Inflammation

See also Anti-inflammatory or Point of inflammation, for fire.

Inflammation on the toes.

Inflammation (from the Latin inflammatio: to ignite, make fire) is the form of manifestation of many diseases. It is a non-specific response to environmental aggressions, and is generated by inflammatory agents. The inflammatory response occurs only in vascularized connective tissues and arises for the defensive purpose of isolating and destroying the damaging agent, as well as repairing the damaged tissue or organ. It is therefore considered a stereotyped innate immunity mechanism, in contrast to the adaptive immune reaction, specific for each type of infectious agent.

The innate immune system is made up of defenses against infection that can be activated immediately once the pathogen attacks. This system is essentially made up of barriers that are intended to remove viruses, bacteria, parasites, and other foreign particles from the body or limit their ability to spread and move throughout the body. Inflammation is an example of an innate immune response.

The adaptive immune system, also called acquired immunity, uses specific antigens to strategically mount an immune response. Unlike the innate immune system, which attacks only on the basis of general threat identification, adaptive immunity is activated by exposure to pathogens, using immunological memory to learn about the threat and enhance the immune response in response to pathogens. consequence. The adaptive immune response is much slower to respond to threats and infections than the innate immune response, which is primed and ready to fight at all times.

Inflammation is identified in medicine with the suffix -itis. The biggest problem that arises from inflammation is that the defense is directed towards both harmful and non-harmful agents, thus causing damage to healthy tissues or organs.

Inflammatory agents

• Biological agents: bacteria, viruses, parasites, fungi; mammal cells have receptors that capture the presence of microbes; among the most important receptors are Toll type receptors, which detect the presence of bacteria, viruses and fungi, and trigger signaling pathways that stimulate the production of different mediators;
• Agents or conditions that produce necrosis of affected tissues: necrotic cells release molecules that activate the inflammatory response, such as uric acid, ADP or even DNA; among these agents we have:
  • Physical agents: radiation (such as UV rays), cold, heat.
  • Chemical agents: poisons, toxins.
  • Traumatisms and strange bodies, which induce inflammation because they damage tissues (necrosis) or provide microbes, which are in the air with which they can cause diseases.
  • Vascular alterations: such as those that produce ischemia.
  • Immune Alterations: such as hypersensitivity or autoimmune responses; in these cases it is the immune response itself that induces inflammation, which is the main cause of tissue damage.

Historical evolution

In the first civilizations there are testimonies of their knowledge and healing. The earliest writings appeared on Egyptian papyri dating from 3000 BC. c.

In Greece and Rome there is preserved a book, of the many written by Aulus Cornelius Celsus, encyclopedist, "De Medicinae" where 4 cardinal signs of inflammation are identified. Virchow later added the fifth sign.

You can currently recognize its five cardinal signs, which are:

• Tumor (Tumefaction): Increased interstitial fluid and formation of edema.
• Rubor: Redness, mainly due to increased vasodilation phenomena.
• Calor: Increased temperature of the swollen area. It is due to vasodilation and increased local oxygen consumption.
• Pain: Pain appears as a result of the release of substances capable of triggering nociceptors, such as prostaglandins. It is the first sign of the Celsius Tetrada. (The 4 Signs → Celsius Tetrada).
• Loss or decrease in function: Called fifth sign of Virchow (laesa).

In 1793, the Scottish surgeon Hunter pointed out something that is now considered obvious: "Inflammation is not a disease, but a non-specific response that produces a salutary effect in the organism in which it occurs".

The pathologist Julius Cohnheim was the first investigator to use the microscope to look at inflamed blood vessels in thin, translucent membranes, such as the frog's mesentery and tongue. After observing the initial changes in blood flow, edema after increased vascular permeability, leukocyte migration. In 1867 he demonstrated that the emigration of white blood cells is the origin of pus.Cohnheim's contribution was fundamental to understanding the entire inflammatory process.

The Russian biologist Elias Metchnikoff discovered the process of phagocytosis by observing the ingestion of rose thorns by the amebocytes of sea star larvae, and of bacteria by mammalian leukocytes (1882); The conclusion of this researcher was that the purpose of the inflammation was to bring the cells with phagocytic capacity to the area of injury so that they phagocytose the infectious agents. However, it soon became clear that both cellular factors (phagocytes) and serum factors (antibodies) were essential for defense against microorganisms, and in recognition of this Metchnikoff and Paul Ehrlich (who developed the humoral theory) shared the Nobel Prize in Medicine in 1908.

