Introduction and Classic Signs
Inflammation is a complex set of responses to infection and injury, involving leukocytes as the principal cellular mediators in the body’s defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing.
Inflammatory responses
Types:
- Physiologic (e.g., wound healing, localizing infection)
- Pathologic (e.g., malignancy, chronic inflammation)
Triggers of acute inflammation:
- Infections/microbial toxins:
- Bacterial (primarily)
- Viral
- Fungal
- Parasitic
- Physical or chemical injury:
- Thermal injury
- Radiation
- Environmental chemicals
- Foreign bodies:
- Splinters
- Dirt, glass, or rust in a wound
- Surgical sutures
- Necrotic tissue due to ischemia or trauma
- Thrombus
- Uric acid (from the breakdown of DNA in cells)
- Mediators from mast cells, macrophages, and fibroblasts
Characteristics of acute inflammation:
- Immediate onset (minutes)
- Short duration: Resolves within days
- Classic signs and symptoms
- Primary response by neutrophils:
- Remove pathogens and necrotic cells/tissues
- Bridge to innate immunity
- Initiate tissue repair
- Release proteases that may damage normal tissues
Characteristics of chronic inflammation:
- Slow onset (days)
- Long duration: months or years
- More specific signs or symptoms
- Monocytes in the circulation become macrophages in the tissues → degrade debris and orchestrate healing versus scarring
Innate inflammation:
- Has proinflammatory and antiinflammatory checks and balances
- Has potential to cause harm
Contrasting acute and chronic inflammation
Image by Lecturio.Classic signs (Latin terms)
- Rubor (redness): due to ↑ blood flow and accumulation at the point of injury or inflammation
- Calor (heat): due to a combination of blood flow and local reaction
- Tumor (swelling): due to inflammatory mediators →↑ fluid extravasation → edema
- Dolor (pain): mediated by cytokines, bradykinin, and prostaglandins
- Functio laesa (loss of function): results from tissue damage
Acute inflammatory response
Image by Lecturio.Mediators of Inflammation
There are multiple mediators of inflammation that bring inflammatory cells into the sites of injury and overlap with innate immunity when they respond to injurious stimuli.
Primary cellular response (WBCs)
- Neutrophils
- Macrophages and monocytes
- Mast cells and basophils
Mediators of inflammation
- Acute-phase proteins (e.g., CRP)
- Cytokines: signaling proteins released by immune cells
- Interleukins:
- Proinflammatory: IL-1β, IL-6, IL-8, interferon (IFN)-γ
- Antiinflammatory: IL-4, IL-10, IL-13
- Tumor necrosis factor (TNF)
- Interleukins:
- Reactive oxygen species (ROS)
- Platelet-activating factor:
- Made from membrane phospholipids
- Causes vasodilation, ↑ vascular permeability, and platelet activation
- Also is a cytokine
- Arachidonic acid (AA) metabolites:
- Prostaglandins → vasodilation; increased vascular permeability
- Prostacyclin (prostaglandin I2 (PGI2)) → vasodilation; inhibits platelet aggregation
- Thromboxane A2 → vasoconstriction; promotes platelet aggregation (opposite effect of prostacyclin)
- Leukotrienes (proinflammatory) → vasoconstriction, bronchospasm, ↑ vascular permeability
Acute-phase reactants (APRs)
- Under the influence of cytokines (IL-6), hepatocytes produce APRs.
- > 30 APRs are produced.
- Used as laboratory markers of acute inflammation
| Reactant | Function |
|---|---|
| CRP |
|
| ESR |
|
| Haptoglobin |
|
| SAA | Causes immune cell recruitment at the site of inflammation |
SAA: serum amyloid A
Physiology of Acute Inflammation
General process
- Recognition of injury → vascular response phase → cellular response phase (neutrophil recruitment, phagocytosis and killing, mediator release) → tissue swelling
- Lines of defense:
- 1st: Resident macrophages begin phagocytosis.
