• Acute respiratory distress syndrome
• Biomarker
• Inflammation
• Lung injury
• Prognosis
• Specificity

• Acute respiratory distress syndrome
• Atypical hemolytic–uremic syndrome
• Complement activation
• Complement system proteins
• Critical illness
• Myasthenia gravis
• Sepsis
• Severe COVID-19

• Humans
• Complement Activation/drug effects
• Complement Activation/immunology
• COVID-19/immunology
• COVID-19/physiopathology
• COVID-19/complications
• COVID-19/therapy
• Atypical Hemolytic Uremic Syndrome/physiopathology
• Atypical Hemolytic Uremic Syndrome/immunology
• Atypical Hemolytic Uremic Syndrome/therapy
• Complement Inactivating Agents/therapeutic use
• Myasthenia Gravis/physiopathology
• Myasthenia Gravis/immunology
• Myasthenia Gravis/therapy
• SARS-CoV-2/immunology
• Complement System Proteins/immunology
• Antibodies, Monoclonal, Humanized

• Acute lung injury
• Baicalin
• Complement alternative pathway
• Inflammation
• Microvascular endothelial cells
• NF-κB

• Animals
• Flavonoids/pharmacology
• Mice
• NF-kappa B/metabolism
• Acute Lung Injury/drug therapy
• Humans
• Disease Models, Animal
• Male
• Complement Pathway, Alternative/drug effects
• Pneumonia/drug therapy
• Mice, Inbred C57BL
• Lung/drug effects
• Elapid Venoms/pharmacology

• QZYY-2023-153 Scientific and Technological Research Projects on Chinese Medicine and Ethnomedicine of the Administration of Traditional Chinese Medicine of Guizhou Province

• Animal models
• Complement
• Influenza
• MAC
• Respiratory syncytial virus
• SARS-CoV-2

• Animals
• Humans
• COVID-19
• Pandemics
• Complement System Proteins
• Influenza, Human
• Respiratory Syncytial Virus, Human

• P51 OD011104 NIH HHS
• R01 DK129881 NIDDK NIH HHS
• R01 HL165265 NHLBI NIH HHS
• 129881 NIDDK NIH HHS
• American Heart Association
• National Institute of Diabetes and Digestive and Kidney Diseases
• NIHBI
• NIHOD

• Complement
• Complement-related therapeutics
• Lung disease

• Humans
• Lung Injury
• Adaptive Immunity
• Asthma
• Transcription Factors

• ARDS
• LPS
• complement therapeutics
• lectin pathway
• lung injury

• Animals
• Humans
• Mice
• Lectins
• Lipopolysaccharides/toxicity
• Lung Injury
• Complement Activation
• Respiratory Distress Syndrome/chemically induced
• Complement C3b/metabolism

• Humans
• COVID-19
• SARS-CoV-2
• COVID-19 Testing
• Pandemics/prevention & control
• Complement System Proteins

• Humans
• COVID-19
• Connectome
• Lung/pathology
• Respiratory Distress Syndrome/drug therapy
• Acute Lung Injury/pathology
• Complement System Proteins/therapeutic use

• U.S. Army Medical Research and Development Command

• COVID-19
• Complement cascade
• Complement inhibition
• Review
• SARS-CoV-2

• Humans
• COVID-19
• SARS-CoV-2
• Complement Activation
• Randomized Controlled Trials as Topic

• C1 inhibitor
• COVID-19
• Complement system
• Contact activation system
• Kallikrein-kinin system
• Thromboinflammation

• Antibodies, Monoclonal
• Anticoagulants/therapeutic use
• Antiviral Agents/therapeutic use
• Complement C1 Inhibitor Protein/therapeutic use
• Disease Progression
• Endothelial Cells
• Humans
• Inflammation/drug therapy
• Kallikreins
• Kinins
• SARS-CoV-2
• Thromboinflammation
• Thrombosis/drug therapy
• COVID-19 Drug Treatment

• Acute lung injury
• CL-11
• IL-6
• Klebsiella pneumoniae
• Lectin pathway
• TNF-α