To these names must be added that of Sir Thomas Lewis who, through simple experiments on the inflammatory response of the skin, established the concept that various chemicals induced locally by the stimulus of injury, such as histamine, are factors mediators of vascular changes in inflammation. This fundamental concept forms the basis of the important discoveries of the chemical mediators of inflammation and of the possibility of using anti-inflammatory drugs.

Lewis called the chemical mediators of inflammation "H1", and defined the triple response to aggression as consisting of:

• Central erythema.
• Hinchazón.
• Peripheral erythema.

Depending on the temporal characteristics of the inflammation, we define two types of response, acute inflammation and chronic inflammation.

Acute inflammation

The acute phase of inflammation is synonymous with innate immune reaction. In acute inflammation we distinguish three key points: hemodynamic changes, alteration of vascular permeability and leukocyte modifications.

Hemodynamic changes

After an inconsistent and transient period of arteriolar vasoconstriction, vasodilation and active hyperemia (increased blood flow to the area of injury) occur, causing redness and increased temperature. Then a period of passive hyperemia occurs in which flow decreases due to increased microvascular permeability with fluid extravasation and increased blood viscosity in smaller vessels, which is called stasis (total paralysis of the flow). As the stasis evolves, peripheral orientation (margination) of the leukocytes occurs, which adhere to the endothelium, cross the vascular wall and go to the interstitium.

Step by step (only in a didactic way, since these events occur overlapping) the following is observed:

1. Arteriolar and capillary vasodilatacion, which causes the opening of capillaries and venulas; induced by the action of different mediators on the vascular smooth muscle, mainly histamine and nitric oxide.
2. Increased speed of blood flow (hyperemia) by the arterioles, which is the cause of the appearance of erythema (redness) on the site of inflammation.
3. Increased permeability of microvasculature: departure from an inflammatory exudate to extravascular tissues and appearance of inflammatory edema.
4. Abnormal and excessive accumulation of blood: fluid output causes increased viscosity of the blood, which increases the concentration of red blood cells (venous congestion).
5. Decreasing blood speed in small vessels (blood stasis).
6. Peripheral accumulation of leukocytes: marginalization and leukocyte paving.
7. At the same time, endothelial cells are activated by inflammation mediators, expressing molecules in their membranes that favor the adherence of leucocytes, mainly neutrophil polymorphonuclears (PMN).
8. Step of leucocytes (PMN in the first place, followed by macrophages) from the vessels to the intersection: cell migration, with formation of inflammatory infiltration. It's called diaperosis.

Similarly, during the repair phase that follows acute inflammation and during chronic inflammation, a phenomenon of blood vessel proliferation called angiogenesis occurs.

Altered vascular permeability

Under normal conditions, the endothelium does not allow the release of proteins and the exchange occurs by pinocytosis. During inflammation, the morphological bases of the endothelium are altered by the action of chemical mediators, producing an alteration of cell junctions and the negative charges of the basement membrane: Majno and Palade saw openings between cells that were not broken. Generally, this effect occurs in the venules, but if it is very intense, it reaches the capillaries and extravasation occurs due to rupture.

The leakage of fluids, proteins, and cells from the blood is called exudation. It is important to distinguish the following concepts:

• A exudate is an extracellular fluid that contains high concentration of proteins and cellular remains, very dense; its presence implies an inflammatory reaction;
• A transudate, however, is a fluid with low protein content (contains mainly albumin); it is an ultrafiltrated plasma due to the existence of a difference of osmotic or hydrostatic pressure through a glass wall, without increased vascular permeability or inflammatory process;
• A edema is an excess of fluid in the interstitial tissue, which can be an exudate or a transudate;
• Pus is a purulent exudate, an inflammatory exudate rich in leucocytes (especially PMNs), remains of dead cells and, in many cases, microbes.

The increase in vascular permeability is generated by several mechanisms, which can occur simultaneously:

Endothelial cell contraction

It is the most common mechanism, triggered by different mediators, such as histamine, bradykinin, leukotrienes and substance P, among others. These substances cause the sudden contraction, by oxidative phosphorylation, of the actin and myosin filaments of the endothelial cells that retract, so that the interendothelial spaces increase. Then the cytoskeleton reorganizes to maintain contraction for longer. Inflammatory substances must dissolve the basement membrane of these openings.

Endothelial damage

The necrosis of the endothelial cells causes their separation from the vessel wall, thus creating an opening in it. It can occur in severe injuries, such as burns, or by the toxic action of microbes that directly affect the endothelium. PMNs that adhere to endothelial cells can also damage them. In this case, fluid loss continues until a thrombus forms or the damage is repaired.

