Introduction

Inflammation is an essential aspect of the innate defense mechanism of the body against infectious or noninfectious etiologies. This mechanism is nonspecific and immediate.[1] The 5 fundamental signs of inflammation include heat, redness, swelling, pain, and loss of function. Increased blood flow leads to redness and heat, while swelling results from fluid accumulation. Pain arises from releasing stimulating chemicals, and loss of function reflects a combination of factors. These signs are evident in acute surface inflammation but may not all be observable in internal acute inflammation, particularly within internal organs.[2] Inflammation can be categorized into 3 types based on the duration of the response to the injurious cause—acute inflammation, which manifests immediately after injury and typically lasts for a few days; chronic inflammation, which can persist for months or even years if acute inflammation fails to resolve; and subacute inflammation, a transitional phase from acute to chronic lasting from 2 to 6 weeks.[3]

Acute inflammation initiates following a specific injury, triggering the release of soluble mediators such as cytokines, acute phase proteins, and chemokines. These substances promote the migration of neutrophils and macrophages to the inflammation site, representing a crucial component of the innate immune response during acute inflammation.[4] If the acute inflammation does not quickly resolve, it progresses to subacute inflammation. If inflammation persists beyond 6 weeks, it transitions from subacute to chronic, marked by the migration of T lymphocytes and plasma cells to the site of inflammation. Prolonged inflammation without recovery leads to tissue damage and fibrosis.[3] Additional varieties of cells, such as macrophages and monocytes, also contribute to acute and chronic inflammation.[5] 

Issues of Concern

Acute inflammation is an immediate, adaptive response with limited specificity caused by noxious stimuli, such as infection and tissue damage. This beneficial response protects 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.[6] The inflammatory pathway involves inducers, sensors, mediators, and effectors.[7] Inducers initiate the inflammatory process, including infectious organisms or noninfectious stimuli such as foreign bodies and signals from damaged tissues or necrotic cells. These inducers activate sensors, which are specialized molecules that stimulate the mediators. Mediators are endogenous chemicals that can induce pain, regulate the inflammatory process, and promote tissue repair. They also activate the effectors, the tissues, and the cells involved in the response.[8] These components work together, leading to various inflammatory pathways depending on the stimuli type. The ultimate goal of the inflammatory process is to restore homeostasis, regardless of the cause.[6]

Causes

The causes or inducers of inflammation can be classified into 2  main groups—exogenous and endogenous inducers.[6]

Exogenous Inducers

Tissues attacked by external sources release signals that induce inflammation. These exogenous inducers can be further subdivided into microbial and nonmicrobial categories. Microbial inducers can be divided into 2 classes. The first class is pathogen-associated molecular patterns, common to all microorganisms. The second class is virulence factors, which are specific to pathogens. Virulence factors trigger the inflammatory response due to the pathogen's activities. Examples include enzymatic activity produced by helminths and exotoxins produced by bacteria, which are detected by sensors. Nonmicrobial inducers 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. 

Endogenous Inducers

Dead, damaged, malfunctioning or stressed tissues release signals that induce inflammation. These inflammatory inducers can be divided into 2 major groups—infectious and noninfectious factors. Infectious factors include bacteria, viruses, and other microorganisms. Noninfectious factors encompass physical and biological injuries. Physical injuries include frostbite, burns, trauma, foreign bodies, ionizing radiation, and chemical compounds such as glucose, fatty acids, toxins, alcohol, and chemical irritants such as nickel and other trace elements. Biological inducers include signals released by damaged cells and physiological responses to excitement.[9]

Clinical Pathology

The assessment of inflammatory markers is used to detect acute inflammation, potentially indicating a specific disease and assessing treatment response. The most common inflammatory markers are C-reactive protein (CRP), erythrocyte sedimentation rate (ESR or Sed-rate), and procalcitonin (PCT).[4] CRP is an acute-phase reactant widely used in laboratory testing to assess inflammation.[10] CRP is synthesized in the liver, and its transcription is directly regulated by interleukin-6 (IL-6) and indirectly influenced by IL-1β, tumor necrosis factor α (TNF-α), and other cytokines. Research has indicated its ability to bind to bacteria and tissue membranes, enhancing phagocytosis. In addition, CRP can activate the classical complement pathway. CRP is usually present in plasma below 5 mg/L.[11] Various stimuli, such as infection, major trauma, surgery, and chronic inflammatory conditions, can significantly increase CRP production. Following these stimuli, CRP concentrations rise within hours, doubling within 5 to 8 hours. In addition, it is widely acknowledged that mild inflammation and viral infections cause CRP concentrations to elevate within the range of 10 to 40 mg/L. In contrast, active inflammation and bacterial infection result in 40 to 200 mg/L concentrations. Concentrations exceeding 200 mg/L are typically observed in severe bacterial infections and burns. CRP has a half-life of 19 hours.[12]

