Today, I review, link to, and excerpt from StatPearls‘ Acute Inflammatory Response. Sally Hannoodee; Dian N. Nasuruddin. Last Update: November 14, 2022.
All that follows is from the above resource.
Introduction
Inflammation is part of the innate defense mechanism of the body against infectious or non-infectious etiologies. This mechanism is non-specific and immediate.[1] There are five fundamental signs of inflammation that include: heat (calor), redness (rubor), swelling (tumor), pain (dolor), and loss of function (functio laesa). Inflammation can divide into three types based on the time of the process that responds to the injurious cause; acute which occurs immediately after injury and lasts for few days, chronic inflammation that may last for months or even years when acute inflammation fails to settle, and subacute which is a transformational period from acute to chronic which lasts from 2 to 6 weeks.[2]
Acute inflammation starts after a specific injury that will cause soluble mediators like cytokines, acute phase proteins, and chemokines to promote the migration of neutrophils and macrophages to the area of inflammation.[3] These cells are part of natural innate immunity that can take an active role in acute inflammation. If this inflammation does not resolve after six weeks, this will cause the acute inflammation to develop from subacute to the chronic form of inflammation with the migration of T lymphocytes and plasma cells to the site of inflammation. If this persists with no recovery, then tissue damage and fibrosis will ensue. Other varieties of cells, such as macrophages and monocytes, play a role in both acute and chronic inflammation. In this article, we will discuss “acute inflammation.”
Issues of Concern
Acute inflammation is an immediate, adaptive response with limited specificity caused by several noxious stimuli, such as infection and tissue damage (tissue necrosis). The controlled inflammatory response is generally beneficial, and this can be seen clearly in providing protection against infectious organisms, including mycobacterium tuberculosis, protozoa, fungi, and other parasites. However, it can become detrimental if not regulated, such as seen in septic shock.[4] The inflammatory pathway consists of a sequence of events involving inducers, sensors, mediators, and effectors.[5]
The process will initiate in the presence of inducers, which can be infectious organisms or non-infectious stimuli such as foreign bodies and signals from necrotic cells or damaged tissues. This will, in turn, activate the sensors, which are specialized molecules. The sensors will then stimulate the mediators, which are endogenous chemicals that can induce pain, activate or inhibit inflammation and tissue repair, and can activate the effectors, which are the tissues and cells.[6] These players can act together and give rise to multiple alternative pathways in the inflammatory process, depending on the type of stimuli. The goal of the inflammatory process is to restore homeostasis regardless of the cause.[4]
Causes
The causes or inducers of inflammation can classify into two main groups: exogenous and endogenous inducers.[4]
1. Exogenous inducers.
This grouping can further subdivide into two classes; microbial and non-microbial exogenous inducers.
A. Microbial inducers.
There are two classes of microbial inducers. The first class is pathogen-associated molecular patterns (PAMPs), which are carried by all microorganisms. The second class is virulence factors restricted to pathogens. Virulence factors trigger the inflammatory response due to the effects of their activity. Examples include enzymatic activity produced by helminths and exotoxins produced by bacteria, which will be sensed by known or unknown sensors.
B. Non-Microbial
Causes include allergens, toxic compounds, irritants, and foreign bodies that are too large to be digested or cause phagosomal damage in macrophages. Examples of foreign bodies include silica and asbestos.
2. Endogenous inducers.
These are signals released by tissues that are either dead, damaged, malfunctioned, or stressed.
As an alternative, we could also divide the inflammatory inducers into two large groups, which are the infectious factors and the non-infectious factors.
I. Infectious factors:
This category includes bacteria, viruses, and other microorganisms.