Increased transcytosis

The transport of fluids and proteins through the endothelial cells themselves (and not between them) can be carried out by means of channels that are formed from interconnected vacuoles and uncoated vesicles (called the vesiculovacuolar organelle). VEGF appears to stimulate the number and size of these channels.

Responses of the lymphatic vessels

Under normal conditions, the lymphatic system filters and controls the small amounts of extravascular fluid that has been lost into the capillaries. During inflammation, the amount of extracellular fluid increases, and the lymphatic system participates in the removal of edema. Also, in this case a greater amount of leukocytes, cell debris and microbes passes into the lymph. As with blood vessels, lymphatics also proliferate in inflammatory processes, to meet the increased demand. It may happen that the lymphatic vessels become secondarily inflamed (lymphangitis), or that the nodes become inflamed (lymphadenitis), due to the hyperplasia of the lymphoid follicles and the increased number of lymphocytes and macrophages.

Leukocyte modifications

Leukocytes engulf pathogens, kill bacteria and microorganisms, and degrade necrotic tissue, but they can also prolong tissue injury by releasing enzymes, chemical mediators, and reactive oxygen species (ROS, or ROS, for example). its acronym in English; also called free oxygen radicals, RLO). The two most important groups of leukocytes in an inflammation process are neutrophil polymorphonuclear leukocytes (PMN) and macrophages.

Connective tissue contains macrophages and mast cells, which are sentinel cells capable of recognizing the presence of microbes, dead cells, or foreign bodies. Macrophages are the main elements in the initiation of the inflammation process, since they have specific receptors capable of recognizing microbes and dead cells. When they recognize these elements, macrophages produce the cytokines IL-1 and TNF-α, which trigger the inflammation itself by acting on the endothelial cells of the nearby blood vessels (especially the post-capillary venules), to allow the transendothelial migration of cells. the leukocytes.

Mast cells react to physical stress detected in the tissues (heat, cold, pressure) and produce the mediators serotonin and histamine, which are potent vasoactive agents that act on the contraction and permeability of both arterial and venous.

As a consequence of the activation of macrophages and mast cells, the release of chemical mediators of inflammation occurs. These mediators induce vasodilation in the affected area, which causes fluid to leak from the blood into the tissues, generating edema. For this reason, the viscosity of the blood increases, due to the increased concentration of red blood cells, which causes a decrease in blood flow (stasis). Under these hemodynamic conditions, leukocytes are redistributed in a peripheral position, a phenomenon called margination. The leukocytes then roll over the surface of the endothelium, establishing transient contacts with the endothelial cells, disengaging, and reattaching. Finally, the leukocytes adhere firmly to the endothelium, before initiating migration through the capillaries (see section "Diapedesis" of neutrophils for details). complete molecular detail).

The leukocytes that have crossed the capillaries are directed towards the area affected by a process of chemotaxis. Once there, they engulf the microbes and destroy them, generating the production of pus. The pus will be removed to the outside if the lesion is in contact with the outside, or it will generate an abscess if the area where the pus has formed is inside an organ.

Once the pus has been removed (either naturally or by surgical intervention in the case of an abscess), the macrophages and lymphocytes proceed to repair the tissue damaged by the acute inflammation. Tissue damage is generally caused by PMNs, which are very numerous and release hydrolytic enzymes and free radicals that damage tissue. Repair occurs thanks to macrophages, which stimulate fibroblasts to synthesize collagen and endothelial cells to generate new vessels, through the secretion of growth factors. However, the repair is always incomplete, since the original structure is not recovered: the glands and hairs in the area do not regenerate.

The nature of the infiltrated leukocytes varies according to the moment of the inflammatory response and the type of stimulus. In most cases of acute inflammation, neutrophils (PMNs) predominate for the first 6-24 h, and are then replaced by monocytes within 24-48 h. The rapid appearance of PMNs is due to the fact that they are more abundant in the blood, respond more quickly to chemokines, and adhere more strongly to adhesion molecules that appear on activated endothelial cells, such as E and P selectins. After entering tissues, PMNs have a short half-life: they undergo apoptosis and disappear after 24-48 h. Monocytes respond more slowly, but not only survive in the tissues, but also proliferate and give rise to macrophages, thus becoming the dominant population in chronic inflammatory reactions. However, in some cases the leukocyte populations may vary: in Pseudomonas infections, neutrophils are recruited continuously for several days, and in viral infections, lymphocytes are the first to arrive, thus example.