CRP is a robust analyte; common laboratory variables such as specimen type, delays in specimen processing, and storage temperature have minimal effects on CRP concentration.[13] However, CRP can increase markedly in inflammatory states from baseline values to very high concentrations, resulting in falsely low results due to overwhelming antigen excess. This prozone effect may occur in single-antibody nephelometric and turbidimetric laboratory assessment methods.[14] ESR is a nonspecific marker of acute inflammation associated with various pathologies. The levels of ESR are influenced by factors such as age, gender, pregnancy, anemia, red blood cell dysmorphia, obesity, and fibrinogen deficiency.[15] However, the use of the ESR as a screening test in asymptomatic persons is limited by its low sensitivity and specificity. The ESR measures the distance in millimeters that red blood cells (erythrocytes) settle in a vertical column of anticoagulated blood over 1 hour. The ESR rises within 24 to 48 hours of the onset of inflammation and gradually decreases as the inflammation resolves.[16] PCT is a 116-amino acid peptide precursor of the hormone calcitonin. PCT levels are typically less than 0.1 ng/mL in healthy individuals. However, PCT levels increase in circulation in individuals with inflammation or infections in response to inflammatory cytokines and bacterial endotoxins.[17] PCT levels correlate with the severity of bacterial infections and the probability of a positive blood culture. PCT blood tests can aid in differentiating between sepsis of viral or bacterial origin.[18]

Biochemical and Genetic Pathology

Numerous mediators play a crucial role in initiating the cascade of the acute inflammatory process. The first group of mediators comprises toll-like receptors (TLRs), membrane-spanning proteins found on the surfaces of innate immune system cells such as macrophages and dendritic cells. These single-pass membrane-spanning receptors recognize the pathogen-associated molecular patterns or can recognize endogenous signals activated during tissue or cell damage known as danger-associated molecular patterns.[9] To date, research has identified more than 10 TLRs. An important example is the CD14 (cluster of differentiation 14), a co-receptor for TLR4, which is on the surface of innate immune system cells preferentially expressed in macrophages, monocytes, and neutrophils. TLR4 recognizes lipopolysaccharide, the major component of the outer membrane of gram-negative bacteria (pathogen-associated molecular patterns). Then, the transmission of pathogen-associated molecular patterns and danger-associated molecular patterns are mediated by the adapter protein MyD88 (myeloid differentiation 88) and the TLRs. Subsequently, signaling is transmitted through a specific cascade, leading to the nuclear translocation of transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein-1 (AP-1), or interferon regulatory factor 3 (IRF3).[19][20]

The second group of mediators consists of arachidonic acid mediators. Arachidonic acid is a phospholipid that constitutes the membrane of the body's cells. When activated by inducers such as infection or tissue damage, the enzyme phospholipase can act on the membrane phospholipids to liberate the arachidonic acid. This component can potentially metabolize into 2 main components through either the cyclooxygenase pathway or the 5-lipooxygenase pathway. The cyclooxygenase pathway forms the prostaglandin (PG) mediators, including prostaglandin D2 (PGD2) and thromboxane (which are the bronchoconstrictive prostaglandins), and the bronchoprotective or inhibitory PGE2 and prostacyclin. On the other hand, the 5-lipooxygenase pathway forms the leukotrienes (LTs). Examples of leukotrienes include LTB4, which is neutrophil adhesive and chemotactic, LTC4, D4, and E4, which are involved in the contraction of smooth muscle bronchioles, vasoconstriction, and edema formation.[21]

The third group of mediators comprises mast cells, which originate from precursors in the bone marrow and are widely distributed in connective tissue. These cells become activated in response to tissue damage, with other immune molecules contributing to activating these molecules, including the C3a and C5a of the complement cascade, which leads to the degranulation of human mast cells. Cross-linking their high-affinity receptors for immunoglobulin E (IgE) can also enhance Mast cells. Upon activation, mast cells secrete various pro-inflammatory molecules such as histamine, TNF, kinins, and leukotrienes. Leukotrienes are crucial in the delayed acute inflammation response triggered by mast cell activation.[22]

