximately 800, i.e., the cleavage rate of C3bB by pro-FD-R/Q was found to be approximately 800-fold lower than that by FD. Moreover, pro-FD-R/Q at approximately 50-fold of the physiological FD concentration could restore half-maximal AP activity of FD-depleted human serum on zymosan. The observed zymogen activity of pro-FD might be relevant in MASP-3 deficiency cases or during therapeutic MASP-3 inhibition.

Cooperation of Complement MASP-1 with Other Proinflammatory Factors to Enhance the Activation of Endothelial Cells.

Endothelial cells play an important role in sensing danger signals and regulating inflammation. Several factors are capable of inducing a proinflammatory response (e.g., LPS, histamine, IFNγ, and bradykinin), and these factors act simultaneously during the natural course of the inflammatory reaction. We have previously shown that the complement protein mannan-binding lectin-associated serine protease-1 (MASP-1) also induces a proinflammatory activation of the endothelial cells. Our aim was to investigate the possible cooperation between MASP-1 and other proinflammatory mediators when they are present in low doses. We used HUVECs and measured Ca2+ mobilization, IL-8, E-selectin, VCAM-1 expression, endothelial permeability, and mRNA levels of specific receptors. LPS pretreatment increased the expression of PAR2, a MASP-1 receptor, and furthermore, MASP-1 and LPS enhanced each other's effects in regulating IL-8, E-selectin, Ca2+ mobilization, and changes in permeability in a variety of ways. Cotreatment of MASP-1 and IFNγ increased the IL-8 expression of HUVECs. MASP-1 induced bradykinin and histamine receptor expression, and consequently, increased Ca2+ mobilization was found. Pretreatment with IFNγ enhanced MASP-1-induced Ca2+ mobilization. Our findings highlight that well-known proinflammatory mediators and MASP-1, even at low effective doses, can strongly synergize to enhance the inflammatory response of endothelial cells.

[Replantation of a traumatically amputated tongue]. / Gjenfesting av traumatisk amputert tungedel.

BACKGROUND: We describe a successful composite graft of a 4.5 cm piece of an amputated tongue, performed without microvascular technique. CASE PRESENTATION: A young adult fell off his bicycle, resulting in a traumatic amputation of part of his tongue, approximately 4.5 cm from the tip. Microvascular expertise was not available but the otolaryngologist on duty was advised to proceed with non-vascular composite graft surgery. Postoperatively the tongue was ischaemic. Marginal blood flow was assessed with ultrasound and pulse oximetry, and surgical reamputation was deferred. Several treatments were initiated to facilitate tongue revitalisation and circulation, including hyperbaric oxygen. Five months postoperatively, the patient was able to protrude his tongue to his teeth, had no problems swallowing, had improved pronunciation, and had regained some sensibility and taste. INTERPRETATION: We strongly recommend microvascular surgery reimplantation when such competency is available, but in locations without this option we have demonstrated that a non-vascular approach with a composite graft can be attempted as a last resort.

Adenosine vs. regadenoson for stress induction in dynamic CT perfusion scan of the myocardium: A single­center retrospective comparison.

Cardiac computed tomography (CT) angiography offers several approaches to determine the hemodynamic severity of coronary artery obstruction. Dynamic myocardial perfusion is based on serial CT imaging of contrast flow into the myocardium and calculation of absolute myocardial perfusion rates. East-Slovak Institute of Cardiovascular Diseases has been the first center in Slovakia intensively using this modern technique to increase the quality level of non-invasive diagnosis of symptomatic patients with a low to moderate pre-test probability of ischemic heart disease. The present study included 46 patients with a mean age of 64 years (33 men and 13 women). Prior to the CT study, myocardial stress was pharmacologically (adenosine, n=15 and regadenoson, n=31) induced by vasodilatation of the coronary arteries. Hemodynamic parameters (myocardial blood flow) were evaluated in all patients following successful CT perfusion without complications, allergic reaction or other severe side effects. The present study revealed that regadenoson increased the heart rate following infusion with a higher magnitude compared with adenosine. Moreover, the effect of regadenoson was independent of patient's body mass index and was associated with a lower incidence of mild adverse effects. The present study provided further clinical evidence for a more wider use of regadenoson over adenosine.

