1.4.2 Lipid mediators

The major constituent of cell membranes are phospholipids. Cellular phospholipases, especially phospholipase A and C, are activated during inflammation and degrade phospholipids to arachidonic acid. Arachidonic acid has a short half-life and can be metabolized by two major routes, the cyclo-oxygenase and lipoxygenase pathways. The cyclo-oxygenase pathway produces prostaglandins, prostacyclin, and thromboxanes; the lipoxygenase pathway produces in one branch leukotrienes and in the second branch lipoxins (Figure 1.1).

 
Figure 1.1:   The metabolic pathway of archidonic acid (HPETE: hydroperoxy-eicosatetraenoic acid; HETE: hydroxy-eicosatetraenoic acid)
The prostaglandins (PG) are a family of lipid-soluble hormone-like molecules produced by different cell types in the body. For example, macrophages and monocytes are large producers of both PGE and PGF, neutrophils produce moderate amounts of PGE, mast cells produce PGD. It is important to note that, unlike histamine, prostanglandins do not exist free in tissues, but have to be synthesized and released in response to an appropriate stimulus. PGE enhances vascular permeability, is pyrogenic, increases sensitivity to pain, and stimulates leukocyte cAMP, which can have an important suppressive effects on release of mediators by mast cells, lymphocytes, and phagocytes.

Thromboxane A (TXA) is produced by monocytes and macrophages, as well as by platelets. It causes platelets to aggregate and constrict blood vessels and airways. These effects are somewhat opposed by the action of prostacyclin (PGI) which is a potent vasodilator.

Leukotrienes. LTB and 5-hydroxyeicosatetranoate (5-HETE), causes the chemotaxis (directed locomotion) and/or chemokinesis (general cell movement) of a number of cell types including neutrophils. The synthesis of LTB is inhibited by colchicine, an anti-inflammatory agent used for treatment of gout. The mixture of LTC, LTD and LTE originally called slow reacting substance of anaphylaxis (SRS-A), is produced by a wide variety of cells, including monocytes and macrophages. They are spasmogenic and cause contraction of smooth muscle, mainly in the bronchus, and they have effects on mucous secretion.

Lipoxins LXA and LXB stimulate changes in microcirculation. For example, LXA induces rapid arteriolar dilation and can also antagonize LTD-induced vasoconstriction. It suggest that LXA may regulate the action of vasoconstrictor leukotrienes. LXA can block neutrophil chemotaxis induced by both LTB and N-formyl-oligopeptides. Both LXA and LXB inhibit cytotoxicity of natural killer cells.

Platelets produce a group of acetyl-alkylglycerol ether analogs of phosphatidylcholine called platelet-activating factors (PAFs). PAFs cause platelet aggregation and are potent phagocyte chemoattractants and stimuli of lysosomal enzyme release and reactive oxygen product formation by neutrophils, eosinophils, and macrophages. In addition, PAFs increase the stickiness of endothelial cells for leukocytes.

The basic activities of bioactive lipids are listed in Table 1.7.

 
Table 1.7:  Lipid mediators and their basic activities

1.4.7 Cytokines mediating inflammatory and effector functions

Cytokines are soluble (glyco)proteins, nonimmunoglobulin in nature, released by living cells of the host, which act nonenzymatically in picomolar to nanomolar concentrations through specific receptors to regulate host cell function. Cytokines make up the fourth major class of soluble intercellular signaling molecules, alongside neurotransmitters, endocrine hormones, and autacoids. They possess typical hormonal activities:

1. they are secreted by a single cell type, react specifically with other cell types (target cells) and regulate specific vital functions that are controlled by feedback mechanisms;
2. they generally act at short range in a paracrine or autocrine (rather than endocrine) manner;
3. they interact first with high-affinity cell surface receptors (distinct for each type or even subtype) and then regulate the transcription of a number of cellular genes by little understood second signals. This altered transcription (which can be an enhancement or inhibition) result in changes in cell behaviour.

Target cells, on which cytokines transform their information signal, may be localized in any body compartment (sometimes a long distance from the site of secretion). Other type of these molecules act mostly on neighbouring cells in the microenvironment where they have been released. These are characterized as local hormones and their secretion is brought about by autocrine (only the cell or organ of secretion is affected) or paracrine mechanisms. During the paracrine secretion some cytokines may escape cell binding and may spill over into general circulation via lymph or plasma. This is important, especially for the products of lymphoid cells, which are mobile after having picked up the message in the microenvironment throughout the body and therefore their immunoregulatory products, (lymphokines, monokines, interleukins and other cytokines), despite being of local hormone character, may act in fact systemically.

