Inflammation And Repair

Vocab

Exudate: High protein fluid with cellular debris.
Transudate: Low protein fluid with cellular debris. Has low specific gravity.
Edema: Swelling caused by excess fluid in in interstitial tissue or serous cavities. Fluid can be either exudate or transudate.
Pus: A leukocyte rich, cell debris rich and sometimes microbe rich exudate. Purulent exudate.

Signals of Inflammation

Tumor (swelling): Increased vascular permeability (leakiness), resulting in edema.
Calor (heat): From increased blood flow
Rubor (redness): From increased blood flow
Dolor (pain): Increased sensory neuron stimulation

Physiology of Vascular Events

Vasodilation

Results in increased blood flow. Triggered by histamine (from mast cells) and nitric oxide (from endothelium/macrophages).

Vascular permeability

Vessel endothelium becomes leaky. Can either be early leakage from direct endothelial damage which lasts 15-30 minutes (from leukotrienes and histamines), or delayed leakage which starts after 2 hours and lasts 12 hours (from kinins and complement).

Cellular events

• Margination: Leukocytes collect in blood vessel lumen near endothelial surface
• Adhesion: Leukocytes have sugar molecules on surface which interact with selectins on endothelial surface. Goes from selectin to selectin as it "rolls" along surface. Eventually integrins activated for firm adhesion
• Diapedesis (Transmigration): Leukocytes move across endothelium. Enhanced by adhesion molecules in intercellular junctions (PE-CAM)
• Chemotaxis: Leukocytes move to site of injury in tissue via chemical gradient. Stimulated by cytokines
• Recognition: Leukocytes express receptors that recognize external stimuli. (TLRs, GPCRs, opsonin receptors, cytokine receptors)
• Removal: Phagocytosis

Acute Inflammation

Immediate response to injury. Triggered by infections (bacterial, fungal, viral) or necrosis (trauma, ischemia).

Chemical mediators

Systemic effects

Fever: From cytokines/PGD
Hypotension: From cytokines
Thrombosis: From Platelet Activating Factor

Morphology

Congestion: Increased blood in vessels
Edema: Increased interstitial fluid
Necrotizing inflammation: Neutrophils destroy cells
Serous inflammation (blistering): Accumulation of thin fluid from plasma
Fibrinous inflammation: Heavy leakage carries proteins and deposits fibrin. Appears red and granular grossly and as pink threads histologically
Suppurative (pus/purulent) inflammation: Characterized by presence of a mass of neutrophils mixed with cellular debris, edema fluid, and microbes (pus)

Possible outcomes

• Resolution
• Healing through fibrosis: Collagen accumulation leads to scarring
• Progression to chronic inflammation

Complications include the possibility of abscess (fibrous capsule of pus - yum) which required drainage, or ulcer (superficial epithelial or mucosal surface defect) which is quite painful.

Chronic Inflammation

The result of persistent infections, exposure to toxic substances, or hypersensitivity disorders.

Cell mediators

Macrophages

For more on macrophages in the innate immune system, see here: Innate Immunity and the Complement System > Macrophages

When activated, they undergo morphologic changes like increasing in size and increasing number of lysosomal enzymes.

Classical activation (M1) comes from IFN-gamma and microbes. These macrophages produce nitric oxide, radical oxygen species, and lysosomal enzymes for pathogen assassination, and interleukins and chemokines for additional response.

Alternative activation (M2) comes from IL-4 and IL-13. These macrophages produce growth factors, activate fibroblasts and promote tissue repair through anti-inflammatory factors/fibrosis.

Lymphocytes

Activated lymphocytes are larger and have a bigger, less basophilic nucleus.

Macrophages and lymphocytes are chatty and exchange information. Macrophages display antigens to T cells and also produce cytokines to recruit more leukocytes (IL-1, IL-6, and TNF). Conversely, lymphocytes will produce IFN-gamma which activates macrophages, as well as IL-17 and TNF for leukocytic recruitment.

Plasma cells

Developed from activated B-cells and produce antibodies. In chronic inflammation, plasma cells accumulate in tissue.

Other involved cells

Eosinophils can contribute to tissue damage. Mast cells are involved in fibrosis.

Granulomatous inflammation

Characterized by a collection of macrophages and other inflammatory cells that form a “ball-like structure” to wall off infections.

Foreign body type

Caused by inert foreign bodies (like sutures or splinters). Multiple macrophages come together to form giant cells in an attempt to phagocytose the material. The material can usually be seen microscopically at the granuloma center under polarized light.

Immune type

Caused by persistent infections from poorly degradable particles. The center of the granuloma is either caseating which have a central necrosis (e.g. tuberculosis), or non-caseating which do not (e.g. syphilis, cat-scratch disease, sarcoidosis).

