4.3 Inflammation
9 min read•august 20, 2024
Inflammation is a complex biological response that protects the body from harm. It involves various cellular and chemical mediators working together to eliminate threats and initiate . Understanding inflammation is crucial for grasping its role in health and disease.
is a rapid, short-lived response, while can persist for extended periods. Both types involve different cellular players and chemical signals. Inflammation can be triggered by infections, injuries, irritants, and immune reactions, leading to a cascade of events aimed at restoring homeostasis.
Inflammation overview
- Inflammation is a complex biological response to harmful stimuli, such as pathogens, damaged cells, or irritants
- Serves as a protective mechanism to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair
- Plays a crucial role in the body's defense against infection and injury, but chronic inflammation can contribute to various diseases (cardiovascular disease, cancer, neurodegenerative disorders)
Acute vs chronic inflammation
Top images from around the web for Acute vs chronic inflammation
Frontiers | Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes View original
Is this image relevant?
Frontiers | The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical ... View original
Is this image relevant?
Frontiers | Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of ... View original
Is this image relevant?
Frontiers | Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes View original
Is this image relevant?
Frontiers | The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical ... View original
Is this image relevant?
1 of 3
Top images from around the web for Acute vs chronic inflammation
Frontiers | Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes View original
Is this image relevant?
Frontiers | The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical ... View original
Is this image relevant?
Frontiers | Cells of the Immune System in Cardiac Remodeling: Main Players in Resolution of ... View original
Is this image relevant?
Frontiers | Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes View original
Is this image relevant?
Frontiers | The Role of Semaphorins and Their Receptors in Innate Immune Responses and Clinical ... View original
Is this image relevant?
1 of 3
- Acute inflammation is a rapid, short-lived response to injury or infection characterized by the classic signs (redness, swelling, heat, pain, and loss of function)
- Chronic inflammation is a prolonged response that can last for weeks, months, or even years, often associated with persistent infections, autoimmune disorders, or long-term exposure to irritants
- Acute inflammation typically involves , while chronic inflammation is characterized by the presence of lymphocytes and
Cellular mediators of inflammation
- Leukocytes (neutrophils, monocytes/macrophages, lymphocytes) play a central role in the inflammatory response by migrating to the site of injury or infection
- Neutrophils are the first responders in acute inflammation, phagocytosing pathogens and releasing reactive oxygen species and proteolytic enzymes
- Monocytes differentiate into macrophages, which phagocytose debris, secrete , and present antigens to lymphocytes
- Lymphocytes (T cells and B cells) are involved in and contribute to chronic inflammation
Chemical mediators of inflammation
- Various chemical mediators are released during inflammation to regulate the inflammatory response and coordinate cell activities
- Histamine, released by mast cells, causes and increases vascular permeability
- , produced by cyclooxygenase enzymes, contribute to vasodilation, pain, and fever
- Cytokines (interleukins, tumor necrosis factor) are signaling proteins that modulate the inflammatory response and facilitate communication between immune cells
- Complement proteins enhance phagocytosis, recruit leukocytes, and promote the inflammatory response
Causes of inflammation
Microbial infections
- Bacterial, viral, and fungal infections can trigger an inflammatory response as the body attempts to eliminate the invading pathogens
- Pathogen-associated molecular patterns (PAMPs) on microbes are recognized by pattern recognition receptors (PRRs) on immune cells, initiating the inflammatory cascade
- Examples of inflammatory infections include pneumonia (bacterial or viral), influenza (viral), and candidiasis (fungal)
Physical injuries
- Trauma, burns, frostbite, and radiation exposure can cause tissue damage and initiate an inflammatory response
- Damaged cells release damage-associated molecular patterns (DAMPs) that activate PRRs on immune cells, leading to the production of inflammatory mediators