- 2nd: Chemokine-induced neutrophil extravasation
- 3rd: Monocyte extravasation → tissue macrophages (phagocytosis)
- 4th: ↑ Cell production by the bone marrow
Recognition of tissue injury
- Tissue damage → stimulates pathogen-associated molecular patterns (PAMPs)
- Neutrophils migrate in response to infection, then recognize these molecules:
- PAMPs (from pathogens such as bacteria):
- Double-stranded RNA (dsRNA)
- Unmethylated islands of DNA (found in bacteria, not humans)
- Lipopolysaccharides
- Mannose
- Phosphorylcholine
- Damage-associated molecular patterns (DAMPs):
- Found in dead tissue; neutrophils respond to degrade it
- Part of the host defense system
- Can also promote pathologic inflammatory responses in chronic inflammatory diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, Alzheimer disease, and cancer)
- Opsonins: proteins that induce phagocytosis
- IgG
- Complement fragments
- Pattern-recognition receptors (PRRs):
- TLR: expressed on sentinel cells such as macrophages
- Pentraxins: proteins involved in immunologic responses, including CRP and serum amyloid
- Immune receptors: Fc receptors, complement receptors
- PAMPs (from pathogens such as bacteria):
- PAMPs and DAMPs → activate proinflammatory cytokines and chemokines →
- Endothelial cells on blood vessels release prostaglandins and nitric oxide.
- Mast cells and basophils release histamine.
- Platelets release prostaglandins and serotonin.
Vascular response phase
Vasodilation:
- Brings more blood flow to the tissue
- Allows delivery of cells and mediators to the injured tissue for response
- Mediators of the vascular response:
- Mast cell degranulation → histamine release → relaxation of smooth muscle (vasodilation)→ ↑ blood flow
- Nitrous oxide (synthesized by endothelium and macrophages) → vasodilation → ↑ blood flow
- Eicosanoids (prostaglandins and leukotrienes): also cause vasodilation
Increased permeability:
- Causes extracellular fluid shift
- Slows blood flow and allows cell recruitment
- Deposits circulating mediators to the site of injury
- Early response (in minutes) → direct endothelial injury and driven by:
- Histamine
- Bradykinin
- Leukotrienes
- Late response (hours later) is by leukocyte-mediated damage through:
- Cytokines:
- IL-1
- TNF
- ROS
- Prostaglandins
- Cytokines:
- Edema is seen because of:
- ↑ Endothelial permeability
- Endothelial damage
- Vasodilation and stasis
Cellular release of chemicals causes:
- Transient vasoconstriction due to endothelial cell contraction
- Followed by endothelial cell retraction → vasodilation
- ↑ Vascular permeability → exudation of fluid and cells into tissue → fluid shift
Cellular response phase
Neutrophil recruitment:
- Chemotactic substances:
- N-formyl methionine (on bacterial cell walls)
- Leukotriene B4
- Complement C5a
- Platelet-activating factor
- Chemokines:
- Activate leukocyte integrins
- Attract leukocytes to move out of the bloodstream
- Activate antimicrobial functions
- Rolling and adhesion:
- Endothelial cells express E-selectin and P-selectin under the influence of TNF and IL-1 →
- Bind to the sialyl-Lewis X glycoprotein on neutrophils →
- Endothelial cells express ICAM-1 (intercellular adhesion molecule 1, a glycoprotein also known as CD54) and chemokines activate the integrins on the neutrophil →
- Activation and adhesion of the neutrophil
- Transmigration:
- Chemotaxis: chemokine-activated neutrophils
- Diapedesis (also known as leukocyte extravasation): neutrophils move to the site of inflammation
Phagocytosis and killing:
- Neutrophils have transmigrated →
- Phagocytosis: Neutrophils bind to PRRs → membrane wraps around and engulfs microorganism →
- Leukocyte killing→ destruction of the engulfed microorganisms by:
- Oxidative burst: ROS kill the pathogens.
- Lysosomal proteases degrade the pathogens.
- The complement pathway → cell death by formation of a membrane attack complex (MAC)
- Definition of complement:
- A collection of circulating proteins from the liver and macrophage-synthesized proteins
- A cascade of activation triggered by antigen–antibody complexes, bacterial polysaccharides, aggregated IgA
- Activated complement fragments cause:
- Vasodilation
- ↑ Permeability
- Leukocyte adhesion
- Chemotaxis
- Neutrophil activation
- Complement fragments are proinflammatory:
- C3a and C5a are potent chemotactic agents (recruit and activate neutrophils).