Systemic effects

• Systemic inflammatory response syndrome: Acute response from prolonged inflammation stemming from IL-1, IL-6, and TNF-alpha. Includes fever, leukocytosis, and acute phase proteins.
• Fever: Elevation of body temperature by 1-4 deg C (IL-1 and TNF-alpha → cyclooxygenases → arachidonic acid → NSAIDs > Prostaglandins → hypothalamus). Typically associated with infection. Helps with controlling invaders. NSAIDs can be taken to relieve fever by blocking prostaglandin production.
• Leukocytosis: Increases white blood cell count and will be reflected on complete blood count (CBC) measure.
• Neutrophilia: Increased number of neutrophils.
• Lymphocytosis: Increased number of lymphocytes.

Acute phase

Liver begins producing cytokines. These serve as markers for chronic inflammatory disorders, autoimmune disorders, or relapse after therapy failure. Other symptoms include tachycardia, peripheral vasoconstriction, rigors, chills, anorexia (loss of appetite), and malaise (tiredness).

Common proteins include C-reactive protein (CRP), fibrinogen, and serum amyloid protein. Higher protein count is reflected by Erythrocyte Sedimentation Rate (ESR) which measures the rate at which RBC descend in a standardized tube. Increased level of acute phase protein is associated with aggregation of RBCs, increasing ESR.

Clinical peals

Mononucleosis

From viral infection. Swollen lymph nodes, increased number of lymphocytes.

Syphilis

From persistent Treponema pallidum (gram negative spirochete). Causes rashes on palms and sores. Forms a gumma (lesion). Central cells are necrotic with a cellular outline.

Asbestos

Will see macrophages and scattered lymphocytes.

Silicone

Will see granulomatous of macrophages and lymphocytes, which surround it.

Arthritis

Autoimmune response results in a rheumatoid nodule and accumulates lymphocytes and plasma cells.

Hepatitis C

Leads to aggregation of lymphocytes in portal triads and destroys surrounding tissue. Immune cells stimulate fibroblasts to secrete collagen to promote fibrosis. However, extensive fibrosis can lead to scarring of liver (cirrhosis).

Bile duct destruction

Lymphocytes surround the duct and result in tissue destruction.

Hashimoto's thyroiditis

Autoimmune response from hypersensitivity disease leads to parenchyma.

Tuberculosis

Caused by mycobacterium tuberculosis. Forms a caseating granuloma.

Leprosy

Caused by mycobacterium leprae. Forms non-caseating granulomas.

Cat-scratch disease

From gram-negative bacillus. Forms rounded or stellate granuloma of central granular debris and recognizable neutrophils.

Sarcoidosis

Forms non-caseating granulomas with lots of macrophages.

Chron's disease (IBD)

Sometimes forms non-caseating granulomas in the intestines with dense chronic inflammatory infiltrate.

Healing and Repair

Regeneration occurs in cells with superficial damage. Epithelial cells will regenerate from stem cells. Scar formation occurs in tissues with severe damage or compromised extracellular matrix (ECM) components. This will involve fibroblastic proliferation and collagen synthesis via TGF-beta.

Growth factors deliver signals to stimulate transcription of genes to regulates the cell cycle. They activate signaling pathways which stimulate DNA replication, promotes changes in metabolism which promote biosynthesis.

Primary intention: Uncomplicated, clean incisions, and minimal scar formation.
Secondary intention: Larger wounds, intensive inflammatory response, wound contracture.

Steps

1. Inflammation

2. Proliferation

Angiogenesis gives rise to new blood vessels by budding off from pre-existing vessels. Critical for formation of granulation tissue, which appears edematous (loose). Fibroblasts are stimulated to secrete collagen and other ECM components.

Ongoing inflammation and stimulation of fibroblasts leads to fibrosis, or the abnormal deposition of collagen that occurs in internal organs with chronic disease.

3. Scar formation

4. Tissue remodeling

Balance of deposition/degradation of ECM and collagen. Matrix metalloproteinases (MMPs) act to degrade collagen.

Wound contraction occurs with periphery myofibroblasts network contraction and production of collagen in large surface wounds.

Common complications

Wound healing can be impacted by poor nutrition/metabolism, blood supply, anti-inflammatory hormones, infection, mechanical stimulation, foreign bodies, size, and location.

• Hypertrophic scar and keloid: Accumulation of excessive amounts of collagen during the repair
  process that becomes raised and/or extend beyond the boundaries of the original wound
• Wound dehiscence: Rupture of the wound that occurs most commonly after abdominal surgery, often due to increased pressure or mechanical stress on the wound.
• Ulceration: Superficial epithelial layer sloughs off; often occur secondary to inadequate vascularization.
• Contractures: Can be a normal part of healing but if becomes excessive, results in deformity that leads to a functional deficit.