- The inflammatory response helps to clear damaged tissue and promote healing, but excessive inflammation can lead to further tissue damage
Chemical irritants
- Exposure to toxins, pollutants, and other irritants can induce inflammation in affected tissues
- Examples include inhaled substances (cigarette smoke, asbestos fibers) and ingested chemicals (alcohol, certain drugs)
- These irritants can cause direct tissue damage or stimulate the production of inflammatory mediators by resident cells
Immune reactions
- Inappropriate or excessive immune responses can lead to inflammation, even in the absence of infection or injury
- Autoimmune disorders (, lupus) involve the immune system attacking the body's own tissues, resulting in chronic inflammation
- Allergic reactions, such as asthma and contact dermatitis, are characterized by an inflammatory response to typically harmless substances (allergens)
Inflammatory response phases
Vascular changes
- Vasodilation: Increased blood flow to the affected area causes redness (erythema) and warmth
- Increased vascular permeability: Gaps form between endothelial cells, allowing plasma proteins and leukocytes to exit blood vessels and enter the tissue (exudate formation)
- Fluid accumulation in the tissue leads to swelling (edema), which can compress nerve endings and cause pain
Cellular events
- Leukocyte migration: Chemokines and adhesion molecules guide leukocytes (neutrophils, monocytes) from the bloodstream to the site of inflammation
- Phagocytosis: Neutrophils and macrophages engulf and destroy pathogens, dead cells, and debris
- Release of inflammatory mediators: Leukocytes secrete cytokines, growth factors, and other signaling molecules to amplify the inflammatory response and stimulate tissue repair
Resolution of inflammation
- Clearance of inflammatory stimuli: Pathogens and damaged cells are eliminated by phagocytosis and other mechanisms
- of neutrophils: Neutrophils undergo programmed cell death to prevent excessive tissue damage and are cleared by macrophages
- Tissue repair: Macrophages and other cells secrete growth factors to stimulate the proliferation of fibroblasts and the synthesis of extracellular matrix components, promoting tissue regeneration
- Return to homeostasis: As the inflammatory stimulus is removed and repair processes are completed, the inflammatory response subsides, and the tissue returns to its normal state
Systemic effects of inflammation
Acute-phase proteins
- Liver synthesizes and releases acute-phase proteins (C-reactive protein, serum amyloid A, fibrinogen) in response to inflammatory cytokines (IL-6)
- C-reactive protein (CRP) binds to phosphocholine on the surface of dead or dying cells and some bacteria, activating the complement system and promoting phagocytosis
- Elevated CRP levels are used as a clinical marker of inflammation and can help monitor the response to treatment
Fever and inflammation
- Pyrogens (IL-1, IL-6, TNF-α) released during inflammation act on the hypothalamus to raise the body's temperature set point
- Fever is a systemic response to inflammation that may help to inhibit microbial growth and enhance immune function
- However, high fevers can cause discomfort, dehydration, and, in severe cases, neurological damage
Leukocytosis in inflammation
- Inflammatory cytokines (G-CSF, GM-CSF) stimulate the production and release of leukocytes from the bone marrow, resulting in an increased white blood cell count (leukocytosis)
- Neutrophilia (elevated neutrophil count) is a common finding in acute inflammation, while chronic inflammation may be associated with lymphocytosis (elevated lymphocyte count) or monocytosis (elevated monocyte count)
- Leukocytosis can be a useful indicator of infection or inflammation, but it is not specific and can occur in other conditions (stress, exercise, malignancy)
Chronic inflammation
Granulomatous inflammation
- Granulomas are organized collections of macrophages and other immune cells that form in response to persistent, indigestible stimuli (certain bacteria, fungi, foreign bodies)
- Macrophages in granulomas can fuse to form multinucleated giant cells and may undergo epithelioid cell transformation
- Examples of granulomatous diseases include tuberculosis (Mycobacterium tuberculosis), sarcoidosis (unknown cause), and Crohn's disease (immune-mediated)
Fibrosis in chronic inflammation
- Persistent inflammation can lead to the excessive deposition of extracellular matrix components (collagen, fibronectin) by activated fibroblasts, resulting in fibrosis
- Fibrosis can disrupt normal tissue architecture and function, leading to organ dysfunction (cirrhosis in the liver, pulmonary fibrosis in the lungs)