- C3b induces opsonization (recognizing and targeting invading particles for phagocytosis) → neutrophils and macrophages bind and kill pathogens
- C3b and cleavage of other complement factors form a MAC → lysis of microbes
- Definition of complement:
Mediator release:
- Inflammatory stimuli on membrane phospholipids → cascade of AA metabolites:
- COX pathway is proinflammatory and produces:
- Prostaglandins → vasodilation, ↑ vascular permeability
- PGI2 → vasodilation, inhibits platelet aggregation
- Thromboxane A2 → vasoconstriction, promotes platelet aggregation (opposite effect of prostacyclin)
- Lipoxygenase pathway produces:
- Leukotrienes (proinflammatory) → vasoconstriction, bronchospasm, ↑ vascular permeability
- Lipoxins (antiinflammatory) → inhibit neutrophil adhesion and chemotaxis
- COX pathway is proinflammatory and produces:
- ROS: involved in leukocyte killing
- Platelet-activating factor: activated platelets set off cascades of kinins and coagulation factors → pain and clotting
Interplay of various chemokines:
Various ligands and receptors bind and promote neutrophil extravasation.
C3a and C5a: complement
ICAM-1: intercellular adhesion molecule 1
LPS: lipopolysaccharides
TNF-α: tumor necrosis factor alpha
Tissue swelling
- Fluid in the interstitial space has ↑ amounts of protein and fibrinogen:
- Fibrinogen promotes clotting to contain the pathogen
- Migration of granulocytes and monocytes → extravasate into the tissue → swelling
- Factor XIIa (Hageman factor):
- Activates the kinin cascade → bradykinin →
- Pain
- ↑ Vascular permeability → swelling
- Activates the coagulation pathway → clotting
- Indirectly activates the fibrinolytic system (anticoagulation) at the same time as coagulation →
- Breaks down fibrin to limit the amount of clotting
- Activates the complement cascade involved in phagocytosis and killing
- Activates the kinin cascade → bradykinin →
- Factor IIa (thrombin):
- Triggers acute inflammation
- Cleaves fibrinogen to fibrin → fibrin-split products
Outcomes of Acute Inflammation
Inflammation can resolve, form abscesses, or become chronic.
- Resolution:
- Mediated by IL-10 and transforming growth factor beta (TGF-beta; antiinflammatory cytokines)
- Most inflammatory mediators will break down on their own (e.g., eicosanoids).
- Neutrophils:
- Die approximately 10 hours after extravasation
- Undergo apoptosis
- Digested by macrophages
- Tissue macrophages remove pathogens and cellular debris → tissue repair → wound healing
- Lymphatic system → resolves edema
- Scarring may occur owing to:
- Lack of stem cells
- Replacement with fibrotic tissue
- Abscess formation may occur:
- Owing to pyogenic organisms
- Mediated by IL-1 and TNF-alpha
- Dead neutrophils, macrophages, and necrosed tissue result in pus.
- Pus that is isolated by fibrosis into a fibrous capsule → abscess
- Systemic effects of acute inflammation:
- Sepsis
- Hypotension (due to cytokine-induced vasodilation)
- Thrombosis (due to mediators causing activation of platelets and clotting factors)
- Chronic inflammation:
- Mediated by IL-6 and IL-12
- Involves activation of T helper cells → infiltrate tissue
- Ongoing, unchecked inflammation → tissue damage and necrosis
Chronic Inflammation
Acute inflammation with persistent reinjury can lead to chronic inflammation. Chronic inflammation can also be seen with viral infections and autoimmune disorders.
Overview of chronic inflammation
- Lymphocytes and macrophages are key cells involved.
