Inflammatory Response Quiz

Acute and Chronic Inflammation, and Repair

• The presentation is about the processes of acute and chronic inflammation and repair.
• The objective of the presentation is for students to gain knowledge on the process of acute and chronic inflammation and all of its components.

Inflammation

• Inflammation is a complex reaction to injurious agents (like microbes) and damaged cells.
• Key components of inflammation include vascular responses, migration and activation of leukocytes, and systemic reactions.
• Inflammation indicates a disease process, and attempts to destroy, dilute, or wall off the injurious agent.
• Inflammation involves a series of events to heal and reconstruct damaged tissue.

Hallmark of Acute Inflammation (Clinical Signs)

• Warmth or fever
• Redness
• Swelling
• Pain in the affected area
• Loss of functionality
• Caused by a series of cellular and tissue responses to the injurious agent.
• The responses are directed at destroying the agent and preventing its spread

Causes of Inflammation

• Infections (viral, bacterial, fungal, parasitic) and microbial toxins
• Tissue necrosis: ischemia (reduced blood flow), trauma, physical/chemical injury
• Foreign bodies (splinters, dirt, sutures) which can be infectious or cause tissue injury
• Substances (urate crystals, cholesterol crystals, lipids) that can be harmful in large amounts
• Immune reactions (hypersensitivity) may damage the individual's own tissues. This response may be against self-antigens (autoimmune disease) or harmless environmental substances (allergies).

Harmful Consequences of Inflammation

• Protective inflammatory reactions often come with local tissue damage and associated symptoms.
• The effects are usually self-limited and resolve.
• In certain diseases, the inflammatory reaction is misdirected (e.g., against self-tissues or normally harmless environmental substances).
• Inflammation can lead to many chronic diseases such as rheumatoid arthritis, atherosclerosis, and lung fibrosis.

Activity and Outcomes of Inflammation

• The inflammatory process may cause damage or destruction to tissue surrounding the injury site.
• The goal is to neutralize the harmful agent, clean up debris, and restore the tissue to its normal state.
• Chronic inflammation can lead to a variety of diseases.

Inflammatory Response Components

• Vascular reaction
• Cellular reaction

Circulating Cells

• Neutrophils
• Platelets
• Monocytes
• Mast cells
• Eosinophils
• Fibroblasts
• Lymphocytes
• Macrophages
• Basophils

Extracellular Matrix

• Structural fibrous proteins (collagen, elastin)
• Adhesive glycoproteins (fibronectin, laminin, nonfibrillar collagen, tenascin)
• Proteoglycans

Types of Inflammation

• Acute inflammation
• Is characterized by rapid onset, short duration, and profound signs/symptoms
• Chronic inflammation
• Is characterized by slow onset, long duration, and less obvious signs/symptoms
• Subacute inflammation
• A transitional form with some features in acute and chronic inflammation
• Granulomatous chronic inflammation
• A special form associated with tuberculosis, sarcoidosis, and other diseases

Acute Inflammation (Three Major Components)

• Alterations in vascular caliber (increased blood flow)
• Structural changes in microvasculature (proteins and leukocytes leave the circulation)
• Emigration (movement) of leukocytes to the injury site to eliminate the offending agent

Stimuli for Acute Inflammation

• Tissue necrosis
• Ischemia
• Trauma
• Physical agent
• Radiation
• Sun exposure
• Chemical exposure
• Acids
• Alkalis
• Solvents
• Immune reactions/hypersensitivity
• Infections
• Autoimmune diseases
• Bacteria
• Viruses
• Fungi
• Parasites
• Foreign bodies
• Splinters
• Sutures
• Dirt

Exudate and Transudate

• Exudate: High protein concentration, cellular debris, and high specific gravity.
• Contains fluid, proteins, and blood cells escaped from vessels
• Transudate: Low protein content, no cellular material, and low specific gravity.
• Edema: Excess fluid in interstitial tissue
• Pus: Inflammatory exudate rich in leukocytes, dead cells, and microbes

Sequence of Events in Acute Inflammation

• Blood vessel dilation (earliest reaction, increasing diameter of arterioles, allowing more blood to flow, causing erythema/heat/redness).
• Induced by histamine and nitric oxide.
• Increased blood vessel permeability.
• Retraction of endothelial cells, endothelial injury.
• Leukocyte mediated vascular injury
• Increased transitosis.