II. Non-Infectious factors:
This group can be due to physical injuries such as frostbite, burn, physical injury, foreign bodies, trauma, ionizing radiation, chemical compounds such as glucose, fatty acids, toxins, alcohol, and chemical irritants such as nickel and other trace elements. Apart from that, there are also biological inducers, including signals released by damaged cells and physiological due to excitement.[7]
Biochemical and Genetic Pathology
Many mediators play a crucial role in initiating the cascade in the acute inflammatory process. The first group of mediators is the toll-like receptors (TLRs), which are membrane-spanning proteins found on the surfaces of the innate immune system cells like macrophages and dendritic cells. These single-pass membrane-spanning receptors recognize the pathogen-associated molecular patterns (PAMPs) or can recognize endogenous signals activated during tissue or cell damage known as danger-associated molecular patterns (DAMPS). To date, research has identified more than ten TLRs. An important example is the CD14 (cluster of differentiation 14), a co-receptor for TLR4, which is present on the surface of innate immune system cells preferentially expressed in macrophages, monocytes, and neutrophils. TLR4 can recognize the Lipopolysaccharide, which is the major component of the outer membrane of the gram-negative bacteria (PAMPs). Then the transmission of PAMPs and DAMPs are mediated by MyD88 (myeloid differentiation 88) along with the TLRs. Subsequently, the signaling will transmit through a specific cascade that leads to nuclear translocation of transcription factors, such as NF-kB, activator protein-1 (AP-1), or interferon regulatory factor 3(IRF3).[7][8][9]
The second groups of mediators are arachidonic acid (AA) mediators. Arachidonic acid is a phospholipid that constitutes the membrane of the body’s cells. Phospholipase can become activated by inducers, such as infection or tissue damage. This enzyme can act on this membrane phospholipids to liberate the arachidonic acid. This component can potentially metabolize into two main components through either the cyclooxygenase pathway or the 5-lipooxygenase pathway. The cyclooxygenase pathway forms the prostaglandins (PG) mediators; this includes the PGD2 and thromboxane, which are the bronchoconstrictive prostaglandins and the bronchoprotective or inhibitory PGE2 and prostacyclin. On the other hand, the 5-lipooxygenase pathway will form the leukotrienes (LTs). Examples of LTs include LTB4, which is neutrophil adhesive and chemotactic, LTC4, D4, and E4, which is involved in contraction of smooth muscle bronchioles, vasoconstriction, and edema formation.[10]
The third group of mediators are the Mast cells, derived from precursors in the bone marrow and widely distributed in the connective tissue. These cells will become activated by tissue damage. Other immune molecules also contribute to the activation of these molecules, including the C3a and C5a, which lead to degranulation of human mast cells. Mast cells can also be enhanced by cross-linking of their high-affinity receptors for IgE. After activation, mast cell secretes a few pro-inflammatory molecules such as histamine, TNF, kinin, and leukotrienes (Leukotrienes play an important role in the delayed response of acute inflammation caused by mast cell activation).[11]
The fourth group of mediators that can activate the acute inflammation is the Complements. The complements are a set of proteins that interact with one another to create a cascade. A large number of these complements can become activated through several pathways like the classical, alternative, or mannose-binding lectin pathway. The most important complement in acute inflammation include the C3a and C5a that mediate the anaphylatoxins, and also the C5a consider as chemotactic for neutrophils, C3b for opsonin for phagocytosis. These complements can then activate the MAC (membrane attack complex) that can activate the neutrophils, monocyte, and mast cells.[12][13]
The last mediators are the Hageman factor, which is a part of clotting factors and also plays an important role in inflammation. Activation of this factor will lead to the activation of the kinin system and the formation of bradykinin. Bradykinin increases the permeability of the walls of blood vessels. This leakage leads to the swelling considered as part of the acute inflammation.[14][15]
Other mediators and biomarkers of acute inflammation include Reactive oxygen and reactive nitrogen oxide species (ROS and RNOS), cytokines such as IL-6, TNF-alpha, and chemokines, the formation of DNA adducts, acute-phase proteins such as C-reactive protein (CRP), inflammation-related growth factors and transcription factors (NF-KappaB) and major immune cell types. The type of the mediators and immune cells involved all are variable and depend on several factors like the type of inducer, the duration of the injury, and multiple genetic loci.[16]