• C5
• Covid-19
• SARS-CoV-2
• complement system
• membrane attack complex

Acute lung injury (ALI) occurs in patients with severe sepsis and has a mortality rate of 40%–60%. Severe sepsis promotes the release of histones from dying cells, which can induce platelet aggregation, activate coagulation and cause endothelial cell (EC) death. We previously reported that the expression of membrane complement receptor type 1‐related gene Y (Crry)/p65, which plays a principal role in defence against abnormal activation of complement in the blood, is reduced in response to peritoneal mesothelial cell injury, and we hence hypothesized that a similar mechanism occurs in pulmonary ECs. In this study, we examined the role of Crry/p65 in histone‐mediated ALI using an experimental animal model. In ALI model mice, exposure to extracellular histones induces lung injury and results in a decrease in Crry/p65 expression. The levels of lactic acid dehydrogenase (LDH), a marker of cell damage, were significantly increased in the serum of ALI model compared with vehicle mice. The significant inverse correlation between the expression of Crry/p65 and LDH levels in plasma revealed an association between Crry/p65 expression and cell damage. The levels of complement component 3a (C3a) were also significantly increased in the serum of the ALI model compared with vehicle mice. Notably, a C3a receptor antagonist ameliorated lung injury induced by histones. We hypothesize that extracellular histones induce complement activation via down‐regulation of Crry/p65 and that C3a might serve as a therapeutic target for the treatment of ALI.

• C3a
• C3a receptor antagonist
• acute lung injury
• complement receptor type 1-related gene Y
• endothelial cell
• extracellular histone

• anaphylatoxins
• complement system
• cytokines
• monoclonal antibodies

Complement is one of the most ancient defense systems. It gets strongly activated immediately after acute injuries like trauma, burn, or sepsis and helps to initiate regeneration. However, uncontrolled complement activation contributes to disease progression instead of supporting healing. Such effects are perceptible not only at the site of injury but also systemically, leading to systemic activation of other intravascular cascade systems eventually causing dysfunction of several vital organs. Understanding the complement pathomechanism and its interplay with other systems is a strict requirement for exploring novel therapeutic intervention routes. Ex vivo models exploring the cross-talk with other systems are rather limited, which complicates the determination of the exact pathophysiological roles that complement has in trauma, burn, and sepsis. Literature reporting on these three conditions is often controversial regarding the importance, distribution, and temporal occurrence of complement activation products further hampering the deduction of defined pathophysiological pathways driven by complement. Nevertheless, many in vitro experiments and animal models have shown beneficial effects of complement inhibition at different levels of the cascade. In the future, not only inhibition but also a complement reconstitution therapy should be considered in prospective studies to expedite how meaningful complement-targeted interventions need to be tailored to prevent complement augmented multi-organ failure after trauma, burn, and sepsis.

This review summarizes clinically relevant studies investigating the role of complement in the acute diseases trauma, burn, and sepsis with important implications for clinical translation.

• Burn
• Clinical translation
• Complement activation
• Sepsis
• Systemic inflammation
• Thromboinflammation
• Trauma

Acute respiratory distress syndrome (ARDS) is a rapidly progressive diffuse lung injury that is characterized by high mortality and acute onset. The pathological mechanisms of ARDS are still unclear. But alveolar macrophages have been shown to play an important role in inflammatory responses during ARDS. We aimed to find the biomarkers for ARDS for early diagnosis, to give ARDS patients timely treatment.

Gene expression profiles were downloaded from Gene Expression Omnibus (GEO) and screened for differentially expressed genes (DEGs). The common upregulated genes in all the datasets were defined as circulating ARDS alveolar macrophage-related genes (cARDSAMGs). We performed a functional enrichment analysis to explore potential biological functions of cARDSAMGs, and we built protein–protein interaction networks. Gene set variation analysis (GSVA) was used to calculate the core gene set variation analysis (CGSVA) score for individual samples. Receiver operating characteristic (ROC) curve analysis was applied on the CGSVA score to evaluate its ability for diagnosis of ARDS.

A total of 60 genes were upregulated in all ARDS datasets and were therefore denominated as cARDSAMGs. The cARDSAMGs were significantly involved in multiple inflammation-, immunity- and phagocytosis-related biological processes and pathways. In the protein–protein interaction network associated with host responses to ADRS, eight genes were identified as a core gene set: PTCRA, JAG1, C1QB, ADAM17, C1QA, MMP9, VSIG4 and TNFAIP3. ROC curve analysis showed that the CGSVA score may be considered as a biomarker for ARDS: it was significantly higher in patients with ARDS than those in healthy in both alveolar lavage fluid and whole blood.

The ARDS alveolar macrophage-related CGSVA score may be useful as a biomarker for ARDS.