The sweet side of wound healing: galectins as promising therapeutic targets in hemostasis, inflammation, proliferation, and maturation/remodeling.

INTRODUCTION: Understanding the molecular and cellular processes involved in skin wound healing may pave the way for the development of innovative approaches to transforming the identified natural effectors into therapeutic tools. Based on the extensive involvement of the ga(lactoside-binding)lectin family in (patho)physiological processes, it has been well established that galectins are involved in a wide range of cell-cell and cell-matrix interactions. AREAS COVERED: In the present paper, we provide an overview of the biological role of galectins in repair and regeneration, focusing on four main phases (hemostasis, inflammation, proliferation, and maturation/remodeling) of skin repair using basic wound models (open excision vs. sutured incision). EXPERT OPINION: The reported data make a strong case for directing further efforts to treat excisional and incisional wounds differently. Functions of galectins essentially result from their modular presentation. In fact, Gal-1 seems to play a role in the early phases of healing (anti-inflammatory) and wound contraction, Gal-3 accelerates re-epithelization and increases tensile strength (scar inductor). Galectins have also become subject of redesigning by engineering to optimize the activity. Clinically relevant, these new tools derived from the carbohydrate recognition domain platform may also prove helpful for other purposes, such as potent antibacterial agglutinins and opsonins.

Public health impact of UK COVID-19 booster vaccination programs during Omicron predominance.

BACKGROUND: We aimed to estimate the public health impact of booster vaccination against COVID-19 in the UK during an Omicron-predominant period. RESEARCH DESIGN AND METHODS: A dynamic transmission model was developed to compare public health outcomes for actual and alternative UK booster vaccination programs. Input sources were publicly available data and targeted literature reviews. Base case analyses estimated outcomes from the UK's Autumn-Winter 2021-2022 booster program during January-March 2022, an Omicron-predominant period. Scenario analyses projected outcomes from Spring and in Autumn 2022 booster programs over an extended time horizon from April 2022-April 2023, assuming continued Omicron predominance, and explored hypothetical program alternatives with modified eligibility criteria and/or increased uptake. RESULTS: Estimates predicted that the Autumn-Winter 2021-2022 booster program averted approximately 12.8 million cases, 1.1 million hospitalizations, and 290,000 deaths. Scenario analyses suggested that Spring and Autumn 2022 programs would avert approximately 6.2 million cases, 716,000 hospitalizations, and 125,000 deaths; alternatives extending eligibility or targeting risk groups would improve these benefits, and increasing uptake would further strengthen impact. CONCLUSIONS: Boosters were estimated to provide substantial benefit to UK public health during Omicron predominance. Benefits of booster vaccination could be maximized by extending eligibility and increasing uptake.

Public health impact of booster vaccination against COVID-19 in the UK during Delta variant dominance in autumn 2021.

AIM: To evaluate the public health impact of the UK COVID-19 booster vaccination program in autumn 2021, during a period of SARS-CoV-2 Delta variant predominance. MATERIALS AND METHODS: A compartmental Susceptible-Exposed-Infectious-Recovered model was used to compare age-stratified health outcomes for adult booster vaccination versus no booster vaccination in the UK over a time horizon of September-December 2021, when boosters were introduced in the UK and the SARS-CoV-2 Delta variant was predominant. Model input data were sourced from targeted literature reviews and publicly available data. Outcomes were predicted COVID-19 cases, hospitalizations, post-acute sequelae of COVID-19 (PASC) cases, deaths, and productivity losses averted, and predicted healthcare resources saved. Scenario analyses varied booster coverage, virus infectivity and severity, and time horizon parameters. RESULTS: Booster vaccination was estimated to have averted approximately 547,000 COVID-19 cases, 36,000 hospitalizations, 147,000 PASC cases, and 4,200 deaths in the UK between September and December 2021. It saved over 316,000 hospital bed-days and prevented the loss of approximately 16.5 million paid and unpaid patient work days. In a scenario of accelerated uptake, the booster rollout would have averted approximately 3,400 additional deaths and 25,500 additional hospitalizations versus the base case. A scenario analysis assuming four-fold greater virus infectivity and lower severity estimated that booster vaccination would have averted over 105,000 deaths and over 41,000 hospitalizations versus the base case. A scenario analysis assuming pediatric primary series vaccination prior to adult booster vaccination estimated that expanding vaccination to children aged ≥5 years would have averted approximately 51,000 additional hospitalizations and 5,400 additional deaths relative to adult booster vaccination only. LIMITATIONS: The model did not include the wider economic burden of COVID-19, hospital capacity constraints, booster implementation costs, or non-pharmaceutical interventions. CONCLUSIONS: Booster vaccination during Delta variant predominance reduced the health burden of SARS-CoV-2 in the UK, releasing substantial NHS capacity.

