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. There are a large number of these complements that 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. Then these complements can 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] 

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 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, and 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]

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 movement of the blood 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 due to replacement of the cells with scar tissue.[20]