• acute respiratory distress syndrome
• differentially expressed genes
• gene expression omnibus
• lung injury

• COVID 19
• complement
• endothelial cell
• hypoxia
• inflammation

• P01 HL014985 NHLBI NIH HHS
• P01 HL152961 NHLBI NIH HHS

• COVID-19
• coagulation system
• complement system
• fibrinolysis system
• kallikrein/kinin system
• prognosis
• thromboinflammation

• Adult
• Aged
• Aged, 80 and over
• Biomarkers/metabolism
• Blood Coagulation
• COVID-19/immunology
• COVID-19/metabolism
• COVID-19/pathology
• COVID-19/virology
• Critical Illness
• Female
• Fibrinolysis/immunology
• Humans
• Immunity, Innate
• Inflammation/immunology
• Inflammation/metabolism
• Inflammation/pathology
• Inflammation/virology
• Kallikrein-Kinin System/immunology
• Male
• Middle Aged
• Prospective Studies
• Respiratory Distress Syndrome/immunology
• Respiratory Distress Syndrome/metabolism
• Respiratory Distress Syndrome/pathology
• Respiratory Distress Syndrome/virology
• SARS-CoV-2/isolation & purification
• Severity of Illness Index
• Thrombosis/immunology
• Young Adult

• Anti-virals
• COVID-19
• Co-morbidities
• Life-cycle
• Pathophysiology
• Pregnancy
• SARS-CoV-2
• Vaccine

• Adaptive Immunity/immunology
• COVID-19/immunology
• COVID-19/prevention & control
• COVID-19/virology
• Host-Pathogen Interactions/immunology
• Humans
• Immunity, Innate/immunology
• SARS-CoV-2/genetics
• SARS-CoV-2/immunology
• SARS-CoV-2/pathogenicity
• Vaccination
• Viral Vaccines/administration & dosage
• Viral Vaccines/immunology
• Virulence/genetics
• Virulence/immunology
• Virus Replication/genetics
• Virus Replication/immunology

• ARDS
• Complement cascade
• Complement inhibitors
• Inflammation
• MASP2
• SARS-CoV-2

• coagulopathy
• complement activation
• complementopathy
• organ failure
• trauma

The complement system plays a critical role as the pathogenic factor in the models of acute lung injury due to various causes. Cobra venom factor (CVF) is a commonly used complement research tool. The CVF can cause acute inflammation in the lung by producing complement activation components. Atorvastatin (ATR) is a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor approved for control of plasma cholesterol levels. This inhibitor can reduce the acute pulmonary inflammatory response. However, the ability of ATR in treating acute lung inflammation caused by complement activation is still unknown. Therefore, we investigated the effect of ATR on lung inflammation in mice induced by activation of the complement alternative pathway in this study.

ATR (10 mg/kg/day via oral gavage) was administered for 7 days before tail vein injection of CVF (25 μg/kg). On the seventh day, all mice were sacrificed 1 h after injection. The lung lobe, bronchoalveolar lavage fluid (BALF), and blood samples were collected. The myeloperoxidase (MPO) activity of the lung homogenate, the leukocyte cell count, and the protein content of BALF were measured. The levels of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), P-selectin, and Intercellular cell adhesion molecule-1 (ICAM-1) in BALF and serum were determined by enzyme-linked immunosorbent assay. The pathological change of the lung tissue was observed by hematoxylin and eosin staining. The deposition of C5b-9 in the lung tissue was detected by immunohistochemistry. The phosphorylation of NF-κB p65 in the lung tissues was examined by immunohistochemistry and western blotting.

The lung inflammation levels were determined by measuring the leukocyte cell numbers and protein content of BALF, the lung MPO activity, and expression and staining of the inflammatory mediators (IL-6 and TNF-α), and adhesion molecules (P-selectin and ICAM-1) for lung lesion. A significant reduction in the lung inflammation levels was observed after 7 days in ATR pre-treated mice with a CVF-induced lung disease. Deposition of C5b-9 was significantly alleviated by ATR pretreatment. Early intervention with ATR significantly reduced the development of acute lung inflammation on the basis of phosphorylation of NF-κB p65 in the lung.

These findings suggest the identification of ATR treatment for the lung inflammation induced by activating the complement system on the basis of its anti-inflammatory response. Together with the model replicating the complement activating characteristics of acute lung injury, the results may be translatable to the overactivated complement relevant diseases.