Cytokines are synthesized, stored and transported by various cell types not only inside of the immune system (lymphokines, interleukins, monokines, tumour necrosis factors, interferons) but also by other cells which are mainly studied in haematology (colony-stimulating factors), oncology (transforming growth factors), and cell biology (peptide growth factors, heat shock and other stress proteins). The main types of cytokines are listed in Table 1.9.

 
Table 1.9:  Main types of cytokines
Lymphokines are cytokines secreted mainly by activated lymphocytes and the term monokines refers to analogous immunoregulators produced by activated macrophages and monocytes. In order to unify the terminology of these factors, the term interleukin was accepted. Besides the term expressing their origin, cytokines may be also named according to their function, as are interferons, growth and differentiation factors, colony-stimulating factors, etc.

The central role of cytokines is to control the direction, amplitude, and duration of immune responses and to control the (re)modeling of tissues, be it developmentally programmed, constitutive, or unscheduled. Unscheduled remodeling is that which accompanies inflammation, infection, wounding, and repair. Individual cytokines can have pleiotropic (multiple), overlaping and sometimes contradictory functions depending on their concentration, the cell type they are acting on, and the presence of other cytokines and mediators. Thus the information which an individual cytokine conveys depend on the pattern of regulators to which a cell is exposed, and not on one single cytokine. It is supposed that all cytokines form the specific system or network of communication signals between cells of the immune system, and between the immune system and other organs. In this inter-cell signalling network, the signal is usually transfered by means of a special set of cytokines.

Because of the potent and profound biological effects of cytokines, it is not surprising that their activities are tighly regulated, most notably at the levels of secretion and receptor expression. Additional regulatory mechanisms are provided by the concomitant action of different cytokines and the presence in biological fluids of specific inhibitory proteins, soluble cytokine-binding factors and specific autoantibodies.

The cytokine system is a very potent force in homeostasis when activation of the network is local and cytokines act vicinally in surface-bound or diffusible form, but when cytokine production is sustained and/or systemic, there is no doubt that cytokines contribute to the signs, symptoms, and pathology of inflammatory, infectious, autoimmune, and malignant diseases. TNF- is an excellent example of such dual action. Locally it has important regulatory and antitumour activities but when TNF- circulates in higher concentrations beyond the organ of origin, it may be involved in the pathogenesis of endotoxic shock, cachexia and other serious diseases.

From the point of inflammation view there are two main groups of cytokines: proinflammatory and anti-inflammatory (Table 1.10). Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the up-regulation of inflammatory reactions. Anti-inflammatory cytokines belong to the T cell-derived cytokines and are involved in the down-regulation of inflammatory reactions.

 
Table 1.10:  Cytokines involved in inflammatory reactions
The central role in inflammatory responses have IL-1 and TNF-, because the administration of their antagonists, such as IL-1ra (IL-1 receptor antagonist), soluble fragment of IL-1 receptor, or monoclonal antibodies to TNF- and soluble TNF receptor, all block various acute and chronic responses in animal models of inflammatory diseases. Some of these antagonists are beginning to utilize as anti-inflammatory agents in diseases such as sepsis and rheumatoid arthritis. IL-1 and TNF- together with IL-6 serve as endogenous pyrogens. The up-regulation of inflammatory reaction is also performed by IL-11, IFN- , IFN- , and especially by the members of chemokine superfamily. On the other hand, anti-inflammatory cytokines (IL-4, IL-10, IL-13) are responsible for the down-regulation of inflammatory responses. They are able to suppress the production of proinflammatory cytokines. Their strong anti-inflammatory activity suggest possible utilization in management of many inflammatory diseases, including sepsis, rheumatoid arthritis, inflammatory bowel disease, psoriasis, T cell-mediated autoimmune diseases such as type I diabetes, as well as in acute graft-versus-host disease. IL-10 is capable of effectively protecting mice from endotoxin-induced shock, a lethal inflammatory reaction mediated by TNF- and IL-1. The production of most lymphokines and monokines such as IL-1, IL-6 and TNF- is also inhibited by transforming growth factor (TGF- ). But, on the other hand, TGF- has a number of proinflammatory activities including chemoattractant effects on neutrophils, T lymphocytes, and unactivated monocytes. TGF- has been demonstrated to have in vivo immunosupressive and anti-inflammatory effects as well as proinflammatory and selected immunoenhacing activities. When administered systemically, TGF- acts as an inhibitor, but if given locally can promote inflammation. Generally, TGF- stimulates neovascularization and the proliferation and activities of connective tissue cells and is a pivotal factor in scar formation and wound healing. But TGF- has antiproliferative effects on most other cell types including epithelial cells, endothelial cells, smooth muscle cells, fetal hepatocytes, and myeloid, erythroid, and lymphoid cells. TGF- is a potent immunosupressive cytokine that supresses cell-mediated as well as humoral immunity (including tumour immunity).