Endothelial Cell Contraction

• Occurs mainly in venules.
• Caused by histamine, bradykinin, leukotrienes, neuropeptide substance P, and other factors.
• Short-lived (30 minutes) and reversible.
• Called immediate transient response.
• Delayed, prolonged leakage (begins 2-12 hours, lasts days)

Direct Endothelial Injury

• Results in endothelial cell necrosis and detachment, causing rapid escape of protein-rich plasma into interstitial space
• The event lasts until the damaged vessel is thrombosed or repaired, which is called the immediate sustained response.
• All vessel types can be affected

Direct Endothelial Injury (Mechanism)

• Increased transport of fluids and proteins through endothelial cells
• Involves vesicle and vacuole channels (vesiculo-vacuolar organelles)
• Vascular endothelial growth factor (VEGF)

Sequence of Events in Acute Inflammation (Cont.)

• Slowing of blood flow: increased blood cell packing and reduced flow.
• Margination: Blood cells contact the endothelial surface.
• Rolling: Leukocytes momentarily adhere to the endothelium.
• Adhesion: Firm attachment to the endothelium.
• Diapedesis: migration across the endothelium.
• Chemotactic factors

Margination

• P-selectins (rolling/adhesion)
• E-selectins (rolling/adhesion)
• Immunoglobulins (ligands for leukocyte integrins)
• Integrins bind to ligands on endothelial cells
• Glycoproteins in the extracellular matrix and on cell surfaces.

Injury Stimulus and Resolution/Healing

• Vascular tissues: short-lived vasodilation and long-lived vasodilation
• Fluid exudate (the result and component of inflammation)
• Mediators (factors that cause the systemic response)

Migration or Diapedesis

• Neutrophils (most common leukocyte, 65% of circulating WBCs, short lifespan = 48 hours, apoptosis-driven death)
• Monocytes: (5% of circulating WBCs, become macrophages upon entering injured tissue, long lifespan, and good tolerance to acidic environments).

Phagocytosis

• Recognition and attachment (Receptors for microbial products, e.g. TLRs and G-protein coupled receptors)
• Engulfment (Phagocyte membrane encloses the microbe).
• Killing and degradation (Fusion of phagosome with lysosome, releasing enzymes/peroxide for killing bacteria/other foreign organisms).

Leukocyte-Mediated Tissue Injury

• Collateral damage (prolonged host response, often more harmful than the microbe itself)
• Inappropriate inflammatory response to self-tissues
• Lack of recognition of attack of self tissues
• Autoimmune disease
• Excessive reaction to harmless substances (allergies)

Chronic Inflammation Mechanisms

• The mechanism of leukocytes damaging tissues is the same as the mechanisms used for antimicrobial defense, but do not distinguish between offender (bacteria/viruses) and host tissue.
• Activation and phagocytosis: neutrophils/macrophages release microbicidal and other products not just within phagolysosomes, but into the extracellular space.
• Key products: lysosomal enzymes, reactive oxygen and nitrogen species. These products can damage normal cells and vascular endothelium.

Etiology (Cause) and Pathogenesis (mechanism) of Chronic Inflammation

• Persistent infections
• Immune-mediated inflammatory diseases.
• Prolonged exposure to potentially toxic agents

Cells Of Chronic Inflammation

• Macrophages are the primary players in chronic inflammation. Macrophages are found in many tissues throughout the body. (scattered/found)

Macrophages

• Monocytes that have entered areas of tissue injury.
• They can persist for months and thrive in acidic environments
• Activation: requires chemical mediators such as lymphokines and fibronectin-coated surfaces; mediators that initate acute inflammation.

Activation Pathways

• Classically activated macrophages (M1)
• Activated in response to microbes/IFN-Y.
• Release ROS, NO, and enzymes to kill bacteria/fungi.
• Produce cytokines like IL-1, IL-12, IL-23 for inflammation.
• Alternatively activated macrophages (M2)
• Activated by growth factors/TGF-β.
• Promote tissue repair/fibrosis.
• Release cytokines like IL-10, TGF-β for anti-inflammatory effects.

The Microscopic Features of Chronic Inflammation

• Lymphocytes and often macrophages are common and stable features of chronic inflammations.
• Plasma cells, eosinophils, and giant cells may be present in certain situations

Role of Lymphocytes in Chronic Inflammation

• Microbes/environmental antigens activate T and B lymphocytes, leading to propagating/persisting inflammation.
• Lymphocytes are the dominant cell type in autoimmune and hypersensitivity diseases.
• CD4+ T-cells promote inflammation.
• Different types of CD4+ T-cells secrete diverse cytokines and influence inflammation.
• Activated B-lymphocytes and plasma cells secrete antibodies.
• Antibodies are specific for foreign or self-antigens in the inflammatory site.

