Inflammation and Cellular Responses

Immunity

• Types of immunity include innate resistance and adaptive (acquired) immunity.
• Lines of defense include first line, second line, and third line.
• The first line is natural barriers like physical, mechanical, and biochemical barriers.
• The second line is inflammation.
• The third line is adaptive (acquired) immunity.

First Line of Defence

• Physical and mechanical barriers include skin, low temperature, pH of skin, and linings of the gastrointestinal, genitourinary, and respiratory tracts.
• Other barriers are highly interconnected junctions, sloughing off of cells, coughing and sneezing, "Washing", vomiting, urinating, mucus, and cilia

First Line of Defence (cont.)

• Biochemical barriers synthesize and secrete substances to trap or destroy microorganisms.
• Antibacterial peptides are in mucus, perspiration (sweat), saliva, tears, and earwax
• Antimicrobial peptides include cathelicidins, defensins (a defensins in neutrophil granules and ẞ defensins), and collectins (lungs).
• Normal microbiome inhibits colonization by pathogens releasing chemicals that prevent infection; Lactobacillus is vaginal and ammonia, phenols, and indoles are intestinal.

Second Line of Defence

• The inflammatory response includes infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, and radiation and has cellular and chemical components
• It is nonspecific, rapidly initiated and has no memory cells.
• Cardinal signs include redness, heat, swelling, pain, and loss of function.
• The vascular response includes blood vessel dilation, increased vascular permeability and leakage, white blood cell (WBC) adherence to the walls of the vessels, and migration through the vessels (diapedesis).
• Once in the tissues, the cells and chemicals associated with the inflammatory response help prevent and limit infection and further damage, limit and control the inflammatory process, interact with components of the adaptive immune system, and prepare the area of injury for healing.

Plasma Protein Systems

• Complement system, clotting system, and kinin system provide a biochemical barrier against invading pathogens
• All contain inactive enzymes (proenzymes).
• They are sequentially activated in a cascade.
• The first proenzyme converts to an active enzyme and the first component activation result in a sequential activation of other components.

Plasma Protein Systems (Cont.)

• The complement system destroys pathogens directly, activating, and collaborating with every other component of the inflammatory response.
• Pathways are classical (antibodies and antigens), lectin (mannose-containing bacterial carbohydrates), and alternative (gram-negative bacterial and fungal cell wall polysaccharides).
• Functions include anaphylatoxic activity resulting in mast cell degranulation, leukocyte chemotaxis, opsonization, and cell lysis.
• The clotting (coagulation) system forms a fibrinous mesh at an injured or inflamed site; the main substance in fibrinous mesh is insoluble protein called fibrin.
• Clotting system prevents the spread of infection, keeps microorganisms and foreign bodies at the site of inflammation for removal, forms a clot to stop bleeding and provides a framework for repair and healing.
• Pathways are extrinsic (activated by tissue factor outside the vascular space or Intrinsic ( is activated in the vascular space when the vessel wall is damaged)
• The kinin system activates and assists inflammatory cells.
• Kinin is primarily bradykinin, causing dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis
• Kininases degrade kinins.
• Interactions among the three plasma protein systems are finely regulated to prevent injury to the host tissue and guarantee activation when needed.
• There are multiple mechanisms to either activate or inactivate (regulate) these plasma protein systems.
• Carboxypeptidase inhibits C3a and C5a, Histaminase and Arylsulfatase inhibit histamine. Kinase inhibits kinins and C1-esterase inhibitor inhibits complement.

Cellular Mediators of Inflammation

• Cellular mediators include mast cells, granulocytes (neutrophils, eosinophils, basophils), monocytes and macrophages, Natural killer (NK) cells and lymphocytes and cellular fragments (platelets).
• Biochemical mediators originate from destroyed or damaged cells, modulate the localization and activities of other inflammatory cells and promote tissue regeneration or repair.
• Cell surface or cellular receptors include Pattern recognition receptors (PRRs) that include Toll-like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs).
• Complement and scavenger receptors recognize complement fragments and promote phagocytosis.
• Also involved are PAMPs and damage-associated molecular patterns (DAMPs).
• Inflammatory response is initiated when tissue injury occurs or when PAMPS are recognized by PRRs on cells of the innate immune system.
• Cellular products such as chemokines and cytokines regulate innate or adaptive resistance by affecting other neighboring cells.
• Actions are pleiotropic (the same molecule may have a variety of different biologic activities, depending on the particular target cell to which it binds) and synergistic or antagonistic.
• They include interleukins, interferons, and tumor necrosis factor (TNF).

