Inflammation is the normal response of the body to infection, trauma and other forms of injury cell (e.g., immune-mediated diseases). The initial response from the body to an infection is inducing to pro-inflammatory state. In this situation, the pro-inflammatory mediators such as tumour necrosis factor (TNF), inteleukin-1 (IL-1) and interleukin-6 (IL-6), besides platelet activating factor (PAF), are released.
Apoptosis is the main mechanism through which dysfunctional cells are normally eliminated. Pro-inflammatory cytokines (IL-1, IL-6, and TNF) can slow down apoptosis as much as in activated neutrophils and macrophages. Nevertheless other tissues, such as intestinal epithelium, can suffer of accelerated apoptosis. As a consequence, an alteration in apoptosis plays a critical role in injury tissue in patients suffering from sepsis.
The sepsis syndrome could be considered as a constellation of signs and symptoms (humans) that represent the answer from the guest to the infection, through which effects of the cytokines (or substances developed by these) are responsible of most of the clinical manifestations.
In simple terms, the concept of sepsis is a dysfunction in the mechanism that normally maintains homeostasis. On the other hand, there is an increase in inflammation and coagulation, which is done through pro-inflammatory mediator, endothelial injury, tissue factor (TF) released and thrombin production. While on the opposite side we have fibrinogenolysis, which normally counteracts pro-clotting forces, is suppressed.
Sepsis affects tissue oxygenation, changing metabolic regulation that provides oxygen to tissues and helping in organic failure. Abnormal procedure in microvasculature and endothelium contribute in default in microcirculation, this is due trough reactive oxygen intermediates (ROI), lytic enzymes and vasoactive substances (e.g., NO).
The sequence of events that lead to sepsis, it is presumed that start with bacteraemia. The most external membrane of all gram-negative bacteria contains lipopolysaccharide (LPS) also called endotoxin, which interacts with the guest's reticuloendothelial system in such a way that it produces a septic state. In contrast, the gram-positive bacteria have in its cellular wall, which is five times thinner according to the gram-negative bacteria, teichoic acid or lipoteichoic acid.
Endotoxin, TNF-α and NO, can cause harm in carrying electrons in mitochondria, leading to disorders in energetic metabolism. This is called like anoxia cytopathic or histotoxic, which means being unable to use oxygen even when it is there.
Not all details about the events that lead to sepsis are known, but the emergent model is the following: Endotoxin bound to receptors found in mononuclear leucocytes (monocytes and macrophages). This interaction results in the secretion of multiple cytokines, when these are produced in excess, interleukin-1 (IL-1) and tumour necrosis factor (TNF) are the first cytokines that start with adversary effects. Many of the effects caused by cytokines are done through nitric oxide (NO), the metabolites of the arachidonic acid (prostaglandins, thromboxane and leukotrienes) and platelet activating factor (PAF). IL-1 and TNF stimulate the production of other cytokines, producing a cascade effect with multiple functions of enlargement and modulation (as much as up-regulation and down regulation). Specific and non specific anti-cytokines substances are currently produced including: glucocorticoids, interleukin-1 receptor antagonist (IL-1Ra) and soluble receptors to cytokines and endotoxin. In the same way some of the released cytokines (IL-4, IL-10 and transforming growth factor-β [TGF-β]), have anti-inflammatory effects in response to endotoxin, such as decreased in the IL-1 and TNF synthesis through mononuclear cells.
To make sure that pro-inflammatory mediator effects don't turn negative, the body sends anti-inflammatory mediators such as IL-4 and IL-10, which under normal conditions controls the down regulator response to the first pro-inflammatory response. These mediators show several overlapped effects, designed to repair existing injury or limited further injury.
Interaction between pro and anti-inflammatory mediators can lead to an imbalance in inflammatory reaction, immunodeficiency could dominate or both could occur.
In spite of the relative preservation of the blood stream to the myocardium, depression in this one is common in the early stages of the septic shock. This depression in the myocardium has been attributed to the direct toxic effects of the NO, TNF and IL-1.
In sepsis, control over an early response to an infection is lost and a massive systemic reaction takes place. An overflow of pro-inflammatory mediators such as TNF-α and IL-1 are released starting a physiologic response that causes tissue injury and developing of diffused capillary injury. Finally the excessive inflammatory response interferes in normal tissue functioning, leading to tissue injury and organic failure.
The result of sepsis depends on the number of organs that fails. Mortality in human patients with multiple organ failure (MOF) (three or more organic systems) is of 80 to 100%.
References
1. Young S. L. Sepsis Syndrome. In: Mandell, Douglas and Bennett's Principles and Practice of Infectious Diseases. Mandell L. G., Bennet E. J. & Dolin R. (Ed). 5th Ed. Churchil Livingstone. USA. 2000. pg. 806-819.
2. Brady A.C. & Otto M.C.. Systemic Inflammatory Response Syndrome, Sepsis and Multiple Organ Dysfunction. In: Critical Care Cardiovascular Focus. Dhupa N. (Ed). The Veterinary Clinics of North America: Small Animal Practice. W. B. Saunders Company. 2001. USA. 31(6). pg 1147-1162.
3. Jawa S. R.. Cellular Effectors of the Septic Process. In: Textbook of Critical Care. Shoemaker C. W., Ayres M. S., Grenvik A. & Holbrook R. P. (Ed.). 4rd Ed. W.B. Saunders Company. Philadelphia USA. 2000. pg. 523-541.