Mediators of inflammation

These mediators are small molecules consisting of lipids (prostaglandins, leukotrienes and thromboxane), modified amino acids (histamine, serotonin) and small proteins (cytokines, growth factors, interleukins...) that represent specific information for cells able to use this information thanks to the presence of specific receptors in their plasma membrane. Inflammation mediators are of plasmatic (synthesized by the liver) or cellular origin.

Arachidonic acid metabolites

Arachidonic acid (AA) is a derivative of the essential fatty acid linoleic acid, with many double bonds, which is normally found esterified as a phospholipid in cell membranes. AA is released by the action of cellular phospholipases, from any activated cell (platelets), stressed or about to die from necrosis. Once released, AA can be metabolized in two ways:

• cycloxigenous (constitutive form COX-1 and inducible COX-2) generate intermediaries that, after being processed by specific enzymes, produce prostaglandins (PGD2 produced by mast cells, PGE2 by macrophages and endothelial cells, among others) and tromboxans (TXA2, the main metabolite of the Alina)
• Lipooxigenas generate intermediaries of leucotriene and lipoxins.

Arachidonic acid derivatives (also called eicosanoids) serve as intracellular or extracellular signals in a wide variety of biological processes, including inflammation and hemostasis. Its main effects are:

• prostaglandins (PGD2, PGE2): vasodilation, pain and fever;
• prostacyclines (PGI2): vasodilation and inhibition of platelet aggregation;
• tromboxanos (TXA2): vasoconstriction and activation of the platelet aggregation;
• leucotrienos: LTB4 is a chemotactic and neutrophil activator; the other leucotrienos are vasoconstrictors, induce bronchospasm and increase vascular permeability (much more powerful than histamine);
• lipoxins: vasodilation, inhibition of the adherence of the NPMs; these AA metabolites produce a decrease in inflammation, so they intervene in the detention of inflammation; unlike the rest of the AA derivatives, they need two cell types to be synthesized: neutrophils produce intermediaries of synthesis, which are converted into lipoxins by platelets.

Vasoactive amines: histamine and serotonin

Histamine and serotonin are the two main vasoactive amines, named for their important action on the vessels. They are stored already preformed in granules, within the cells that produce them, which is why they are early mediators of inflammation. The main producer of histamine are mast cells, although it is also produced by basophils and platelets. In the case of mast cells, histamine is released when these cells produce degranulation, in response to different types of stimuli:

• Physical damage, such as trauma, cold or heat;
• Union of antibodies to mast cells, which is the basis of allergic reactions;
• Union of elements of the complement system called aafilotoxines (especially C3a, C5a);
• Proteins that induce the release of histamine from leukocytes;
• Neuropeptides (e.g. substance P);
• Cytokines (IL-1, IL-8).

Histamine dilates arterioles and increases the permeability of venules. It is the main mediator of the immediate transient increase in vascular permeability, producing interendothelial spaces in the venules that favor the outflow of plasmatic exudate. This effect is carried out through H1 receptors present on endothelial cells.

Serotonin is another preformed mediator that produces similar effects. It is present in platelets and in certain neuroendocrine cells, for example in the gastrointestinal tract. Serotonin (and histamine) release is activated when platelets aggregate in contact with collagen, thrombin, ADP, and antigen-antibody complexes (see Haemostasis for more detail on this process).

Cytokines

Cytokines are small proteins (between 5 and 20 kD) that allow the exchange of information between different cells during the process of inflammation, hematopoiesis, and immune responses. The growth factors used by epithelial cells to stimulate their renewal are also cytokines.

In general, cytokines can be considered as hormones with a limited radius of action, with the exception of IL-1 and TNF-α, which function as true hormones, transmitting information throughout the entire organism.

Cytokines released by macrophages during inflammation will affect endothelial cells, PMNs (during the acute phase) and then fibroblasts and endothelial cells again during the repair phase. The information emitted by a cytokine will only be received by those cells that present specific receptors for that cytokine. Cytokine messages are multiple; The main ones are:

• Proliferation (growth factors);
• Differentiation;
• Migration (Chemokin);
• Apoptosis (TNF family);
• Pro-inflammatory action (IL-1 and TNF-α);

Some very important messages, such as the stimulation of T lymphocytes, are delivered by many cytokines. This redundancy ensures the transmission of information.

Platelet Activating Factor

Platelet activating factor (PAF) is another phospholipid-derived mediator. It is found on platelets, mast cells, basophils, PMNs, monocytes, macrophages, and endothelial cells. Its main actions are:

• aggregation of platelets;
• vasoconstriction and broncoconstriction;
• leucocyte adherence to the endothelium;
• chemotaxis;
• degranulation and oxidative bursting;
• activation of the synthesis of eicosanoids.