• Acute lung inflammation
• Aspirin
• Atorvastatin
• Cobra venom factor
• Complement

• COVID-19
• SARS-CoV-2
• complement proteins
• lectin pathway
• therapeutics

• Adult
• Alveolar Epithelial Cells/immunology
• Alveolar Epithelial Cells/metabolism
• Alveolar Epithelial Cells/virology
• Angiotensin-Converting Enzyme 2
• Animals
• Betacoronavirus/physiology
• COVID-19
• Child
• Complement Activation/drug effects
• Complement C3b/antagonists & inhibitors
• Complement C3b/physiology
• Complement Inactivating Agents/pharmacology
• Complement Inactivating Agents/therapeutic use
• Coronavirus Infections/drug therapy
• Coronavirus Infections/immunology
• Cytokine Release Syndrome/drug therapy
• Cytokine Release Syndrome/etiology
• Cytokine Release Syndrome/immunology
• Glycosylation
• Humans
• Immunity, Innate
• Ligands
• Mice
• Models, Animal
• Models, Molecular
• Pandemics
• Pattern Recognition, Automated
• Peptidyl-Dipeptidase A/metabolism
• Pneumonia, Viral/drug therapy
• Pneumonia, Viral/immunology
• Protein Conformation
• Protein Processing, Post-Translational
• Receptors, Virus/metabolism
• Respiratory Distress Syndrome/etiology
• Respiratory Distress Syndrome/immunology
• SARS-CoV-2
• Spike Glycoprotein, Coronavirus/chemistry
• Spike Glycoprotein, Coronavirus/metabolism
• COVID-19 Drug Treatment

• MR/J004553/1 UK Medical Research Council
• MR/L012758/1 Medical Research Council
• MR/L012758/1 UK Medical Research Council
• MR/J006742/1 Medical Research Council
• MR/M007871/1 UK Medical Research Council
• G1001141 UK Medical Research Council
• MR/J006742/1 UK Medical Research Council
• 607690 European Union Marie Curie Initial Training Network (UniVacFlu)
• MR/M007871/1 Medical Research Council
• G1001141 Medical Research Council
• MR/J004553/1 Medical Research Council
• MR/L020254/1 Medical Research Council
• MR/L020254/1 UK Medical Research Council
• 38639 The Bill and Melinda Gates Foundation
• RE12572 National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas's NHS
• UK Medical Research Council
• National Institute for Health Research (NIHR) Biomedical Research Centre based at Guy's and St Thomas's NHS
• The Bill and Melinda Gates Foundation
• European Union Marie Curie Initial Training Network (UniVacFlu)

• TTP-like syndrome
• acute respiratory distress syndrome (ARDS)
• complement activation
• disseminated intravascular coagulation (DIC)
• disseminated intravascular microthrombosis (DIT)
• endotheliopathy
• endotheliopathy-associated vascular microthrombotic disease (EA-VMTD)
• hemostatic disorder
• microthrombogenesis
• multi-organ dysfunction syndrome (MODS)
• vascular microthrombotic disease (VMTD)

Liposomes hold great potential as gene and drug delivery vehicles due to their biocompatibility and modular properties, coupled with the major advantage of attenuating the risk of systemic toxicity from the encapsulated therapeutic agent. Decades of research have been dedicated to studying and optimizing liposomal formulations for a variety of medical applications, ranging from cancer therapeutics to analgesics. Some effort has also been made to elucidate the toxicities and immune responses that these drug formulations may elicit. Notably, intravenously injected liposomes can interact with plasma proteins, leading to opsonization, thereby altering the healthy cells they come into contact with during circulation and removal. Additionally, due to the pharmacokinetics of liposomes in circulation, drugs can end up sequestered in organs of the mononuclear phagocyte system, affecting liver and spleen function. Importantly, liposomal agents can also stimulate or suppress the immune system depending on their physiochemical properties, such as size, lipid composition, pegylation, and surface charge. Despite the surge in the clinical use of liposomal agents since 1995, there are still several drawbacks that limit their range of applications. This review presents a focused analysis of these limitations, with an emphasis on toxicity to healthy tissues and unfavorable immune responses, to shed light on key considerations that should be factored into the design and clinical use of liposomal formulations.