NCBI searches:

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The inflammation hypothesis of aging: molecular modulation by calorie restriction

The inflammation hypothesis of aging: molecular modulation by calorie restriction.

 

Innate immunity and inflammation in ageing: a key for understanding age-related diseases

CRP, named for its capacity to precipitate the somatic C-polysaccharide of Streptococcus pneumoniae, was the first acute-phase protein to be described, and is an exquisitely sensitive systemic marker of inflammation and tissue damage. It is a member of the pentraxin family of plasma proteins, which are part of the lectin fold superfamily of calcium-dependent ligand-binding and lectin (carbohydrate-binding) proteins. In healthy blood donors, the median concentration of CRP is 0.8 mg/l, but following an acute-phase stimulus, values may increase 10 000-fold. In an apparently healthy population the median baseline value is slightly higher and tends to increase with age with females showing slightly higher circulating concentrations. In most, but not all diseases, the circulating value of CRP reflects on-going inflammation much more accurately than do other biochemical parameters of inflammation, such as plasma viscosity or the erythrocyte sedimentation rate [10].

Introduction

Inflammation is the response of living tissue to damage. The acute inflammatory response has 3 main functions.

1. The affected area is occupied by a transient material called the acute inflammatory exudate. The exudate carries proteins, fluid and cells from local blood vessels into the damaged area to mediate local defenses.
2. If an infective causitive agent (e.g. bacteria) is present in the damaged area, it can be destroyed and eliminated by components of the exudate.
3. The damaged tissue can be broken down and partialy liquefied, and the debris removed from the site of damage.

The cause of acute inflammation may be due to physical damage, chemical substances, micro-organisms or other agents. The inflammatory response consist of changes in blood flow, increased permeability of blood vessels and escape of cells from the blood into the tissues. The changes are essentially the same whatever the cause and wherever the site.

Acute inflammation is short-lasting, lasting only a few days. If it is longer lasting however, then it is referred to as chronic inflammation. Various examples of acute inflammation that you may be aware of are sore throat, reactions in the skin to a scratch or a burn or insect bite, and acute hepatitis and so on. However, there are occasional historical exceptions such as pneumonia, inflammation of the lung rather than pneumonitis and pleurisy, inflammation of the pleura, rather than pleuritis.

Causes of Acute Inflammation

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Microbial infections

One of the commonest causes of inflammation is microbial infection. Viruses lead to death of individual cells by intracellular multiplication . Bacteria release specific exotoxins – chemicals synthesised by them which specifically initiate inflammationÑor endotoxins, which are associated with their cell walls. Additionally, some organisms cause immunologically-mediated inflammation through hypersensitivity reactions. Parasitic infections and tuberculous inflammation are instances where hypersensitivity is important.

Hypersensitivity reactions

A hypersensitivity reaction occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction which damages the tissues. The types of reaction are classified here, but all have cellular or chemical mediators similar to those involved in inflammation.

Physical agents

Tissue damage leading to inflammation may occur through physical trauma, ultraviolet or other ionising radiation, burns or excessive cooling ('frostbite').

Irritant and corrosive chemicals

Corrosive chemicals (acids, alkalis, oxidising agents) provoke inflammation through gross tissue damage. However, infecting agents may release specific chemical irritants which lead directly to inflammation.

Tissue necrosis

Death of tissues from lack of oxygen or nutrients resulting from inadequate blood flow (infarction) is a potent inflammatory stimulus. The edge of a recent infarct often shows an acute inflammatory response.

Clinical Aspects of Acute Inflammation

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The four principal effects of acute inflammation were described nearly 2,000 years ago by Celcus:
Redness (rubor)
An acutely inflamed tissue appears red, for example skin affected by sunburn, cellulitis due to bacterial infection or acute conjunctivitis. This is due to dilatation of small blood vessels within the damaged area.