Nitric oxide

Nitric oxide (NO) is a gas produced in some brain neurons, macrophages, and endothelial cells. It acts in a paracrine manner (action and local) on target cells, through the induction of cGMP, which initiates a series of intracellular events that cause smooth muscle relaxation (vasodilation). The in vivo half-life of NO is very short, so it only acts on cells very close to the place of production.

NO is synthesized from L-arginine by the enzyme NO-synthase (NOS). There are three types of NOS: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). The first two are constitutive, are expressed at low levels, and can be rapidly activated by increasing intracellular calcium levels. However, iNOS is activated only when macrophages and other cells are activated by cytokines (such as IFN-γ) or microbial products.

Oxygen Free Radicals (ORR)

Oxygen free radicals are a type of reactive oxygen species (ERO, or also ROS, for its acronym in English). These radicals can be released into the extracellular milieu by leukocytes after they have been activated by the presence of microbes, chemokines, immune complexes, or after phagocytosis. Its production depends on the activation of the NADPH oxidase system. The main species produced intracellularly are the superoxide anion (O₂^-), hydrogen peroxide H2O2 and the hydroxyl radical (*OH). Superoxide anion can combine with nitric oxide to form reactive nitrogen species. These substances attack all biological materials (DNA, proteins, lipids...), either removing electrons, removing hydrogen atoms or adding to double bonds: they react as powerful oxidants. The consequence is, therefore, the alteration and subsequent loss of function of the affected molecules.

The extracellular release of these potent substances at low concentrations activates chemokines, cytokines, and leukocyte endothelial adhesion molecules, amplifying the inflammatory response. They are involved in the following inflammatory responses:

• Damage to endothelial cells, which consequently produces an increase in vascular permeability; when PMNs adhere to endothelial, if activated, they can not only release these products, but induce the production of ERO in the endothelio;
• Damage to other cells, such as red blood cells or parenchyma cells;
• Inactivation of antiprotease, such as α1-antitripsin, which causes an increase in tissue destruction; this occurs, for example, in pulmonary emphysema;

Plasma, tissue fluids, and cells possess antioxidant mechanisms to protect themselves from oxygen free radicals. Among these are:

• The superoxide dismutase enzyme, which converts superoxide anion into hydrogen peroxide;
• The Catalan enzyme, which detoxifies hydrogen peroxide;
• Peroxidase glutathione, another powerful H detoxifier₂O₂;
• uric acid, a potent antioxidant present in plasma at a much higher concentration than ascorbate (vitamin C);
• Ceruloplasmin protein, the main copper conveyor in the serum;
• The iron-free plasma fraction of the transferrin protein.

In addition, there are compounds of food origin with antioxidant capacity that are also involved in the neutralization of ROS:

• α-tocopherol (vitamin E), soluble, with capacity to protect cell membranes;
• Carotenoids (such as β-carotene) and polyphenols (such as caffeic acid and quercetin);
• Ascorbate (vitamin C), hydrosoluble, capable of regenerating other antioxidants, such as glutathione or α-tocopherol.

For this reason, the negative effect of ROS is observed if an imbalance occurs due to an exaggerated production of these substances or due to a decrease in the defense systems, enzymatic and non-enzymatic.

Constituents of leukocyte lysosomes

Neutrophils and monocytes contain lysosomal granules necessary for the digestion of phagocytosed materials. If these compounds are released abroad, they can amplify the inflammatory response, since they have a destructive effect on tissues (elastases, collagenases, proteases...). To counteract its effect, there are antiproteases in the serum, mainly α1-antitrypsin, which is the main inhibitor of elastase. Another important antiprotease is α2-macroglobulin.

Neuropeptides

Neuropeptides are substances secreted by sensory nerves and various types of leukocytes, and play a role in the propagation of the inflammatory response. Among them are substance P and neurokinin A, belonging to the family of tachinins and produced in the CNS and peripheral. The lungs and gastrointestinal tract are rich in fibers that contain substance P. Substance P has many functions: transmission of pain signals, regulation of blood pressure, stimulation of endocrine cell secretion, and increased vascular permeability.

