Editing Sepsis (section)

== Pathophysiology ==

Sepsis is caused by a combination of factors related to the particular invading pathogen(s) and the status of the immune system of the host.<ref name=Critical2005 /> The early phase of sepsis characterized by excessive inflammation (sometimes resulting in a [[cytokine storm]]) may be followed by a prolonged period of [[immunosuppression|decreased functioning of the immune system]].<ref name=Shukla2014/><ref name="pmid31611560" /> Either of these phases may prove fatal. On the other hand, systemic inflammatory response syndrome (SIRS) occurs in people without the presence of infection, for example, in those with [[burn]]s, [[polytrauma]], or the initial state in [[pancreatitis]] and [[chemical pneumonitis]]. However, sepsis also causes similar response to SIRS.<ref name="1992consensus"/>

[[Platelet]]s have a potentially key role in immune modulation during sepsis.<ref name="xu">{{cite journal |vauthors=Xu X, Wang Y, Tao Y, Dang W, Yang B, Li Y |title=The role of platelets in sepsis: A review |journal=Biomolecules & Biomedicine |volume=24 |issue=4 |pages=741–752 |date=January 2024 |pmid=38236204 |pmc=11293227 |doi=10.17305/bb.2023.10135}}</ref> Systemic inflammation, endothelial injury, and dysregulated coagulation activate platelets in the early phases of the condition.<ref name=xu/> These activated platelets interact with [[leukocyte]]s and [[Endothelium|endothelial cells]], amplifying both inflammatory and [[Thrombosis|thrombotic]] responses.<ref name=xu/> This interaction contributes to microvascular thrombosis and progression to [[multiple organ dysfunction syndrome]].<ref name=xu/>

=== Microbial factors ===
Bacterial [[virulence factor]]s, such as [[glycocalyx]] and various [[adhesins]], allow colonization, immune evasion, and establishment of disease in the host.<ref name=Critical2005/> Sepsis caused by [[gram-negative]] bacteria is thought to be largely due to a response by the host to the [[lipid A]] component of [[lipopolysaccharide]], also called [[endotoxin]].<ref name="Park2013"/><ref name="Cross2014"/> Sepsis caused by [[gram-positive]] bacteria may result from an immunological response to cell wall [[lipoteichoic acid]].<ref name=Fournier2005/> Bacterial [[exotoxin]]s that act as [[superantigens]] also may cause sepsis.<ref name=Critical2005 /> Superantigens simultaneously bind [[major histocompatibility complex]] and [[T-cell receptor]]s in the absence of [[antigen presentation]]. This forced receptor interaction induces the production of pro-inflammatory chemical signals ([[cytokines]]) by T-cells.<ref name=Critical2005 />

There are a number of microbial factors that may cause the typical septic [[Inflammation|inflammatory cascade]]. An invading pathogen is recognized by its [[pathogen-associated molecular pattern]]s (PAMPs). Examples of PAMPs include lipopolysaccharides and [[flagellin]] in gram-negative bacteria, [[muramyl dipeptide]] in the [[peptidoglycan]] of the gram-positive bacterial cell wall, and [[CpG dinucleotide|CpG bacterial DNA]]. These PAMPs are recognized by the [[pattern recognition receptors]] (PRRs) of the innate immune system, which may be membrane-bound or cytosolic.<ref name=Leentjens2013/> There are four families of PRRs: the [[toll-like receptors]], the [[C-type lectin]] receptors, the [[NOD-like receptor]]s, and the [[RIG-I-like receptor]]s. Invariably, the association of a PAMP and a PRR will cause a series of intracellular signalling cascades. Consequentially, transcription factors such as [[nuclear factor-kappa B]] and [[AP-1 transcription factor|activator protein-1]], will up-regulate the expression of pro-inflammatory and anti-inflammatory cytokines.<ref name=Antonopoulou2011/>