Heat (calor)
Increase in temperature is seen only in peripheral parts of the body, such as the skin. It is due to increased blood flow (hyperaemia) through the region, resulting in vascular dilatation and the delivery of warm blood to the area. Systemic fever, which results from some of the chemical mediators of inflammation, also contributes to the local temperature.

Swelling (tumor)
Swelling results from oedema, the accumulation of fluid in the extra vascular space as part of the fluid exudate, and to a much lesser extent, from the physical mass of the inflammatory cells migrating into the area.

Pain (dolor)
For the patient, pain is one of the best known features of acute inflammation. It results partly from the stretching and distortion of tissues due to inflammatory oedema and, in particular, from pus under pressure in an abscess cavity. Some of the chemical mediators of acute inflammation, including bradykinin, the prostaglandins and serotonin, are known to induce pain.

Loss of function
Loss of function, a well-known consequence of inflammation, was added by Virchow (1821-1902) to the list of features drawn up by Celsus. Movement of an inflamed area is consciously and reflexly inhibited by pain, while severe swelling may physically immobilise the tissues.

Early Stages of Acute Inflammation

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In the early stages, oedema fluid, fibrin and neutrophil polymorphs accumulate in the extracellular spaces of the damaged tissue. The presence of the cellular component, the neutrophil polymorph, is essential for a histological diagnosis of acute inflammation. The acute inflammatory response involves three processes:

• changes in vessel calibre and, consequently, flow
• increased vascular permeability and formation of the fluid exudate
• formation of the cellular exudate by emigration of the neutrophil polymorphs into the extravascular space.

Briefly, the steps involved in e acute inflammatory response are:

1. Small blood vessels adjacent to the area of tissue damage initially become dilated with increased blood flow, then flow along them slows down.
2. Endothelial cells swell and partially retract so that they no longer form a completely intact internal lining.
3. The vessels become leaky, permitting the passage of water, salts, and some small proteins from the plasma into the damaged area (exudation). One of the main proteins to leak out is the small soluble molecule, fibrinogen.
4. Circulatirlg neutrophil polymorphs initially adhere to the swollen endothelial cells (margination), then actively migrate through the vessel basement membrane (emigration), passing into the area of tissue damage.
5. Later, small numbers of blood monocytes (macrophages) migrate in a similar way, as do Iymphocytes.

Chemical Mediators of Acute Inflammation

The spread of the acute inflammatory response following injury to a small area of tissue suggests that chemical substances are released from injured tissues, spreading outwards into uninjured areas. These chemicals, called endogenous chemical mediators, cause vasodilatation, emigration of neutrophils, chemotaxis and increased vascular permeability.

Chemical mediators released from cells

Histamine. This is the best-known chemical mediator in acute inflammation. It causes vascular dilation and the immediate transient phase of increased vascular permeability. It is stored in mast cells, basophil and eosinophil leukocytes, and platelets. Histamine release from those sites (for example, mast cell degranulation) is stimulated by complement components C3a and C5a, and by Iysosomal proteins released from neutrophils.

Lysosomal compounds. These are released from neutrophils and include cationic proteins, which may increase vascular permeability, and neutral proteases, which may activate complement. Prostaglandins. These are a group of long-chain fatty acids derived from arachidonic acid and synthesised by many cell types. Some prostaglandins potentiate the increase in vascular permeability caused by other compounds. Others include platelet aggregation (prostaglandin 1. is inhibitory while prostaglandin A2 is stimulatory). Part of the anti-inflammatory activity of drugs such as aspirin and the non-steroidal anti-inflammatory drugs is attributable to inhibition of one of the enzymes involved in prostaglandin synthesis.

Leukotrienes. These arc also synthesised from arachidonic acid, especially in neutrophils, and appear to have vasoactive properties. SRS-A (slow reacting substance of anaphylaxis), involved in type I hypersensitivity, is a mixture of leukotrienes. 5-hydroxytryptamine (serotonin). This is present in high concentration in mast cells and platelets. It is a potent vasoconstrictor.

Lymphokines. This family of chemical messengers released by Iymphocytes. Apart from their major role in type IV hypersensitivity, Iymphokines may also have vasoactive or chemotactic properties.

Plasma factors. The plasma contains four enzymatic cascade systems complement, the kinins, the coagulation factors and the fibrinolytic system which are inter-related and produce various inflammatory mediators.