Mediators derived from plasma proteins

A great variety of phenomena in the inflammatory response are mediated by plasma proteins that belong to three interrelated systems:

• The complement system: the proteins of this system are present in plasma in an inactive way, and when activated they become protein enzymes that degrade other supplement proteins, forming a cascade; the elements involved in the inflammatory process are C3a, C5a and to a lesser extent C4a, called C4a. aafilotoxines, which stimulate the release of histamine by mastocytes, and therefore produce vasodilation; C5a also has chemotactic capacity and activates lipooxigenase, generating leucotrienos;
• Coagulation; inflammation increases the production of some coagulation factors and turns the endothelium into thrombogenic; in counterpart, the thrombin promotes inflammation by activating receptors called PAR (protease-activated receivers), which activate different responses: mobilisation of selectina-P, production of chemists and cytokines, expression of receptors for integralins in the endothelio, induction of COX-2 and production of prostaglandins, production of NO and PAF, and changes in the endothelial form. Since coagulation and inflammation can start a vicious amplification circle, coagulation interference can be a therapeutic strategy in some pathologies to reduce inflammation;
• Quinins are vasoactive peptides derived from plasma proteins, called quiningens, by the action of specific enzymes called calicreins; the quinine system is intimately linked to coagulation: the active form of factor XII, FXIIa, converts plasma precalicrein into calicreine, which cuts a protein from high molecular weight plasma to generate bradiquin. Bradiquinin increases vascular permeability and causes contraction of the smooth muscle, dilation of the vessels and pain, effects similar to those of histamine. On the other hand, calicreine has chemotactic effect, converts C5 from the plug-in system into C5a (also chemotactic) and converts plasmin to degrade the secondary clot.

Of these three systems, probably the most important mediators of inflammation in vivo are bradykinin, C3a, C5a and thrombin .

General effects of inflammation

The cytokines IL-1 and TNF-α produced by macrophages function like "hormones" of inflammation, and act on the body as a whole to mobilize all available resources to fight against the infectious agent. In particular, its action on the fever center makes it possible to raise the temperature, which compromises bacterial survival. Its action on the liver increases the synthesis of acute phase proteins, which are also antibacterial (complement system, C-reactive protein).

Stopping the acute inflammatory response

Since this powerful defense process can cause extensive damage to host tissues, it is important to keep it under tight control. In part, inflammation subsides simply because the mediators are produced in rapid bursts, only while the stimulus persists, have short half-lives, and are degraded upon release. Neutrophils also have a short half-life and die by apoptosis within a few hours after leaving the blood. In addition, during the development of the inflammatory process, a series of STOP signals are triggered that serve to end the reaction actively:

• Change in the type of metabolites produced from arachidonic acid, changing the pro-inflammatory leucotrienos by anti-inflammatory lipoxins;
• Macrophages and other cells release anti-inflammatory cytokines, such as TGF-β and IL-10;
• Production of anti-inflammatory lipid mediators (such as solvents and protectins), derived from polyunsaturated fatty acids;
• Generation of nervous impulses (colinergic loads) that inhibit TFN production by macrophages.

Chronic inflammation

When the inflammation persists for a long time (weeks or months), we speak of chronic inflammation, in which tissue damage and attempts at repair coexist, in various combinations. It can occur due to maintenance of acute inflammation (if the cause is not resolved), or start progressively and not very evident, without the manifestations of acute inflammation. This second case is responsible for tissue damage in some of the most disabling human diseases, such as rheumatoid arthritis, atherosclerosis, tuberculosis or pulmonary fibrosis. In addition, it is important in the development of cancer and in diseases that were previously considered exclusively degenerative, such as Alzheimer's.

In case of non-resolution, the bacteria are also drained and the infection spreads through the lymphatics: lymphangitis (inflammation of the lymphatic vessels) and lymphadenitis (inflammation of the lymph nodes).

Causes

Among the causes of chronic inflammation can be distinguished:

Persistent infections

For microbes that are difficult to eradicate, such as mycobacteria, certain fungi, viruses, and parasites. They can lead to the formation of granulomas.

Immune-mediated diseases

In some diseases in which the immune response is produced in an exaggerated or inappropriate way in relation to the triggering agent, chronic inflammation plays an important role in the pathological aspect of the disease. In these cases, as the immune response is oversized, it does not produce benefit, but harm. For example:

• In autoimmune diseases, an individual's immune system produces antibodies against his own tissues, causing a continuous immune reaction that results in chronic inflammation and tissue damage; it is the case of rheumatoid arthritis and multiple sclerosis;
• In other cases, there is an exaggerated immune response to microbes, such as Crohn's disease, in which a reaction occurs against intestinal bacteria;
• In allergic reactions, there is a disproportionate response to common environmental agents, such as bronchial asthma.

In this type of disease, repeated outbreaks of inflammation usually occur, so mixed characteristics of acute and chronic inflammation can be observed.