Clinicopathologic Correlations
Cardiovascular Disease and Acute Inflammation
Cardiovascular diseases, including atherosclerosis, are recognized as the most common cause of death worldwide. During the formation of atherosclerosis, the inflammatory mediators play a principal role in the initial cell recruitment until the rupture of the plaque. Cardiac stress, due to any reason, will first appear as inflammation. In affected cardiac tissues, there are elevated levels of inflammatory chemokines and cytokines synthesis and release. In cardiac injury, the most immediate defense mechanism against any cardiac tissue damage is innate immunity. Coronary atherosclerosis is the most common cause of myocardial infarction that results in cardiac tissue loss. In myocardial infarction, as the cardiac cells die and become necrotic, the inflammatory cells would start to come to the site of the necrotic tissue to clear the dead cells and debris. Cell death is the inducer that triggers the acute inflammation process resulting in the release of endogenous signals recognized as a danger signal. Subsequently, the TLRs-mediated pathways trigger inflammatory responses by activating the NF-kB pathway. Next, the chemokines recruit the leukocytes to the areas of the infarct, and the cytokines allow the adhesion between leukocytes and endothelial cells. TGF-B and IL-10 promote cardiac repair by suppressing inflammation.[7]
Pancreas and Acute Inflammation
Acute pancreatitis is an inflammatory disease of the pancreas caused by either pancreatic duct obstruction, gene mutation, or alcoholism. Acute pancreatitis is among the most common causes of hospitalization in the United States. Inflammation in acute pancreatitis occurs by activation of neutrophils and granulocytes, which secrete inflammatory cytokines. NF-kB, JAK-STAT, and MAPK pathways play an important role in cell activation during pancreatitis.[17]
Liver and Acute Inflammation
The liver is the largest internal human body organ. As the inflammation is a protective mechanism by the body, it will protect the liver from infection and injury, but if this occurs extensively, this will cause hepatocytes injury, metabolic changes, ischemia-reperfusion trauma, and constant hepatic impairment. Acute inflammation of the liver can develop to damage the parenchyma of the liver, and if it persists, this will turn to chronic hepatitis. The inducer of liver inflammation involves both the non-infectious and infectious pathologies. The infectious agent includes the Hepatitis B virus (HBV) and Hepatitis C virus (HCV), while the non-infectious agent includes alcoholic or non-alcoholic steatohepatitis, drug-induced, or ischemic hepatitis.[7]
Kidney and Acute Inflammation
The most common cause of acute kidney inflammation is an infection, ischemia/reperfusion, immune complex formation, or complement dysregulation. The most important promoters of kidney inflammation are the epithelial cells of the renal tubules that secrete cytokines in response to the inducers. These mediators activate the pathways NF-kB or MAPK.[18]
Intestinal tract and Acute Inflammation
Acute inflammatory diseases of the intestinal tract can decrease patients’ quality of life worldwide. Polygenic inflammatory bowel disease (IBDs) is characterized by an excessive inflammatory response to gut microbial flora. IBDs include Crohn disease (CD) and ulcerative colitis (UC). These two diseases are cytokine driven. Apart from that, other causes include non-infectious inflammation of the bowel. The system can recognize the microbial agent through the TLRs. These PAMPs that bind to the TLRs (mainly TLR4) activate the signaling pathways (NF-kB, MAPK) that cause the production of cytokines and chemokines to start the resistance to the infection.[19]
Clinical Significance
There are five cardinal signs of inflammation, namely redness (rubor), heat (calor), swelling (tumor), pain (dolor), and loss of function (functio laesa). The sensation of heat is caused by the increased blood movement in dilated vessels into environmentally cooled extremities. This reaction will also lead to redness due to an increase in the number of erythrocytes passing through the injured area. The swelling of the area occurs due to an increase in the permeability and dilatation of the blood vessels. Pain is due to an increase in the pain mediators, either due to direct damage or resulting from an inflammatory response itself. Loss of function occurs due to either simple loss of mobility due to either edema or pain or replacement of the cells with scar tissue.[20]
