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Cellular Environment Inflammation and Infection
According to McCance et al. (2010) the distribution of water and solutes in the various compartments of the organism are important to maintain a state of equilibrium. Homeostasis is maintained by the coordinated action of hormonal, renal and vascular adaptations. The body\’s total water corresponds to (50-75%) of body mass depending on age, sex and fat content. It is distributed between the extracellular space that constitutes 20-25% of the weight (1/3 part of the total water) and the intracellular space that represents 30-40% of the weight (2/3 parts of the total water). The extracellular fluid is formed by plasma (5%), interstitium (15%) and transcellular water (1-3%). Intracellular space is altered by: (a) disturbances in the osmolarity of the extracellular space. (B) disturbances in the contribution of energy requirements. The volume of extracellular fluid varies in the critically ill patient by sequestration and accumulation of liquids in potential spaces such as pleural, pericardial and intraperitoneal.
The electrolytes according to Kaplan (2008) intervene in many functions, but they are not evenly distributed in the three liquid compartments. In spite of this, their distribution must always comply with the physiological principle that the total number of anions and the total number of cations in a compartment must be equal. In the plasma or intravascular compartment the sum of anions and cations ranges from 320 to 340 mEq / L. The most important cation is sodium (134 to 142 mEq / L). It is obtained with food, is eliminated by urine and sweat, and its main function is to intervene in acid-base balance and facilitate the transport of CO2 in the form of bicarbonate. Potassium facilitates the progression of the nerve and muscle impulse, and also participates in cardiac contractility. However, potassium, like calcium and magnesium, is found in small amounts. Other cations, such as iron and copper, are found in almost imperceptible amounts (indicia). Calcium contributes to bone formation, plays a role in the coagulation processes, and modifies the permeability of membranes. Magnesium contributes to calcium in muscle contraction and bone formation, and is an activator of many enzymes. Iron is an essential cation to form hemoglobin in red blood cells. Finally, copper is needed to form certain defensive cells and is involved in immunity. The main and most abundant anion is chlorine. Its revenues and losses are similar to those of sodium, to which it is linked as ClNa. Intervenes in acid-base balance and is essential for the formation of hydrochloric acid. Proteins are considered as negatively charged electrolytes and are of vital importance, although they are found in less quantity than bicarbonate.
The electrolytes that are in the gap range between 300 and 340 mEq / L and are distributed practically the same as in the plasma. The big difference is that in the interstice the proteins must be in a very low quantity or completely lacking. This difference is explained by the great difficulty of proteins to leave the capillaries and by the action of lymphatic vessels that flow between the interstitial tissue, whose mission is to recover and drain the proteins that are in the interstitial fluid.
The intracellular compartment is the most important because it constitutes the cytoplasm of all cells. In this case, the distribution of the electrolytes presents two marked differences with the previous compartments. (A) the sum of intravascular electrolytes is greater (between 350 and 400 mEq / L). (B) the amount of anions and cations inside the cell has a very different distribution from that of the outside. The main intracellular cation is potassium (150 mEq / L), followed by magnesium (40 mEq / L) and sodium (only 10 mEq / L). The major anions are proteins (85 mEq / L), followed by phosphates (75 mEq / L), bicarbonate (15 mEq / L), sulfates (21 mEq / L) and chlorine ). Potassium, which is obtained from the diet and is eliminated by the kidney, is essential for cardiac diastole and the use of glucose by the cells, facilitates the transport of oxygen (as potassium oxyhemoglobin) and is involved in acid-base balance , Among other functions.
Inflammation is a tissue process constituted by a series of molecular, cellular and vascular phenomena of defensive purpose against physical, chemical or biological aggressions. The basic aspects that stand out in the inflammatory process are, firstly, the targeting of the response, which tends to circumscribe the area of fight against the aggressor. Secondly, the inflammatory response is immediate, of urgency and therefore, predominantly non-specific, although it may favor the later development of a specific response. Third, the inflammatory focus attracts immune cells from nearby tissues. The vascular alterations will allow, in addition, the arrival from the blood of immune molecules. Classically the inflammation has been considered integrated by the four signs of Celsus: Heat, Flushing, Tumor and Pain. As we will see later, the heat and flushing are due to vascular alterations that determine a blood accumulation in the focus. The tumor is caused by edema and accumulation of immune cells, while pain is produced by the action of certain mediators on the nerve endings of pain. In a schematic way we can divide the inflammation into five stages:
(1) Mediator release: molecules, most of them, of elemental structure that are released or synthesized by the mast under the action of certain stimuli.