• cancer
• gene and drug delivery
• immunomodulation
• liposomes
• toxicity

Transfusion-related acute lung injury (TRALI) is a life-threatening complication of acute respiratory distress occurring within 6 hours of blood transfusion. TRALI is one of the leading causes of transfusion-related fatalities and specific therapies are unavailable. Neutrophils are recognized as the major pathogenic cells, whereas T regulatory cells and dendritic cells appear to be important for protection against TRALI. The pathogenesis, however, is complex and incompletely understood. It is frequently postulated that the complement system plays an important role in the TRALI pathogenesis. In this article, we assess the evidence regarding the involvement of complement in TRALI from both human and animal studies. We hypothesize about the potential connection between the complement system and neutrophils in TRALI. Additionally, we draw parallels between TRALI and other acute pulmonary disorders of acute lung injury and acute respiratory distress syndrome regarding the involvement of complement. We conclude that, even though a role for complement in the TRALI pathogenesis seems plausible, studies investigating the role of complement in TRALI are remarkably limited in number and also present conflicting findings. Different types of TRALI animal models, diverse experimental conditions, and the composition of the gastrointestinal microbiota may perhaps all be factors which contribute to these discrepancies. More systematic studies are warranted to shed light on the contribution of the complement cascade in TRALI. The underlying clinical condition of the patient, which influences the susceptibility to TRALI, as well as the transfusion factor (antibody-mediated vs non–antibody-mediated), will be important to take into consideration when researching the contribution of complement. This should significantly increase our understanding of the role of complement in TRALI and may potentially result in promising new treatment strategies.

•

Studies investigating complement and TRALI are limited in number and present conflicting findings.

• C5Ar
• C5a
• Complement
• NETs
• TRALI
• Transfusion-related acute lung injury

• PI-PLC
• Staphylococcus aureus
• complement
• tissue damage

The complement system is a critical part of host defense to many bacterial, viral, and fungal infections. It works alongside pattern recognition receptors to stimulate host defense systems in advance of activation of the adaptive immune response. In this study, we directly test the role of complement in SARS-CoV pathogenesis using a mouse model and show that respiratory disease is significantly reduced in the absence of complement even though viral load is unchanged. Complement-deficient mice have reduced neutrophilia in their lungs and reduced systemic inflammation, consistent with the observation that SARS-CoV pathogenesis is an immune-driven disease. These data suggest that inhibition of complement signaling might be an effective treatment option following coronavirus infection.

Acute respiratory distress syndrome (ARDS) is immune-driven pathologies that are observed in severe cases of severe acute respiratory syndrome coronavirus (SARS-CoV) infection. SARS-CoV emerged in 2002 to 2003 and led to a global outbreak of SARS. As with the outcome of human infection, intranasal infection of C57BL/6J mice with mouse-adapted SARS-CoV results in high-titer virus replication within the lung, induction of inflammatory cytokines and chemokines, and immune cell infiltration within the lung. Using this model, we investigated the role of the complement system during SARS-CoV infection. We observed activation of the complement cascade in the lung as early as day 1 following SARS-CoV infection. To test whether this activation contributed to protective or pathologic outcomes, we utilized mice deficient in C3 (C3^–/–), the central component of the complement system. Relative to C57BL/6J control mice, SARS-CoV-infected C3^–/– mice exhibited significantly less weight loss and less respiratory dysfunction despite equivalent viral loads in the lung. Significantly fewer neutrophils and inflammatory monocytes were present in the lungs of C3^–/– mice than in C56BL/6J controls, and subsequent studies revealed reduced lung pathology and lower cytokine and chemokine levels in both the lungs and the sera of C3^–/– mice than in controls. These studies identify the complement system as an important host mediator of SARS-CoV-induced disease and suggest that complement activation regulates a systemic proinflammatory response to SARS-CoV infection. Furthermore, these data suggest that SARS-CoV-mediated disease is largely immune driven and that inhibiting complement signaling after SARS-CoV infection might function as an effective immune therapeutic.

• SARS-CoV
• animal models
• complement
• coronavirus
• respiratory viruses

• Acute Lung Injury/drug therapy
• Acute Lung Injury/genetics
• Acute Lung Injury/physiopathology
• Animals
• Blast Injuries/drug therapy
• Blast Injuries/genetics
• Blast Injuries/pathology
• CD55 Antigens/administration & dosage
• Complement Activation/drug effects
• Complement C3a/antagonists & inhibitors
• Disease Models, Animal
• HMGB1 Protein/genetics
• Humans
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/physiopathology
• Lung/drug effects
• Lung/metabolism
• Lung/physiopathology
• NF-kappa B/genetics
• Pressure/adverse effects
• Rats
• Rats, Sprague-Dawley

• Defense Medical Research and Development Program

• Cecal ligation and puncture (CLP)
• Intracellular calcium ([Ca(2+)]i)
• NLRP3 inflammasome
• Na+/Ca(2+)exchanger (NCX)
• Na+/K+-ATPase
• Sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA2)