- Transforming growth factor-beta (TGF-β) is a key mediator of fibrosis, stimulating fibroblast activation and collagen synthesis
Chronic inflammatory diseases
- Rheumatoid arthritis: Autoimmune disorder characterized by chronic inflammation of the synovial joints, leading to cartilage and bone destruction
- Inflammatory bowel diseases (Crohn's disease, ulcerative colitis): Chronic inflammation of the gastrointestinal tract, causing abdominal pain, diarrhea, and malnutrition
- Psoriasis: Chronic inflammatory skin condition characterized by red, scaly patches, driven by an exaggerated immune response in the skin
- Asthma: Chronic inflammation of the airways, leading to bronchial hyperresponsiveness, mucus production, and airflow obstruction
Anti-inflammatory therapies
Nonsteroidal anti-inflammatory drugs (NSAIDs)
- NSAIDs (ibuprofen, naproxen, celecoxib) inhibit cyclooxygenase (COX) enzymes, reducing the production of prostaglandins and thromboxanes
- By decreasing prostaglandin synthesis, NSAIDs can reduce pain, fever, and inflammation
- However, NSAIDs can cause gastrointestinal side effects (ulcers, bleeding) and may increase the risk of cardiovascular events
Corticosteroids for inflammation
- Corticosteroids (prednisone, dexamethasone) are potent anti-inflammatory drugs that mimic the effects of endogenous glucocorticoids
- They act by binding to glucocorticoid receptors and modulating the transcription of genes involved in the inflammatory response
- Corticosteroids can suppress multiple aspects of inflammation, including leukocyte migration, cytokine production, and prostaglandin synthesis
- Long-term use of corticosteroids can cause side effects (osteoporosis, diabetes, immunosuppression), so they are typically reserved for severe or refractory cases
Biological therapies targeting inflammation
- Monoclonal antibodies and fusion proteins can target specific inflammatory mediators or their receptors, providing a more targeted approach to anti-inflammatory therapy
- TNF-α inhibitors (infliximab, adalimumab) are used to treat rheumatoid arthritis, inflammatory bowel diseases, and psoriasis by neutralizing the pro-inflammatory effects of TNF-α
- IL-1 receptor antagonists (anakinra) and IL-6 receptor antibodies (tocilizumab) are used in the treatment of rheumatoid arthritis and other inflammatory conditions
- Janus kinase (JAK) inhibitors (tofacitinib, baricitinib) block the signaling of multiple cytokines and are used in the treatment of rheumatoid arthritis and ulcerative colitis
Inflammation and disease
Inflammation in cardiovascular disease
- Chronic low-grade inflammation plays a central role in the development and progression of atherosclerosis, the underlying cause of most cardiovascular diseases
- Inflammatory cells (macrophages, T cells) and mediators (cytokines, chemokines) contribute to the formation and instability of atherosclerotic plaques
- Elevated levels of inflammatory markers (CRP, IL-6) are associated with an increased risk of cardiovascular events (myocardial infarction, stroke)
- Anti-inflammatory therapies, such as low-dose colchicine and canakinumab (IL-1β antibody), have shown promise in reducing cardiovascular risk in selected patient populations
Inflammation and cancer
- Chronic inflammation can create a microenvironment that promotes tumor development and progression
- Inflammatory cells and mediators can contribute to cancer by inducing DNA damage, promoting angiogenesis, and suppressing anti-tumor immunity
- Examples of inflammation-associated cancers include colorectal cancer in inflammatory bowel diseases, hepatocellular carcinoma in chronic hepatitis, and gastric cancer in Helicobacter pylori infection
- Anti-inflammatory agents, such as aspirin and other NSAIDs, have been associated with a reduced risk of certain types of cancer (colorectal, breast, prostate)
Neuroinflammation in neurodegenerative disorders
- Neuroinflammation, characterized by the activation of microglia (resident immune cells in the brain) and the production of inflammatory mediators, is increasingly recognized as a contributor to neurodegenerative disorders
- In Alzheimer's disease, amyloid-beta plaques and tau tangles can activate microglia, leading to chronic neuroinflammation and neuronal damage
- In Parkinson's disease, the accumulation of alpha-synuclein and the loss of dopaminergic neurons in the substantia nigra are associated with microglial activation and neuroinflammation
- Anti-inflammatory strategies, such as targeting microglial activation or inflammatory cytokines, are being explored as potential therapeutic approaches for neurodegenerative disorders
Experimental models of inflammation
In vitro models