(2) Effect of mediators: once released, these molecules produce vascular alterations and chemotactic effects that favor the arrival of molecules and cells immune to the inflammatory focus.
(3) Arrival of molecules and cells immune to the inflammatory focus: they come mostly from the blood, but also from the areas surrounding the focus.
(4) Regulation of the inflammatory process: like most of the immune responses, the inflammatory phenomenon also integrates a series of inhibiting mechanisms tending to finalize or balance the process.
(5) Repair: phase consisting of phenomena that will determine the total or partial repair of the tissues damaged by the aggressor agent or by the inflammatory response itself.
A wide variety of infectious agents (viruses, bacteria, protozoa, fungi and helminths) are capable of infecting humans. In many cases, the infectious agent can colonize a tissue or organ and maintain its number without causing harm (colonization). Infectious disease occurs when it causes signs and symptoms of inflammation or functional disturbance of organs resulting in a clinical problem and is not necessarily a consequence of infection.
Pathogenicity is a relative term, resulting from the balance between virulence, or intrinsic pathogenic power, and the defensive resources used by the host to neutralize the infectious threat. Virulence factors are the components of the microorganism that allow them to colonize, proliferate, invade and destroy host tissues and determine their ability to cause disease. Among the factors that stimulate the growth of microorganisms and favor colonization and tissue invasion are surface molecules (adhesins), digestive enzymes secreted by the invading microorganism, bacterial toxins, which can be secreted (exotoxins), or highly structural lipopolysaccharides Heterogeneous bacteria that are part of the wall of Gram-negative bacteria (endotoxins). Exotoxins are proteins that can cause disease without prior infection.
There is a great variety of mechanical, chemical, cellular and immunological mechanisms that have developed throughout the evolution of the human species to prevent the invasion of microorganisms. Among the latter the most important is the immune system. A slight disturbance in one of these mechanisms can lead to an infection by microorganisms little virulent and a major alteration, even to avirulent microorganisms. Many microorganisms whose pathogenicity is low may lead to severe disease in depressed hosts and are called opportunistic microorganisms.
About the defense mechanisms of the host we can mention that the defense reactions can take place of specific form or nonspecific. Nonspecific, albeit indiscriminate and non-specific responses of Ag have the advantage of intervening rapidly during an acute infection and may allow the survival of the host until specific responses congregate new defenses. Nonspecific responses, most of which occur minutes or hours after infection, make up what is called a natural or innate response or immunity whose level is not increased by repeated immunization. In contrast, adaptive immunity or specific Ag is increased by repeated immunization of the inducing Ag, it takes days or weeks to appear after primary exposure, but is often indispensable for complete resolution of the disease. Although most defense mechanisms are described separately, they are intimately related systems that rarely act independently.
Natural immunity involves nonspecific, mechanical, chemical, cellular and some of the immunological mechanisms that prevent the colonization or infection of healthy individuals by the surrounding microorganisms.
One of the most important defenses against infection is professional host phagocytes, polymorphonuclear (PMN) and monocytes / macrophages. When an infection occurs, the PMNs are the cells that first come to the site of the same. PMNs guided by chemotactic substances diffused from the infected region alter their adhesion mechanisms adhering to and traversing the endothelium. Subsequently, these same factors lead to a targeted migration of PMNs to the site of inflammation and infection. These chemotactic factors are substances released by the host in response to infection and microbial products, among which are the formyl peptides produced by bacteria that are recognized by phagocytes. Several microorganisms activate the alternative pathway of C, generating C5a. In addition, phagocytes secrete leukotriene LTB4. Both C5a and LTB4 are chemotactic.
Phagocytes are able to enter endocytosis and destroy a number of microorganisms, although these functions are enhanced by components of the specific immune response among which are: (a) cytokines, secreted mainly by lymphocytes after recognition of Ag, Necessary for its activation. (B) antibodies, secreted by B lymphocytes, that give them opsonic and effector properties increasing the recognition and union of the microorganisms.