• C5L2
• C5a anaphylatoxin
• LPS
• acute lung injury

• C5aR1
• C5aR2 (GPR77)
• Complement C5a
• Na(+)/Ca(2+) exchanger (NCX)
• Na(+)/K(+)-ATPase
• Sarco/endoplasmic reticulum Ca(2+)-ATPase 2 (SERCA2)

The complement pathway is best known for its role in immune surveillance and inflammation. However, its ability of opsonizing and removing not only pathogens, but also necrotic and apoptotic cells, is a phylogenetically ancient means of initiating tissue repair. The means and mechanisms of complement-mediated tissue repair are discussed in this review. There is increasing evidence that complement activation contributes to tissue repair at several levels. These range from the chemo-attraction of stem and progenitor cells to areas of complement activation, to increased survival of various cell types in the presence of split products of complement, and to the production of trophic factors by cells activated by the anaphylatoxins C3a and C5a. This repair aspect of complement biology has not found sufficient appreciation until recently. The following will examine this aspect of complement biology with an emphasis on the anaphylatoxins C3a and C5a.

• Complement activation
• Embryonic and adult stem cells
• C3a
• C5a
• Tissue repair

• R21 AI109150 NIAID NIH HHS
• R21 HL094878 NHLBI NIH HHS

Intriguingly, activated complement and anti-microbial peptides share certain functionalities; lytic, phagocytic, and chemo-attractant activities and each may, in addition, exert cell instructive roles. Each has been shown to have distinct LPS detoxifying activity and may play a role in the development of endotoxin tolerance. In search of the origin of complement, a functional homolog of complement C3 involved in opsonization has been identified in horseshoe crabs. Horseshoe crabs possess anti-microbial peptides able to bind to acyl chains or phosphate groups/saccharides of endotoxin, LPS. Complement activity as a whole is detectable in marine invertebrates. These are also a source of anti-microbial peptides with potential pharmaceutical applicability. Investigating the locality for the production of complement pathway proteins and their role in modulating cellular immune responses are emerging fields. The significance of local synthesis of complement components is becoming clearer from in vivo studies of parenchymatous disease involving specifically generated, complement-deficient mouse lines. Complement C3 is a central component of complement activation. Its provision by cells of the myeloid lineage varies. Their effector functions in turn are increased in the presence of anti-microbial peptides. This may point to a potentiating range of activities, which should serve the maintenance of health but may also cause disease. Because of the therapeutic implications, this review will consider closely studies dealing with complement activation and anti-microbial peptide activity in acute inflammation (e.g., dialysis-related peritonitis, appendicitis, and ischemia).

• acute inflammation
• deficiencies
• histidine tag
• immune cells
• innate immunity

• fibrosis
• immune complexes
• immunology
• transplantation

• C3a
• C5a
• acute lung injury
• inflammation
• tight junctions

Activation of polymorphonuclear granulocytes (PMNs) by C5a is thought to be important in the pathogenesis of multiple organ failure during sepsis and after trauma. In our experiment exposure of human PMNs to autologous zymosan activated plasma (ZAP) leads to a rapid increase in chemiluminescence. Heating the ZAP at 56^°C for 30 min did not alter the changes, while untreated plasma induced only baseline activity. The respiratory burst could be completely abolished by decomplementation and preincubation with rabbit antihuman C5a antibodies. Observation of human omentum using electron microscopy showed intravascular aggregation of PMNs, with capillary thrombosis and diapedesis of the cells through endothelial junctions 90 s after exposure to ZAP. PMNs caused disruption of connections between the mesothelial cells. After 4 min the mesothelium was completely destroyed, and connective tissue and fat cells exposed. Native plasma and minimum essential medium did not induce any morphological changes. These data support the concept that C5a activated PMNs can cause endothelial and mesothelial damage in man. Even though a causal relationship between anaphylatoxins and organ failure cannot be proved by these experiments C5a seems to be an important mediator in the pathogenesis of changes induced by severe sepsis and trauma in man.

There is evidence in sepsis, both in rodents and in humans, that activation of the complement system results in excessive production of C5a, which triggers a series of events leading to septic shock, multiorgan failure, and lethality. In rodents following cecal ligation and puncture (CLP), which induces polymicrobial sepsis, in vivo blockade of C5a using neutralizing antibodies dramatically improved survival, reduced apoptosis of lymphoid cells, and attenuated the ensuing coagulopathy. Based on these data, it seems reasonable to consider therapeutic blockade of C5a in humans entering into sepsis and septic shock. Strategies for the development of such an antibody for use in humans are presented.