Other Cells in Chronic Inflammation

• Eosinophils: abundant in IgE-mediated immune responses and parasitic infections. They contain a harmful protein toxic to parasites/mammalian cells.
• Mast cells: widely distributed in connective tissue, participate in both acute and chronic inflammation. They express the FcɛRI receptor that binds to IgE antibodies, releasing histamine/prostaglandins during allergic reactions, as well as other inflammatory reactions.
• Neutrophils: characteristic of acute inflammation, but may persist for extended times in chronic cases (persistent microbes, activated macrophages, and T lymphocytes), such as chronic osteomyelitis

Granulomatous Inflammation

• Distinctive pattern of chronic inflammation
• Occurs for containing a substance that's difficult to eradicate (e.g, bacteria).
• Tuberculosis is the prototype, involving a pattern of epithelioid cells and a central necrotic region
• Other diseases include sarcoidosis, cat-scratch disease, lymphogranuloma inguinale, and some mycotic infections, hypersensitivity to irritant lipids, and some autoimmune diseases

Granulomatosis Chronic Infection (Tissue Reactions)

• Tuberculosis (Mycobacterium tuberculosis)
• Caseating granulomas (tubercles): activated macrophages, fibroblasts, lymphocytes
• Leprosy (Mycobacterium leprae)
• Acid-fast bacilli in macrophages
• Syphilis (Treponema pallidum)
• Gumma: microscopic to grossly visible
• Cat-scratch Disease (Gram negative bacillus)
• Rounded/stellate granulomas, central granular debris, recognizable neutrophils.
• Sarcoidosis (Unknown etiology
• Noncaseating granulomas, abundant activated macrophages

Regeneration

• The growth of cells/tissues replacing lost structures
• Tissues with high proliferative capacity (hematopoietic system, epithelial cells of skin, gastrointestinal tract) constantly renew themselves.

Healing

• Tissue response to wounds/inflammatory processes/cell necrosis in organs that cannot regenerate
• Two distinct processes: regeneration (restitution of normal structure) and repair (scar formation/fibrous tissue)

Repair by Healing, Scar Formation, and Fibrosis

• The process begins early after injury.
• Formation of new blood vessels (angiogenesis).
• Proliferation of fibroblasts for depositing extra cellular matrix components.
• Wound contraction and increase in wound strength as ECM is formed

Angiogenesis

• Blood vessel formation in adult tissues.
• Crucial for chronic inflammation, fibrosis, and cancer development.
• VEGF (vascular endothelial growth factor) is important for adult tissues undergoing angiogenesis

Scar Formation

• Three processes involved: emigration and proliferation of fibroblasts, deposition of extracellular matrix components, and tissue remodeling.
• Fibroblasts migrate to injury site and proliferate under the influence of growth factors, cytokines, clearing debris by macrophages.

Healing by First Intention (Primary Union)

• Surgical incision is approximated by surgical sutures.
• Narrow incisional space fills with clotted blood and cells, dehydration causes scab formation

Healing by First Intention (Steps)

• Neutrophils move towards fibrin clot
• Epithelial cells migrate along cut margins of dermis, depositing basement membrane components.
• Cells fuse in the midline beneath the scab to produce a continuous but thin epithelial layer that closes the wound.

Healing by Second Intention (Secondary Union)

• Healing of wounds with extensive tissue loss.
• More intense inflammatory response,
• More granulation tissue growth.
• Significant wound contraction
• Substantial scar formation, epidermal thinning

Wound Strength

• First week: 10% of unwounded skin strength
• The third month: 70-80% unwounded strength; strength can persist for life

Local and Systemic Factors Influencing Wound Healing

• Systemic factors: Nutrition (protein/vitamin C deficiencies), metabolic status (diabetes), circulatory status (inadequate blood supply), hormones (glucocorticoids)
• Local factors: Infection, mechanical factors (early motion), foreign bodies (sutures/metal fragments), size, location, and blood supply to the wound.

Complications in Cutaneous Wound Healing

• Deficient scar formation
• Excessive repair components formation
• Contracture formation.