The complement system is the fourth group of mediators capable of activating acute inflammation. Complements are a set of proteins that interact with each other to initiate a cascade. Many complements can be activated through various pathways, such as the classical, alternative, or mannose-binding lectin pathways. Among the most important complements in acute inflammation are C3a and C5a, which mediate the anaphylatoxins. C5a is known for its chemotactic effect on neutrophils, while C3b is an opsonin for phagocytosis. These complements can further activate the membrane attack complex (MAC), activating neutrophils, monocytes, and mast cells.[23][24] The last mediator is the Hageman factor—a component of clotting factors crucial in inflammation. Activation of this factor subsequently triggers the kinin system and the production of bradykinin. Bradykinin, in turn, enhances the permeability of blood vessel walls, allowing for leakage. This leakage results in swelling, a component of acute inflammation.[25][26] Other mediators and biomarkers of acute inflammation include reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), cytokines (such as IL-6, TNF-α, and chemokines), the formation of DNA adducts, acute-phase proteins such as CRP, inflammation-related growth factors, transcription factors (such as NF-kB), and major immune cell types. The specific mediators and immune cells involved vary and depend on several factors, such as the type of inducer, the duration of the injury, and multiple genetic loci.[27]

Clinicopathologic Correlations

Cardiovascular Disease and Acute Inflammation

Cardiovascular diseases, including atherosclerosis, are the leading cause of death worldwide. In atherosclerosis, inflammatory mediators play a crucial role, from the initial cell recruitment in plaque development to the eventual rupture. Cardiac stress, regardless of its cause, first manifests as inflammation with elevated levels of inflammatory chemokines and cytokines in the affected cardiac tissues. Innate immunity is the most immediate defense mechanism against any cardiac tissue damage. Coronary atherosclerosis is the most common cause of myocardial infarction, resulting in cardiac tissue loss. During myocardial infarction, inflammatory cells migrate to the site of necrotic tissue to clear dead cells and debris as the cardiac cells die and become necrotic. Cell death triggers acute inflammation, releasing endogenous signals recognized as danger signals. This activates TLR-mediated pathways, activating the NF-kB pathway and triggering inflammatory responses. Chemokines recruit leukocytes to the infarcted areas, and cytokines facilitate the adhesion between leukocytes and endothelial cells. TGF-β and IL-10 promote cardiac repair by suppressing inflammation.[9]

Pancreas and Acute Inflammation

Acute pancreatitis is an inflammatory disease of the pancreas caused by obstruction of the pancreatic duct, gene mutation, or alcoholism. Acute pancreatitis is among the most common causes of hospitalization in the United States. Inflammation in acute pancreatitis occurs by activating neutrophils and granulocytes, which secrete inflammatory cytokines. NF-κB, Janus kinase-signal transducer and activator of transcription (JAK-STAT), and mitogen-activated protein kinase (MAPK) pathways play crucial roles in cell activation during pancreatitis.[28]

Liver and Acute Inflammation

The liver is the largest internal organ in the human body, and it responds to infection and injury with inflammation as a protective mechanism. Extensive inflammation can cause hepatocyte injury, metabolic changes, ischemia-reperfusion trauma, and persistent hepatic impairment. Acute liver inflammation can progress to damage the liver parenchyma. If acute hepatitis persists, it can develop into chronic hepatitis. The inducer of liver inflammation involves both noninfectious and infectious pathologies. Infectious agents include the hepatitis B virus (HBV) and hepatitis C virus (HCV), while noninfectious agents include alcoholic or nonalcoholic steatohepatitis, drug-induced hepatitis, and ischemic hepatitis.[9]

Kidney and Acute Inflammation

The most common causes of acute kidney inflammation are infection, ischemia or reperfusion, immune complex formation, and complement dysregulation. The primary promoters of kidney inflammation are the epithelial cells of the renal tubules, which secrete cytokines in response to these inducers. These mediators activate the NF-κB and MAPK pathways.[29]

Intestinal Tract and Acute Inflammation

Acute inflammatory diseases of the intestinal tract can decrease a patient's quality of life worldwide. An excessive inflammatory response to gut microbial flora characterizes polygenic inflammatory bowel disease. Inflammatory bowel diseases include Crohn disease and ulcerative colitis. These 2 diseases are cytokine-driven. Other causes include noninfectious inflammation of the bowel. The system recognizes microbial agents through Toll-like receptors (TLRs). These pathogen-associated molecular patterns that bind to the TLRs (mainly TLR4) activate the signaling pathways (NF-kB, MAPK), and this activation leads to the production of cytokines and chemokines to combat the infection.[30]

Clinical Significance

There are 5 cardinal signs of inflammation: redness, heat, swelling, pain, and loss of function. The heat sensation results from increased blood flow in dilated vessels, which carries heat from the core to the naturally cooler extremities. This increased blood flow also causes redness due to an increase in the number of erythrocytes passing through the injured area. Swelling of the area occurs due to increased permeability and dilation of the blood vessels. Pain results from an increase in the pain mediators, either due to direct damage or resulting from an inflammatory response itself. Loss of function can occur due to restricted mobility caused by edema or pain or from replacing cells with scar tissue.[31]