- Cell culture systems using primary cells or cell lines (macrophages, endothelial cells, fibroblasts) can be used to study specific aspects of the inflammatory response
- Stimulation with inflammatory mediators (LPS, cytokines) or co-culture with other cell types can mimic the inflammatory microenvironment
- In vitro models allow for the investigation of signaling pathways, gene expression, and cellular interactions in a controlled setting
- Examples include the use of human umbilical vein endothelial cells (HUVECs) to study leukocyte adhesion and transmigration, and the use of RAW 264.7 macrophages to study cytokine production and phagocytosis
In vivo animal models
- Animal models of inflammation allow for the study of complex interactions between different cell types and organ systems in a living organism
- Common models include the carrageenan-induced paw edema model in rats (acute inflammation), the collagen-induced arthritis model in mice (rheumatoid arthritis), and the dextran sulfate sodium (DSS)-induced colitis model in mice ()
- Genetically modified animals (knockout or transgenic) can be used to study the role of specific genes or pathways in the inflammatory response
- Limitations of animal models include differences in anatomy, physiology, and immune responses compared to humans, as well as ethical considerations
Human studies of inflammation
- Observational studies can provide insights into the association between inflammatory markers and disease risk or progression in human populations
- Clinical trials are used to evaluate the safety and efficacy of anti-inflammatory therapies in patients with inflammatory disorders
- Ex vivo studies using human tissues or cells obtained from patients can help to validate findings from animal models and provide a more relevant context for understanding human inflammation
- Challenges in human studies include the heterogeneity of patient populations, the influence of environmental and lifestyle factors, and the limited availability of certain tissues or cell types for analysis
Key Terms to Review (18)
Acute inflammation: Acute inflammation is a rapid and immediate response of the body to tissue injury or infection, characterized by redness, heat, swelling, pain, and loss of function. This process serves as a protective mechanism aimed at eliminating the initial cause of cell injury, clearing out damaged cells, and initiating tissue repair. The key components involved in acute inflammation include the vascular system, immune cells, and various signaling molecules that orchestrate the healing process.
Adaptive immunity: Adaptive immunity is a specialized immune response that develops over time and involves the activation of lymphocytes, such as T cells and B cells, to specifically recognize and remember pathogens. This type of immunity is characterized by its ability to adapt and improve its response upon subsequent exposures to the same pathogen, leading to enhanced protection and a quicker response time.
Apoptosis: Apoptosis is a form of programmed cell death that occurs in a regulated and controlled manner, allowing for the elimination of unwanted or damaged cells without causing harm to surrounding tissues. This process is crucial for maintaining cellular homeostasis, development, and responses to cellular stress, linking it to various biological phenomena.
Chemotaxis: Chemotaxis is the directed movement of cells or organisms in response to a chemical gradient, often toward higher concentrations of beneficial substances or away from harmful ones. This phenomenon plays a crucial role in various biological processes, including immune responses where immune cells migrate to sites of infection or injury, facilitating inflammation and healing.
Chronic inflammation: Chronic inflammation is a prolonged and persistent inflammatory response that can last for months or years, often leading to tissue damage and various diseases. Unlike acute inflammation, which is a short-term process that resolves after the harmful stimulus is removed, chronic inflammation can occur due to ongoing infection, autoimmune disorders, or long-term exposure to irritants and toxins. This type of inflammation is characterized by the continued presence of immune cells and can contribute to conditions such as arthritis, cardiovascular disease, and cancer.
Cytokines: Cytokines are small proteins that act as signaling molecules in the immune system, playing a crucial role in cell communication during immune responses. They help regulate inflammation, hematopoiesis, and the differentiation of various immune cells, making them essential for maintaining homeostasis and coordinating the body’s response to pathogens or injury.