- Can be prolonged (weeks to years)
- A central component of various chronic conditions:
- Autoimmune diseases, such as:
- Rheumatoid arthritis
- Systemic lupus erythematosus
- Multiple sclerosis
- Neurodegenerative diseases
- Granulomatous inflammation, such as with TB
- Cancer
- Chronic obstructive pulmonary disease (COPD)
- Inflammatory bowel disease:
- Crohn disease
- Ulcerative colitis
- Autoimmune diseases, such as:
Etiology
- Failure of complete removal of the pathogen (e.g., TB)
- Persistent stimuli (e.g., an inhaled foreign body such as silica)
- Inflammatory response producing continuous oxidative damage stimulating chronic inflammation (e.g., atherosclerosis)
Mediators of chronic inflammation
- Macrophages:
- Sources of cytokines and chemokines
- Produce complement and coagulation factors
- Also make:
- Proteases
- ROS
- Eicosanoids
- T lymphocytes
- B cells (plasma cells)
- Eosinophils, mast cells
- Cytokines:
- IL-12
- TNF
Types of chronic inflammation
- Nonspecific:
- Proliferative
- Nonspecific granulation tissue → fibroblast overgrowth
- Granulomatous inflammation:
- Granulomas are:
- An aggregation of macrophages, epithelioid cells, and giant cells
- Surrounded by fibroblasts and lymphocytes
- Maintained by TNF-alpha secreted by epithelioid cells
- Caseating granuloma: necrotizing core due to infectious material (e.g., TB)
- Noncaseating granuloma: nonnecrotized core owing to immune-mediated cellular damage (e.g., sarcoidosis)
- Granulomas are:
(A) Schematic representation and (B) histological appearance of an artificial pulmonary granuloma induced in mouse 4 days after injection of purified protein-derivative (PPD)-coated beads (H&E staining; magnification: ×800)
rbead: radius of the bead
rg: radius of the granuloma
Outcome of chronic inflammation
- Scarring and fibrosis within the organ → damage and loss of function
- Continuous inflammation → neoplasm
- Amyloidosis
Clinical Relevance
Examples of inflammation becoming a pathologic response:
- Atherosclerosis: common form of arterial disease in which lipid deposition forms a plaque in the blood vessel walls. Atherosclerosis starts with endothelial injury secondary to turbulent flow and is followed by lipid retention through monocytic response, leading to the formation of foam cells. This process ultimately results in the formation of a fibrous plaque. The plaque narrows the lumen and can cause ischemia, resulting in MI, stroke, CKD, and other organ compromise.
- Multiple sclerosis (MS): chronic inflammatory autoimmune disorder leading to demyelination of the CNS. Inflammation occurs when the oligodendrocyte recognizes self myelin as a foreign antigen and results in the removal of the myelin sheath. Symptoms arise owing to the swelling plus loss of tissue function and include neurologic symptoms affecting vision, motor functions, sensation, and autonomic function.
- Pulmonary fibrosis: type of interstitial lung disease. Environmental exposure to minute inhalants such as smoke, pollutants, and dust causes an inflammatory process within the lung tissue, resulting in fibrosis on injury repair. Individuals often present in a moderate-to-advanced stage with progressive dyspnea and nonproductive cough. The diagnosis is made on the basis of imaging findings and pulmonary function testing. Lung transplantation is the only curative intervention.
Disorders due to deficiency in some mediators of the inflammatory response:
- Defects in adhesion: Leukocyte adhesion deficiency I (LAD I) is due to defective synthesis of integrin in the cellular response phase and deficient binding to immunoglobulins, which result in recurrent infections. Leukocyte adhesion deficiency II (LAD II) is a rare disorder in which neutrophils are deficient in the expression of sialyl-Lewis X, which is needed for rolling in the cellular response phase of inflammation. Leukocyte adhesion deficiency II is characterized by recurrent infections, persistent leukocytosis, and severe deficits in development and growth.
- Defect in phagolysosome formation: Chediak-Higashi syndrome is an autosomal recessive disorder caused by mutations affecting a lysosomal trafficking regulator protein, whereby phagocytosed bacteria are not destroyed by lysosomal enzymes. Chemotaxis is also disrupted, resulting in poor neutrophil recruitment and function. Individuals exhibit recurrent pyogenic infections, easy bleeding and bruising, and neurologic manifestations. The diagnosis is based on analysis of the individual’s blood or bone marrow smear and genetic testing.
- Defect in microbicidal activity: Chronic granulomatous disease (CGD), seen in individuals with a genetic mutation for NADPH oxidase, which is responsible for the respiratory burst in phagocytic leukocytes. Infections may be contained; however, lysis does not occur, thus resulting in chronic granuloma formation. Individuals with CGD are at increased risk of life-threatening infections with fungi and catalase-positive bacteria.
References
- Hall, J. E., Guyton, A. C. (2011). Resistance of the body to infection I. Chapter 33 of Guyton and Hall Textbook of Medical Physiology, 12th ed. Philadelphia: Saunders Elsevier, pp. 428–430.
- Kumar, V., Abbas, A. K., Aster, J. C. (2017). Inflammation and repair. Chapter 3 of Robbins Basic Pathology, 10th ed. Elsevier, pp. 57–70, 79–82.
- Johnston, R. B. (2021). An overview of the innate immune system. UpToDate. Retrieved September 14, 2021, from https://www.uptodate.com/contents/an-overview-of-the-innate-immune-system
- Stone, W. L., Basit, H., Burns, B. (2020). Pathology, inflammation. StatPearls. Retrieved September 14, 2021, from https://www.ncbi.nlm.nih.gov/books/NBK534820/