Complement system. The complement system is a cascade system of enzymatic proteins. It can be activated during the acute inflammatory reaction in various ways: * In tissue necrosis, enzymes capable of activating complement are released from dying cells. * During infection, the formation of antigen-antibody complexes can activate complement via the classical pathway, while the endotoxins of Gram-negative bacteria activate complement via the alternative pathway. * Products of the kinin, coagulation and fibrinolytic systems can activate complement. The products of complement activation most important in acute inflammation include:

• * C5a: chemotactic for neutrophils; increases vascular permeability; releases histamine from mast cells
• * C3a: similar properties to those of C5a, but less active * C567: chemotactic for neutrophils
• * C56789: cytolytic activity
• * C4b, 2a, 3b: opsonisation of bacteria (facilitates phagocytosis by macrophages) .

Kinin system. The kinins are peptides of 9-11 amino acids; the most important vascular permeability factor is bradykinin. The kinin system is activated by coagulation factor XII. Bradykinin is also a chemical mediator of the pain which is a cardinal feature of acute inflammation.

Coagulation system. The coagulation system is responsible for the conversion of soluble fibrinogen into fibrin, a major component of the acute inflammatory exudate. Coagulation factor XII (the Hageman factor), once activated by contact with extracellular materials such as basal lamina, and various proteolytic enzymes of bacterial origin, can activate the coagulation, kinin and fibrinolytic systems.

Fibrinolytic system. Plasmin is responsible for the Iysis of fibrin into fibrin degradation products, which may have local effects on vascular permeability

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Prostaglandins (PGs) are members of the eicosanoid family (oxygenated C₂₀ fatty acids) and are produced by nearly all cells within the body [1]. Prostaglandins are lipid mediators that are not stored by cells; rather, they are synthesized from arachidonic acid via the actions of cyclooxygenase (COX) enzymes, either constitutively or in response to cell-specific trauma, stimuli, or signaling molecules [1], [2] and [3].

 Arachidonic acid is a polyunsaturated fatty acid derived from dietary sources that resides in the cell membrane. It is first liberated from cell membrane phospholipids via the hydrolysis of sn-2 bond by phospholipase A₂ enzymes (PLA₂) [3]. Arachidonic acid is then oxygenated by a COX to form PGG₂ and subsequently reduced by the same COX to yield the unstable intermediate, PGH₂ [9]. The release of arachidonic acid from cell membrane phospholipids determines the amount of eicosanoid production that occurs. Therefore, PLA₂ determines eicosanoid levels [10] and [11]. Fifteen genes are responsible for encoding the diverse PLA₂ enzymes that exist in mammals [12]. There are three main classes of phospholipase A₂ enzymes: (1) secreted PLA₂ (sPLA₂), (2) intracellular group VI calcium-independent PLA₂ (GVI iPLA₂), and (3) group IV cytosolic PLA₂ (GIV cPLA₂) (Table 1).

 

 

 

"Figure 1. Coordinate production of PGE₂ by cPLA₂α, COX-1, and cPGES. (A) Unstimulated cell. Prior to cellular activation by inflammatory stimuli, cPLA₂α and cPGES are present in the cytoplasm of cells whereas COX-1 is constitutively expressed in the nuclear envelope and endoplasmic reticulum. (B) Stimulated cell. Activation by inflammatory stimuli results in calcium influx, leading to translocation of cPLA₂α to the nuclear membrane where it enzymatically hydrolyzes membrane phospholipids to release arachidonic acid. The enzymatic activity of COX-1 on arachidonic acid results in an unstable intermediate (PGG₂) which is subsequently converted by COX-1 to PGH₂. Constitutively expressed cPGES may be stimulated to translocate from the cytosolic to the nuclear fraction, where it preferentially coordinates with COX-1 to convert PGH₂ to PGE₂. PGE₂ may exit the cell by simple diffusion, or by active transport via the MRP4 transporter."

Table 3.

Phenotypic changes in COX knockout mice

Enzyme	Phenotypic changes in KO mice
COX-1	Reduced platelet aggregation
	Decreased AA-induced inflammation
	Sensitive to radiation injury
	Resistant to indomethacin-induced gastric ulceration
COX-2	Defective ovulation, fertilization, implantation, decidualization
	Decreased brain injury induced by ischemia
	Suppression of tumorigenesis
	Renal nephropathy
	Cardiac fibrosis
	Peritonitis
	Failure of patent ductus arteriosus closure

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