Cytokines

• Interleukins (ILs) are produced primarily by macrophages and lymphocytes in response to microorganisms or stimulation by other products of inflammation.
• They help regulate inflammation.
• IL-1, IL-6 are pro inflammatory cytokines and TGF-β and IL- 10 are anti-inflammatory cytokines.
• IL-1 causes fever and IL-6 helps with healing.
• Interferons (IFNs) protect against viral infections; produced and released by virally infected host cells in response to viral double-stranded ribonucleic acid (RNA) and prevent viruses from infecting additional healthy cells.
• IFN-a and IFN-B induce production of antiviral proteins and IFN-y increases microbiocidal activity of macrophages.
• Chemokines induce WBC chemotaxis.
• Produced by macrophages, fibroblasts, and endothelial cells and classified as either CC or CXC.
• CC chemokines affect mainly monocytes, lymphocytes, and eosinophils while CXC chemokines generally affect neutrophils.

Mast Cells

• Are cellular bags of granules located in loose connective tissues close to blood vessels found in the skin, digestive lining, and respiratory tract
• Activated by Physical injury, chemical agents, immunologic processes, and TLRs (toll linked receptors).
• Activation releases chemicals via degranulation and synthesis of lipid-derived chemical mediators.

Mast Cell Degranulation

• Release of histamine, causes vasoconstriction of blood vessels and dilation of postcapillary venules.
• Endothelial cells that line the capillaries are retracted.
• H1 receptor (proinflammatory) that is present in smooth muscle cells of the bronchi which induces bronchoconstriction.
• H2 receptor (antiinflammatory) present on parietal cells of the stomach mucosa, induces the secretion of gastric acid.
• Also releases Neutrophil chemotactic factor which attracts neutrophils and Eosinophil chemotactic factor of anaphylaxis (ECF-A) which attracts eosinophils

Mast Cell Synthesis of Mediators

• Leukotrienes are products of arachidonic acid from mast cell membranes.
• They have similar effects to histamine and are more important in later stages of inflammation.
• Prostaglandins have similar effects to leukotrienes and induce pain.
• Platelet-activating factor also has similar effects to leukotrienes and additionally activates platelets.

Endothelium

• Maintained Normal blood flow.
• Endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2).
• NO and PGI2 maintain blood flow and pressure and inhibit platelet activation and NO maintains vascular tone.
• During inflammation, the endothelium expresses receptors that help leukocytes leave the circulation and retracts to allow fluid to pass into the tissues.
• Damage to the endothelium promotes clotting.

Platelets

• Are cellular fragments formed from megakaryocytes and are also called thrombocytes.
• Activation of platelets stops bleeding and degranulation.
• Platelets contain alpha and dense granules.

Phagocytes

• Neutrophils and polymorphonuclear neutrophils (PMNs) predominate in early inflammatory responses; ingest bacteria, dead cells, and cellular debris; are short-lived and become components of the purulent exudate (pus).
• Primary roles: removal of debris in sterile lesions and Phagocytosis of bacteria in nonsterile lesions
• Eosinophils provide defense against parasites and regulate vascular mediators; help control vascular effects of inflammation
• Basophils are similar to but not mast cells; important source for cytokine IL-4; associated with allergies and asthma; their role is uncertain
• Dendritic cells provide link between innate and acquired immune responses; phagocytic cells located periphery
• Migrate to lymphoid tissue and interact with T lymphocytes to cause acquired immune response.
• Guide development of T-cells (helper cells).
• Monocytes are produced in the bone marrow, enter circulation, migrate to the inflammatory site, and develop into macrophages; precursors to macrophages in tissues.
• Kuppfer cells are liver cells, alveolar macrophages are lung cells, and microglia are brain cells
• Macrophages are larger and more active as phagocytes than monocytes and are important cellular initiators of inflammation and help in wound healing.

Phagocytosis

• Process by which a cell ingests and disposes of foreign material
• Includes destruction of microorganisms and cellular debris, production of adhesion molecules, margination (pavementing) in which leukocytes adhere to endothelial cells.
• Diapedesis occurs where cells emigrate through endothelial junctions with the help of cell junctions

Phagocytosis (cont.)