Histopathology: Histopathology is the study of the microscopic structure of tissues in relation to disease. It provides crucial insights into the cellular changes that occur during inflammation, helping to diagnose conditions and understand disease mechanisms. By examining tissue samples under a microscope, histopathology reveals the patterns of injury and healing associated with various inflammatory processes.
Immunohistochemistry: Immunohistochemistry is a laboratory technique used to visualize the presence and location of specific proteins in tissue sections using antibodies. This method allows researchers to study the cellular composition and distribution of proteins, helping to identify changes in tissues, particularly during inflammatory responses.
Inflammatory bowel disease: Inflammatory bowel disease (IBD) refers to a group of chronic inflammatory conditions affecting the gastrointestinal tract, primarily including Crohn's disease and ulcerative colitis. These disorders lead to inflammation, which can cause a range of symptoms such as abdominal pain, diarrhea, and malnutrition. The underlying mechanisms involve a combination of genetic, environmental, and immune factors that disrupt the normal function of the gut.
Innate immunity: Innate immunity is the body's first line of defense against pathogens, consisting of physical barriers, immune cells, and various biochemical responses that respond quickly and non-specifically to invaders. This type of immunity is present at birth and acts as an immediate response to infection or injury, without the need for prior exposure to a specific pathogen. It plays a crucial role in the inflammatory response, helping to prevent the spread of infection and initiate healing processes.
Macrophages: Macrophages are a type of white blood cell that play a crucial role in the immune system, primarily involved in detecting, engulfing, and destroying pathogens and apoptotic cells. They originate from monocytes and are key players in inflammation, acting as both scavengers and messengers to coordinate immune responses during injury or infection.
MAPK Pathway: The MAPK pathway, or Mitogen-Activated Protein Kinase pathway, is a crucial signaling cascade that transmits extracellular signals to elicit cellular responses, particularly in the context of growth, differentiation, and inflammation. It plays a significant role in regulating various biological processes by modulating gene expression, cell division, and responses to stress, making it integral to understanding how cells react during inflammatory responses.
Neutrophils: Neutrophils are a type of white blood cell that plays a crucial role in the body's immune response, particularly during inflammation. They are the most abundant type of granulocytes and act as the first line of defense against invading pathogens, such as bacteria and fungi. By migrating to sites of infection or injury, neutrophils help to initiate and amplify the inflammatory response through the release of various signaling molecules and enzymes.
Nf-kb pathway: The NF-κB pathway is a critical signaling cascade that regulates the immune response, inflammation, and cell survival. It plays a key role in controlling the transcription of DNA, thereby influencing the production of various cytokines and chemokines involved in inflammatory processes. By activating NF-κB, cells can respond to stimuli such as stress, cytokines, and free radicals, which is essential for mounting an effective immune response.
Prostaglandins: Prostaglandins are lipid compounds that are derived from fatty acids and have important roles in various physiological processes, including inflammation. They act as local hormones, influencing processes such as vasodilation, pain modulation, and the immune response, making them crucial players in the body's inflammatory response and healing processes.
Rheumatoid arthritis: Rheumatoid arthritis is a chronic inflammatory disorder that primarily affects joints, leading to painful swelling, joint deformity, and loss of function. This autoimmune disease occurs when the immune system mistakenly attacks the body's own tissues, particularly the synovium, which is the lining of the membranes that surround the joints. The inflammation can also extend beyond joints, affecting other systems in the body, making it a systemic condition.
Tissue repair: Tissue repair is the process by which the body restores damaged tissues following injury or inflammation. This process involves a complex interplay of cellular responses, signaling pathways, and extracellular matrix formation that ultimately leads to the restoration of tissue integrity and function. It is essential for maintaining homeostasis and involves both regenerative and scarring mechanisms.
Vasodilation: Vasodilation is the process by which blood vessels widen due to the relaxation of smooth muscle cells within the vessel walls. This physiological response leads to increased blood flow and a decrease in blood pressure, playing a crucial role during inflammatory responses by allowing more immune cells to reach the affected tissues.