Prolonged exposure to toxic agents

These agents can be:

• Exogenous, such as silica powder, inert and non-degradable material, which inhaled for prolonged periods can produce inflammatory disease of the lungs known as silicosis;
• Endogens: The accumulation of toxic endogenous lipids (see also LDL) in the blood vessels causes chronic inflammation of the blood vessels, causing atherosclerosis.

New theories: increased intestinal permeability

Spray of the wall of the intestine with increased permeability. The two most powerful factors that cause it are certain intestinal bacteria and gliadine (main toxic fraction of gluten), regardless of genetic predisposition, i.e., both in celiacs and in non celiacs. This allows the uncontrolled passage of substances to the bloodstream, with the consequent possible development of inflammatory, autoimmune diseases, infections, allergies or cancers, both intestinal and other organs.

The alteration of intestinal permeability is implicated in the development of a growing number of diseases, among them certain inflammatory diseases, in which the increase in intestinal permeability allows the passage of antigens from the intestine to the blood, producing a immune response that can be directed against any organ or tissue.

The intestinal epithelium is the largest mucosal surface in the body and interacts with the environment. When the intestinal mucosa is healthy, with intact permeability, it constitutes the main barrier to prevent the passage of macromolecules (incompletely digested nutrients, toxins and certain intestinal bacteria). When intestinal permeability is damaged (increased), the intestinal barrier loses its protective function and molecules that should not pass enter the bloodstream, causing the appearance of immune reactions. In most cases, increased intestinal permeability occurs before the disease and causes an abnormality in antigen exposure that triggers the inflammatory process. This implies that the inflammatory response can theoretically be stopped, and possibly reversed, if the environmental trigger(s) are removed.

The two most potent factors that cause increased intestinal permeability are certain intestinal bacteria and gliadin (the main toxic fraction of gluten), regardless of genetic predisposition, that is, both in celiac and non-celiac patients. Other possible causes are prematurity, radiation exposure, and chemotherapy.

Features

While acute inflammation is characterized by the appearance of vascular changes, edema, and neutrophil infiltration, chronic inflammation presents the following distinctive features:

• Mononuclear cell infiltration: macrophages, lymphocytes and plasma cells;
• Destruction of tissues, due to the persistence of the agent or inflammatory cells;
• Reconstruction attempts, replacing damaged tissue with connective tissue, with proliferation of vessels (angiogenesis) and, above all, fibrosis.

In addition to cellular infiltrates, in chronic inflammation the growth of blood vessels (angiogenesis) and lymphatics is very important, stimulated by growth factors such as VEGF, produced by macrophages and endothelial cells.

Cells involved in chronic inflammation

Macrophages

Macrophages are the dominant cell type in chronic inflammation. They are one of the components of the mononuclear phagocytic system, also called the reticulo-endothelial system, which is made up of cells originating in the bone marrow. Macrophages are tissue-resident cells, which originate from plasma monocytes. However, while monocytes have a short half-life (1 day), tissue macrophages survive for months or years. Depending on the tissue in which they are found, tissue macrophages are called by different names: for example, histiocytes of connective tissue, Kupffer cells of the liver, Langerhans cells of the epidermis, osteoclasts of bone tissue, microglia of the CNS or the alveolar macrophages of the lung. Tissue macrophages are sentinel cells, together with mast cells, since they present specific receptors capable of detecting infectious agents, such as Toll-type receptors. The binding of these receptors to their ligands causes macrophage activation, a process that can also be induced by the presence of cytokines such as interferon-γ (IFN-γ), a molecule secreted by activated T lymphocytes and NK cells.

The products of activated macrophages kill microbes and initiate the tissue repair process, and are responsible for most tissue damage in chronic inflammation. Among these products, we can highlight reactive oxygen (ROS) and nitrogen species, as well as lysosomal enzymes, cytokines, growth factors, and other inflammatory mediators. Some of these products, such as free radicals, are toxic and destroy both microbes and tissue; others attract other cell types or induce collagen production by fibroblasts or angiogenesis. In fact, there could be two different populations of activated macrophages, depending on the type of activation they have undergone:

• Activation by microbes or IFN-γ: production of inflammatory substances, harmful to tissues (ROS and RNS, proteases, cytokines, coagulation factors, metabolites of arachidonic acid);
• Activation by IL-4 and other cytokines: production of tissue repair mediating substances (growth factors, fibrogenic cytokines, angiogenic factors such as FGF...).