Phagocytes produce a series of molecules that mediate their anti-infective action that have been classically divided into dependent or independent of oxygen metabolism. These include a series of extremely basic microbicidal compounds such as lysozyme, lactoferrin, cathepsin, elastase and the recently described defensins (a set of homologous peptides that damage a wide variety of prokaryotic and eukaryotic microorganisms). They also produce cytokines that serve to eliminate certain bacteria, either by promoting opsonization in the presence of antibodies, either directly, or by increasing the cellular permeability associated with inflammatory responses. Eosinophils contain a number of toxic proteins that destroy helminths.
Oxygen-dependent mechanisms include a number of compounds derived from the consumption of O2, such as O2-, H2O2, and hydroxyl radical, which are very reactive and are very important in the destruction of intracellular pathogens. Recently, a new mechanism has been described that involves the synthesis of reactive intermediates of nitrogen oxides, such as NO, from L-arginine, by an enzyme called NO synthetase. This enzyme is inducible in macrophages by cytokines such as TNF and IFN-g or by bacterial endotoxins as LPS and appears to be the most important mechanism in the destruction of intracellular pathogens.
NK cells are a group of large granular lymphocytes that destroy some cells infected by intracellular viruses and parasites by direct cytotoxicity not restricted by the MHC or by mechanisms of cellular activation dependent Cell cytotoxicity (ADCC).
The products of the microorganisms also directly stimulate the synthesis of cytokines by macrophages and NK cells, so that some cytokines can be considered as part of the natural immunity. However, their amount increases after a specific immune response due to their direct synthesis or their control by the Ag-specific T lymphocytes. Bacterial endotoxins directly stimulate the synthesis of IL-1 and TNF by macrophages increasing the adhesion of phagocytes and lymphocytes to the endothelium. TNF plays a central role in the anti-infective response by its inflammatory properties, activating the macrophages and PMNs, besides having an important role as inducer of necrosis and to induce fever. This cytokine also induces the production of prostaglandins, activates the antithrombocytic properties, the synthesis of platelet activating factor (PAF) and the expression of adhesion molecules in endothelial cells and the proliferation of fibroblasts. In addition, TNF stimulates the cytotoxicity of other immune effector cells, such as eosinophils, NK cells and T lymphocytes.
Viruses induce the synthesis of several IFNs that play a very important role in resistance to certain viral infections. IFNs are able to exert antiviral action in a number of synergistic ways: block viral replication, increase MHC expression, and activate NK cells and macrophages.
The specific immune response is usually slow and not very effective when faced with a microorganism for the first time. However, when immune memory is induced, the second time is much faster and more effective. This response, which is characterized by specificity and memory, is mediated by both T and B lymphocytes that have specific Ag receptors in their membranes capable of recognizing various antigenic determinants.
Adaptive immune responses can be of three main types considering the main effector mechanisms. Monocytes are unable to destroy certain pathogens, but their destruction capacity is greatly increased if they are activated by cytokines secreted by Th1 cells. This activation is mediated by IFN-g, although other lymphokines, especially TNF, play a costimulatory role in IFN activity. Activation of macrophages implies a greater increase of all the mechanisms of destruction of the same ones especially of those dependent of oxygen and NO.
B lymphocytes secrete specific Acs with the cooperation of Th2 lymphocytes and to a lesser extent Th1 lymphocytes. These Acs are able to eradicate certain infections by several mechanisms: (a) they prevent the union of the microorganisms to their cellular and tissue receivers. (B) neutralize or inactivate directly the microorganism; Occurs when the Acs join an Ag that has a vital function for the parasite, such as toxins. (C) activate fixation and the C system promoting lysis of microorganisms. (D) favor the phagocytosis of monocytes, macrophages and PMNs through binding to the FcR (opsonization). (E) Promotes Ac-dependent cellular cytotoxicity (ADCC) reactions of cytotoxic and eosinophilic cells.
Cytotoxic CD8 + T cells destroy cells infected with intracellular microorganisms through recognition of MHC-associated Ag. Its activation requires the cooperation of cytokines produced by Th1 cells, IL-2 and to a lesser extent IFN-g. They preferably determine antiviral activity but are also effective against some intracellular protozoa. Their action may be directly cytotoxic or due to the secretion of lymphokines such as IFN-g. Induction of one or another T lymphocyte subpopulation (Th1 or Th2), which involves the concomitant synthesis of the respective lymphokines, is key to induce a protective immune response in most infections by microorganisms.