• Steps include:
  • Opsonization where the phagocyte adheres onto a foreign cell by use of C3b.
  • Engulfment where small pseudopods surround the microorganism.
  • Phagosome formation
  • Fusion with lysosomal granules resulting in phagolysosome.
  • Destruction of the target using primary and secondary granules.
• Respiratory burst and oxygen dependent mechanism occur.
• al-antitrypsin minimizes destructive effects of enzymes released by dying phagocytes and helps control respiratory function; emphysema may caused by its deficiency.
• Natural killer (NK) cells recognize and eliminate cells infected with viruses and cancer cells in the blood.
• Lymphocytes are main components of the adaptive immune response

Local Manifestations of Inflammation

• Local manifestations of inflammation result from vascular changes and corresponding leakage of circulating components into the tissue and include Heat, Redness, Swelling, Pain, and Loss of function
• Functions of inflammation include diluting toxins, carrying plasma proteins and leukocytes to the injury site, and carrying bacterial toxins and debris away from the site.

Exudative Fluids

• Exudate is fluid and cells, such as protein and debris.
• Serous transudative exudate indicates early inflammation and a fibrinous exudate indicates more advanced inflammation.
• Purulant (suppurative) exudate pus indicates a bacterial infection and Hemorrhagic exudate indicates blending.

Systemic Manifestations of Inflammation

• Fever is caused by exogenous and endogenous (IL-1) pyrogens, acts directly on the hypothalamus.
• Leukocytosis is increased numbers of, circulating leukocytes and left shift (increase in immature cells).
• Increased plasma protein synthesis of acute-phase reactants are C-reactive protein, fibrinogen, haptoglobin, amyloid A, and ceruloplasmin

Chronic Inflammation

• Acute pain is caused by a-delta fiber, chronic pain is caused by c-fiber
• Is inflammation that lasts 2 weeks or longer associated with an unsuccessful acute inflammatory. response.
• Other causes include High lipid content, a microorganisms, its ability to survive inside the macrophage, toxins and chemicals
• Characteristics are dense infiltration of lymphocytes and macrophages and Granuloma, Epithelioid cell, and Giant cell formations.

Wound Healing

• Regeneration is the most favorable outcome.
• Resolution involves returning injured tissue to its original structure and function.
• Repair involves replacement of destroyed tissue with scar tissue composed of collagen for tensile strength.
• The wound healing process is comprised of filling, sealing, and shrinking phases.

Wound Healing (cont.)

• Primary intention is for wounds with minimal tissue loss where original structure and function are restored.
• Secondary intention is for Significantly more tissue replacement which will causes scar formation

Wound Healing (Cont.)

• Phase I: Inflammation begins with coagulation and infiltration of platelets
• Fibrin mesh of blood clot acts as scaffold Platelets release growth factors.
• Neutrophils and macrophages clean wound then Debridement occurs
• Phase II: Reconstruction involves healing and begins 3-4 days after the injury lasting for 2 weeks
  • Fibroblast proliferation
  • Collagen synthesis by fibroblasts
  • Epithelialization cells from the edge of the wound grow into the healing area
  • Contraction caused by Myofibroblasts
  • Cellular differentiation
• Phase III: Remodeling and Maturation heals a wound; begins several weeks post injury and lasts for 2 years

Dysfunctional Wound Healing

• Dysfunction during the inflammatory response includes ischemia, hemorrhage, hypovolemia, fibrous adhesions, excess scar formation, infection, wound sepsis, hypoproteinemia, and medications,
• Dysfunction during the reconstructive phase includes impaired collagen matrix assembly (due to malnutrition), keloid and hypertrophic scars and impaired Epithelialization (due to anti-inflammatory), and impaired contraction resulting in contractures

Dysfunctional Wound Healing (cont.)

• Wound disruption of Dehiscence, is wound which results in excessive strain, wound sepsis, and obesity that pull away from suture line in 5-12 days
• Increases serous drainage, feels like "gave way", and requires surgery.

Pediatrics: Innate Immunity

• Neonates are transiently depressed with suppressed Inflammatory and immune function, neutrophils unable to have efficient chemotaxis, a deficient complement system, less collectins & susceptible to bacterial infections.

Aging: Innate Immunity in the Older Adult

• Impaired or delayed inflammation is likely a result of chronic Illness such as Diabetes mellitus and cardiovascular disease; Medications that may interfere with wound healing.
• Infections are more common in older adults and in their lungs, urinary tract, and skin.
• Older adults have diminished immune function and lower expression and function of TLR's.

Explore triggers for mast cell activation. Learn about Histamine, ECF-A, Leukotrienes, NO and prostacyclin. Understand the roles of endothelium, platelet degranulation, C3b and phagocytosis.