Plasma Cascade Systems in Inflammation
Available Resources for The Study of Plasma Cascade Systems in Inflammation
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- Our broad portfolio includes essential items such as recombinant proteins, which play a critical role in unraveling the functions and mechanisms of plasma cascade systems in inflammation.
- We have a team of experienced experts with deep knowledge in the study of plasma cascade systems in inflammation, and we are committed to providing tailored solutions to meet the unique requirements of each researcher.
- In addition, we provide comprehensive resource support including involved pathways, protein function, interacting proteins, and other valuable information. Ultimately, our goal is to increase the impact of research efforts.
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About Plasma Cascade Systems in Inflammation
Plasma cascade systems are intricate networks of enzymatic reactions that play a crucial role in inflammation. These systems involve a series of proteases and their associated substrates, which are activated in a cascade-like fashion. The activation of one component leads to the activation of subsequent components, amplifying the inflammatory response. During the inflammatory process, three major plasma cascade systems, including the complement system, coagulation system, and kinin system, play important roles. In addition, the fibrinolytic system and Toll-like receptors (TLRs) are also closely related to inflammation. The fibrinolytic system is involved in processes such as inflammatory cell migration and tissue repair, while Toll-like receptors are a type of immune receptor that regulates inflammatory and immune responses by recognizing and interacting with pathogens in inflammation.
- The complement system is a group of proteins that helps in the immune defense against infections. It can be activated by different stimuli such as pathogens, immune complexes, or damaged cells. Once activated, the complement system generates inflammatory molecules that promote the recruitment and activation of immune cells at the site of inflammation.
- The coagulation system, also known as the blood clotting system, is responsible for stopping bleeding and initiating tissue repair. In inflammation, the coagulation system can become activated, leading to the formation of blood clots. These clots can impede blood flow, prevent the spread of pathogens, and create a scaffold for tissue repair.
- The kinin system is involved in regulating blood pressure, inflammation, and pain. It is activated when there is tissue damage or inflammation. Activation of the kinin system leads to the release of bradykinin, a potent inflammatory mediator that causes blood vessels to dilate, increases vascular permeability, and stimulates pain receptors.
- The fibrinolysis system is responsible for maintaining a balance between blood clot formation and clot dissolution. It involves the conversion of plasminogen to plasmin, which breaks down fibrin clots. Plasmin also has proteolytic activity and can degrade extracellular matrix components and modulate inflammation. The fibrinolysis system can regulate the inflammatory response by controlling the formation and degradation of fibrin, which in turn affects immune cell recruitment and tissue remodeling.
- Toll-like Receptors (TLRs) are a family of pattern recognition receptors that play a vital role in innate immunity and inflammation. They recognize conserved molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), as well as endogenous molecules released during tissue damage, known as damage-associated molecular patterns (DAMPs). Activation of TLRs triggers intracellular signaling pathways that lead to the production of pro-inflammatory cytokines, chemokines, and antimicrobial factors. TLRs are expressed on various immune cells and play a crucial role in initiating and shaping the immune response during infection and inflammation.
Fig.1 Potential significance of plasma kallikrein- kinin system in inflammation. (Stadnicki A, 2011)
PG-PS: peptidoglycan-polysaccharide; LPS: lipopolysaccharide; EC: endothelial cell; M: monocyte; N: neutrophil, HK: high molecular weight kininogen; TF: tissue factor; NO: nitric oxide, uPAR: urokinase plasminogen activated receptor. Solid arrows designate activation or cofactor amplification, dashed arrows designate conversion, and open arrows indicate release, expression, or synergistic properties
Activation and regulation of Plasma Cascade Systems
The activation and regulation of plasma cascade systems involve complex signaling pathways and interactions within the body. While the specific mechanisms may vary for different cascade systems, here is a general overview of the activation and regulation processes:
Activation
- Cascade Initiation: Activation of plasma cascade systems usually requires an initial trigger, such as tissue injury, infection, or immune activation.
- Protease Activation: Activation typically involves the cleavage and activation of specific proteases present in the plasma or on cell surfaces. This initial activation step sets off a cascade of enzymatic reactions.
- Enzymatic Amplification: Once activated, the initial protease activates subsequent proteases in a cascading manner, leading to amplification of the response. This amplification ensures a robust and effective inflammatory response.
Regulation
- Inhibitory Proteins: Various inhibitory proteins and regulators exist to prevent excessive or prolonged activation of plasma cascade systems. These inhibitors can directly inhibit specific proteases or block crucial interactions within the cascade.
- Receptor-Mediated Regulation: Receptors on cell surfaces can recognize and bind to specific components of the cascade, leading to the activation or inhibition of downstream signaling pathways. This receptor-mediated regulation helps fine-tune the inflammatory response.
- Feedback Loops: Feedback mechanisms exist within the cascade systems to regulate their activation and maintain a balance. These feedback loops can involve the production of inhibitory factors or the downregulation of receptors or proteases.
- Complement Control Proteins: In the case of the complement system, regulatory proteins, such as decay-accelerating factor (DAF) and complement receptor 1 (CR1), prevent the excessive activation of complement proteins on self-cells, protecting them from damage.
Signaling and Interactions
- Cell-Cell Interactions: Plasma cascade systems can interact with various cell types, including immune cells, endothelial cells, and platelets. These interactions are mediated through specific receptors, proteases, and their substrates, leading to the activation of downstream signaling pathways.
- Inflammatory Mediator Production: Activation of plasma cascade systems can trigger the release of various inflammatory mediators, such as cytokines, chemokines, and lipid mediators, which further propagate and modulate the inflammatory response.
- Crosstalk with Other Systems: Plasma cascade systems often interact and crosstalk with other immune and inflammatory pathways, such as Toll-like receptor signaling, cytokine networks, and cell adhesion molecules. These interactions help integrate and coordinate the overall immune and inflammatory response.
Fig.2 Crosstalks between coagulation, fibrinolysis and complement systems. (Kurosawa S, et al., 2014)
The coagulation cascade is roughly divided into TF pathway and contact activation. The TF pathway is well known to get activated by TCC, trauma, and some cytokines. Both pathways will merge at FXa level, which will generate thrombin. Thrombin is one of the most potent activator of platelets. Upon platelet activation, medium-size polyphosphate in the platelet granules will be released, which can induce contact activation. FXIIa can activate the classical complement pathway. FXIIa can activate plasma kallikrein, which in turn can activate both C3 and C5. Other members of blood coagulation and fibrinolysis, such as FSAP, thrombin and plasmin can independently activate both C3 and C5. DAMPs, immune complex and PAMPs are known to activate the classical complement pathway. PAMPs and apoptotic cells will activate lectin pathway. PAMPs will trigger alternative pathway activation, all leading to C3 activation, which will activate C5. C3a and C5a will recruit and activate leukocytes, as well as induce platelet activation and aggregation, inducing thrombosis and inflammation, which are known to further enhance coagulation. C5b will lead to TCC formation, which not only lyse microorganisms but also lyse host cells, which will release DAMPs. TCC will induce TF pathway, induce platelet activation, and enhance coagulation by negatively charged phospholipid surfaces.
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References:
- Stadnicki A. Kallikrein Kinin System and Coagulation System in Inflammatory Bowel Diseases[J]. 2011. DOI:10.5772/26815.
- Kurosawa S, Stearns-Kurosawa D J. Complement, thrombotic microangiopathy and disseminated intravascular coagulation[J].Journal of Intensive Care, 2014, 2(1):1-8.DOI:10.1186/s40560-014-0061-4.