Unfortunately, infectious agents have adapted in the most convenient way for their own survival, developing sophisticated systems of evasion of the host\’s protective responses. Thus, certain facultative intracellular parasites, especially protozoa and bacteria, are protected from a large part of the immune effector systems because of their intracellular localization and although the host cell a can express Ags of the parasite in its membrane, these, in fact, do not usually Trigger a protective immune response against infected cells, unlike what happens with viral infections. Many other parasites have developed various strategies to avoid the antigenic recognition on which all immunological mechanisms depend: mimicry, due to the absorption of host proteins or by imitation of host surface proteins; Release of Ags to the medium blocking the interaction of the Acs with the microorganism; Change of Ags during the different stages of development.
(1) Antigenic variation: The most obvious mechanism of immune evasion is antigenic variation, known especially well in some African trypanosomes bacteria and viruses. This can be by mutation, gene change or gene recombination. In theory the antigenic shift may be related to the response to effector immune mechanisms, but in practice, no parasite using antigenic variation does so, possibly because it prevents its elimination by an effective immune response.
(2) Avoiding C-mediated lysis: many microorganisms prevent C-mediated lysis either by inhibition of C-cascade activation or C-action. Inhibition of activation can be achieved by synthesis or acquisition Of regulatory molecules, blockade of C activation or formation of a non-lytic complement C5b-9 complex.
(3) Evasion of microbicidal systems: certain facultative intracellular microorganisms are able to evade the microbicidal systems of phagocytes. There are basically 3 types of evasion: (a) Inhibition of fusion between phagosome and lysosome. (B) Escape from the phagocytic vacuole to the cytoplasm (c) Resistance to the degradation systems of lysosomes.
(4) Immune response suppression induction: to avoid being eliminated by the immune system the parasites generally induce a suppression of the immune response. Mechanisms are very varied and include induction of suppressor cells, alteration of cytokine functions or preferential induction of non-protective Th subpopulation. Sometimes immunosuppression caused by an infection leads to states of severe immunosuppression. This is the case of HIV-1 infection which is known to lead to immunosuppression, hence the name AIDS (acquired immunodeficiency syndrome) that is reached when infection progresses. Other cases of immunological deficiencies such as a viral infection appear in measles, hepatitis A, B and C, influenza and rubella. After immunological infections, immunological defects have also been observed.
There are many factors that determine why certain pathological complications are associated with infections and not others. The pathology may be mediated by the parasite or by the host\’s own response. In some microorganisms the tissue damage occurs as a consequence of the replication itself, to allow colonization, to evade the immune response or due to toxins. In many other cases it is the immune response itself to the microorganism that causes an Immunopathology. Immune responses may be potentially dangerous due primarily to autoimmune or hypersensitivity reactions.
Autoimmunity, is usually a consequence of the antigenic mimicry used as a mechanism of evasion of the immune response performed by several microorganisms. There is a growing belief that certain autoimmune diseases have an infectious etiology due to the antigenic similarity between microorganisms and the host.
When inflammatory reactions are mild or moderate in intensity, they are an important defense mechanism, favoring the arrival of immune cells at the sites of infection. However, an excess of immune response, hypersensitivity, can be detrimental to the host by destroying normal tissues.
Excess production of certain cytokines can also cause pathology. The most dramatic example is the role of TNF in septic shock associated with multiple bacterial infections and in cerebral malaria.
The predominance, in the immune response to an infectious agent, of one or the other subpopulation of T lymphocytes (Th1 or Th2), and of the respective lymphokines that they produce results in either resistance or Immunopathology in many infections. Inhibition of one type of Th with the consequent stimulation of the other is associated with the pathology of many diseases including AIDS.
In summary, a better understanding of all the phenomena involved in host-infectious agent relationships is essential in overcoming infections by correctly stimulating the immune response by: (a) Correcting factors predisposing to infection. (B) A chemoprophylaxis and, above all, a better passive immunoprophylaxis that includes, in addition to Igs, cytokines. (C) To greatly improve the processes of active immunization (stability, route of administration) to increase the effectiveness of the new vaccines.
Kaplan. (2008). Medical Pathology USMLE Step 1 Lecture Notes
Le Tao. (2008). First Aid for the USMLE Step 1: A Student to Student Guide.
McCance K. (2010). Pathophysiology: The Biological Basis for Disease in Adults and Children.
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