The destructive artillery at the disposal of macrophages makes them effective combatants in the fight against the invasion by pathogens, but it becomes a fearsome double-edged sword when directed towards the tissues themselves. For this reason, tissue destruction is a characteristic element of chronic inflammation, since unlike acute inflammation, in which macrophages disappear when the cause is eliminated (they die or enter the pathways). lymph nodes), in chronic inflammation macrophages accumulate, increasing collateral damage.

Lymphocytes

Lymphocytes are cells that are mobilized in the specific response of the immune system, activating with the aim of producing antibodies and cells capable of identifying and destroying the pathogenic microbe. Macrophages secrete cytokines (especially TNF and IL-1) and chemokines capable of recruiting leukocytes from the blood and mobilizing them towards the affected area. The interactions between lymphocytes and macrophages are bidirectional, since macrophages recruit and activate lymphocytes, and these in turn secrete cytokines (especially IFN-γ) with a potent capacity to activate macrophages. So once the lymphocytes kick in, the inflammation tends to escalate, becoming chronic and severe.

Plasma cells

Plasma cells differentiate from activated B lymphocytes. Its function consists in the production of large amounts of antibodies directed against the pathogenic microbe, or sometimes against endogenous antigens (in autoimmune diseases). In some patients with chronic inflammation (such as rheumatoid arthritis), plasma cells, lymphocytes, and antigen-presenting cells accumulate in lymph node-like nodules that even contain well-defined germinal centers. These nodes are called tertiary lymphoid organs.

Eosinophils

Eosinophils are abundant in IgE-mediated inflammatory reactions and in parasitic infections. These leukocytes have granules that contain the major basic protein, a very basic cationic protein that is toxic to both parasites and tissues. They therefore have an important role in the destruction of tissues in immune reactions, such as allergies.

Mast cells

Mast cells, like macrophages, are sentinel cells widely distributed throughout tissues, which react to physical stress (heat, cold, pressure), and are involved in both acute and chronic inflammation. In their membranes they have receptors for IgE, which in immediate hypersensitivity reactions, stimulate degranulation, releasing mediators such as histamine and prostaglandins. This type of reaction occurs in allergic reactions, being able to produce an anaphylactic shock. In chronic inflammation, as they have a wide variety of mediators, they can promote or limit inflammation, depending on the circumstances.

Neutrophils

Although neutrophils (PMN) are characteristic of acute inflammation, in many cases of chronic inflammation the presence of PMN can be detected for months, either due to the persistence of the infection or mediators produced by lymphocytes. This occurs, for example, in osteomyelitis (chronic bacterial infection of the bone) or in chronic lung damage induced by tobacco smoke and other irritants.

Granulomatous inflammation

It is a characteristic pattern of chronic inflammation that is only found in a few well-defined cases of chronic inflammation. A granuloma is a cellular attempt to isolate a foreign body that cannot be phagocytosed. Normally there is a strong activation of T lymphocytes, which in turn induces the intense activation of macrophages. As a result of this activation, granulomas are produced, which are foci of chronic inflammation, in which the pathogenic agent is in the center, surrounded by macrophages transformed into pseudo-epithelial cells, surrounded by mononuclear leukocytes, especially lymphocytes and sometimes plasma cells. The prototype of granulomatous disease is tuberculosis, but granulomas can be identified in other diseases, such as syphilis, vasculitis, sarcoidosis, leprosy, or Crohn's disease. Two fundamental types of granulomas can be detected:

• By strange body: generated by relatively inert external materials, such as talc (associated with intravenous drug abuse), sutures or other materials that are not easily fed; often due to the use of prosthesis, surgical material, silice, berylium...;
• Immune: Induced by a variety of agents capable of inducing a cell-mediated immune response, when the pathogen is difficult to degrade.

The granuloma can be associated with:

• Necrosis.
  • Casey: produced by micobacteria.
  • Abscessified: in cat scratch disease, bartonella infections...
• Fibrosis: which perfectly limits granuloma as it occurs in sarcoidosis.
• Plasmatic lymphocytes and cells: surrounding it.
• Other granulomas: not individual, but merged (tuberculosis or brucellosis).

When there is a lot of fibrosis, the granuloma is perfectly differentiated and is called sarcoidosis: a disease that mainly affects the lungs, lymph nodes, skin, conjunctiva, kidney... Other times a space with gas can be formed; uric acid crystals may also appear, which are deposited forming the granuloma (gout). And in tuberculosis, the granuloma is characterized by central caseous necrosis without inclusions and without fibrosis, which differentiates it from sarcoidosis. However, there are so many atypical presentations of granulomas that it is always necessary to identify the pathogenic agent by other methods: specific stains, cell cultures, molecular techniques (such as the polymerase chain reaction or PCR technique) or serological studies.