Other immunological responses related to microbial infections, such as [[Neutrophil extracellular traps|NETs]], can also play a role or be observed in sepsis. NET formation only occurs via neutrophil cell death, which occurs during microbial infections. Neutrophil extracellular traps called NETs eliminate bacteria from blood flow. These compounds are part of the innate immune system, which is activated initially during infections.<ref>{{Cite journal |last1=Denning |first1=Naomi-Liza |last2=Aziz |first2=Monowar |last3=Gurien |first3=Steven D. |last4=Wang |first4=Ping |date=2019-10-30 |title=DAMPs and NETs in Sepsis |journal=Frontiers in Immunology |language=English |volume=10 |page=2536 |doi=10.3389/fimmu.2019.02536 |doi-access=free |pmid=31736963 |pmc=6831555 |issn=1664-3224}}</ref>

=== Host factors ===
Upon detection of microbial [[antigen]]s, the host systemic immune system is activated. Immune cells not only recognise pathogen-associated molecular patterns but also [[damage-associated molecular pattern]]s from damaged tissues. An uncontrolled immune response is then activated because leukocytes are not recruited to the specific site of infection, but instead, they are recruited all over the body. Then, an immunosuppression state ensues when the proinflammatory [[T helper cell]] 1 (TH1) is shifted to TH2,<ref name="Yuki"/> mediated by [[interleukin 10]], which is known as "compensatory anti-inflammatory response syndrome".<ref name="Polat"/> The [[apoptosis]] (cell death) of lymphocytes further worsens the immunosuppression. [[Neutrophil]]s, [[monocytes]], [[macrophages]], [[dendritic cell]]s, [[CD4|CD4+ T cells]], and [[B cell]]s all undergo apoptosis, whereas [[regulatory T cell]]s are more apoptosis-resistant.<ref name="pmid31611560" /> Subsequently, [[multiple organ dysfunction syndrome|multiple organ failure]] ensues because tissues are unable to use oxygen efficiently due to inhibition of [[cytochrome c oxidase]], possibly as part of a "cell hibernation" mechanism, in order to conserve oxygen.<ref name="Yuki"/>

Inflammatory responses cause [[multiple organ dysfunction syndrome]] through various mechanisms as described below. Increased permeability of the lung vessels causes leaking of fluids into alveoli, which results in [[pulmonary edema]] and [[acute respiratory distress syndrome]] (ARDS). Impaired utilization of oxygen in the liver impairs [[bile salt]] transport, causing [[jaundice]] (yellowish discoloration of the skin). In kidneys, inadequate oxygenation results in tubular epithelial cell injury (of the cells lining the kidney tubules), and thus causes [[acute kidney injury]] (AKI). Meanwhile, in the heart, impaired calcium transport, and low production of [[adenosine triphosphate]] (ATP), can cause myocardial depression, reducing cardiac contractility and causing [[heart failure]]. In the [[gastrointestinal tract]], increased permeability of the mucosa alters the microflora, causing mucosal bleeding and [[paralytic ileus]]. In the [[central nervous system]], direct damage of the brain cells and disturbances of neurotransmissions causes altered mental status.<ref name=Fujishima2016/> Cytokines such as [[TNF-alpha|tumor necrosis factor]], [[Interleukin 1 family|interleukin 1]], and [[interleukin 6]] may activate [[coagulation|procoagulation]] factors in the [[endothelium|cells lining blood vessels]], leading to endothelial damage. The damaged endothelial surface inhibits anticoagulant properties as well as increases [[antifibrinolytic|antifibrinolysis]], which may lead to intravascular clotting, the formation of [[thrombus|blood clots]] in small blood vessels, and multiple organ failure.<ref name= Nimah2003/>

The low blood pressure seen in those with sepsis is the result of various processes, including excessive production of chemicals that [[Vasodilation|dilate blood vessels]] such as [[nitric oxide]], a deficiency of chemicals that [[vasoconstriction|constrict blood vessels]] such as [[vasopressin]], and activation of [[ATP-sensitive potassium channel]]s.<ref name="Marik2014"/> In those with severe sepsis and septic shock, this sequence of events leads to a type of [[circulatory shock]] known as [[distributive shock]].<ref name="Marik2014Chest"/>