Complement lectin pathway components MBL and MASP-1 promote haemostasis upon vessel injury in a microvascular bleeding model.

Background: Complement lectin pathway components, in particular mannan-binding lectin (MBL) and MBL-associated serine proteases (MASPs) have been shown to interact with coagulation factors and contribute to clot formation. Here we investigated the role of MBL and MASP-1 in the haemostatic response following mechanical vessel injury in a human microfluidic bleeding model. Methods: We studied haemostasis in a microvascular bleeding model in the presence of human endothelial cells and human whole blood under flow conditions. We monitored incorporation of proteins into the clot with fluorescently labelled antibodies and studied their effects on clot formation, platelet activation, and bleeding time with specific inhibitors. Platelet activation was also studied by flow cytometry. Results: Upon vessel injury, MBL accumulated at the injury site in a well-defined wall-like structure. MBL showed partial colocalisation with fibrin, and strong colocalisation with von Willebrand factor and (activated) platelets. Flow cytometry ruled out direct binding of MBL to platelets, but confirmed a PAR4- and thrombin-dependent platelet-activating function of MASP-1. Inhibiting MBL during haemostasis reduced platelet activation, while inhibiting MASP-1 reduced platelet activation, fibrin deposition and prolonged bleeding time. Conclusion: We show in a microvascular human bleeding model that MBL and MASP-1 have important roles in the haemostatic response triggered by mechanical vessel injury: MBL recognises the injury site, while MASP-1 increases fibrin formation, platelet activation and shortens bleeding time. While the complement lectin pathway may be harmful in the context of pathological thrombosis, it appears to be beneficial during the physiological coagulation response by supporting the crucial haemostatic system.

Proprotein Convertases and the Complement System.

Proteins destined for secretion - after removal of the signal sequence - often undergo further proteolytic processing by proprotein convertases (PCs). Prohormones are typically processed in the regulated secretory pathway, while most plasma proteins travel though the constitutive pathway. The complement system is a major proteolytic cascade in the blood, serving as a first line of defense against microbes and also contributing to the immune homeostasis. Several complement components, namely C3, C4, C5 and factor I (FI), are multi-chain proteins that are apparently processed by PCs intracellularly. Cleavage occurs at consecutive basic residues and probably also involves the action of carboxypeptidases. The most likely candidate for the intracellular processing of complement proteins is furin, however, because of the overlapping specificities of basic amino acid residue-specific proprotein convertases, other PCs might be involved. To our surprise, we have recently discovered that processing of another complement protein, mannan-binding lectin-associated serine protease-3 (MASP-3) occurs in the blood by PCSK6 (PACE4). A similar mechanism had been described for the membrane protease corin, which is also activated extracellularly by PCSK6. In this review we intend to point out that the proper functioning of the complement system intimately depends on the action of proprotein convertases. In addition to the non-enzymatic components (C3, C4, C5), two constitutively active complement proteases are directly activated by PCs either intracellularly (FI), or extracellularly (MASP-3), moreover indirectly, through the constitutive activation of pro-factor D by MASP-3, the activity of the alternative pathway also depends on a PC present in the blood.

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

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