Patho: Inflammation and Dysfunctional Wound Healing EX1

Inflammation steps generally

• Injury

• Bleed

• Stop bleed

• Redness, pain, swell, heat, loss of function

• heals

Inflammation Response types (Following VASCULARIZED Tissue Injury)

Inflammation (Innate immune response) lead to:

1. Immune response (adaptive immune response)

2. Tissue regeneration

3. Scar formation

4. Cellular adaptation (As a result of chronic inflammation)

Inflammation + Aims (3)

• Nonspecific, protective, coordinated defense to tissue injury

  • Intensity proportional to injury

• Aims of inflammation (3 aims)

  • Wall of injury

  • Prevent spread of injurious agent

  • Bring body’s defenses to region

2 Types inflammation

1. Acute: Occurs rapidly in reaction to injury

   1. Rids body of offending agent

   2. Enhance healing

   3. Terminate quickly (few days max)

2. Chronic

   1. Inflammation persists

   2. INHIBITS HEALING (doesnt help)

   3. Causes continual cellular and organ damage

Local vs Systemic Responses

Local

• Vascular stage: dilation, permeability

• Cellular stage: cellular chemotaxis

Systemic

• White blood cell response

• Acute phase response

Vascular Stage

• Inflammatory mediators enable vasodilation + increased permeability

  • Histamine + Bradykinin

• Increased permeability = fluids, WBCs, and platelets travel OUT to injury site (from vessel)

• Vasodilation arterioles followed + enhanced capillary permeability = blood out to tissue = SWELLING

5 Cardinal Sings of Acute Inflammation

• Rubor/ redness

• Tumor/ swelling

• Calor/ heat

• Dolor/ pain

• Loss of function

Edematous Fluid

• Purulent Exudate (pus): edema fluid rich in protein from WBCs, debris, microbial organism

• Transudate: Edema fluid contains mostly water filtrate of blood (little protein) like blister fluid

Cellular Phase: Chemotaxis

• Movement of WBC following chemical gradient

• Chemical signal from microbial agents, WBCs, endothelial cells ATTRACTS PLATLETS AND WBCs to injury

• Margination: new WBCs arrive and line up along ENDOTHELIUM in area of inflammation

  • WBCs release inflammatory mediators to amplify or dampen inflammation, or attract more WBCs

STEPS:

• WBCs and other things release signal to recruit more

• Margination: New WBCs(leukocytes) arrive and line up against endothelial wall

• Rolling: Roll against wall to site of injury

• Adhesion: adhere to endothelial receptors

• Transmigration: WBCs squeex through endothlial lining into the cell/cells

• Chemotaxis; WBCs follwo chemical gradient to specific injury site

• Phagocytosis occurs at same time as chemotaxis, after they enter the cell

KNOW THIS 4 Chemotaxis stuff

Steps:

• Margination

• Transmigration (passing through endothelial

• Chemotaxis

• Phagocytosis

(Chemotaxis and phagocytosis happen simultaneously)

WBCs + 5 types

• Major inflammation player

1. Neutrophils (granulocyte)

2. Lymphocytes (agranulocyte)

3. Eosinophils (granulocyte)

4. Basophils (granulocyte)

5. Monocytes/Macrophages (agranulocyte)

Granulocytes

• Contain cytoplasmic granules = enzymes + mediators to fight infection

• Neutrophil, basophil, eosinophil

PHILS = Gran

Neutrophil

• First responder (24-48 hr)

• Begin phagocytosis

• Short life 10hr-few day

  • Bone marrow release more as they die

• Likely to find in blood test with MRSA or other BACTERIAL

  • Viral = cold, flu, chicken pox and stuff not bacterial

Monocytes/ Macrophages

• Activated after 24-48hr

• Mono turn INTO MACRO (engluf pathogens)

• Life span = long (weeks to months)

• PREDOMINANT CELLS at injury site

CBC w/ differnetial

• Used in diagnosis of infection and inflammation

• Measures TOTAL NUMBERS WBCS and calculates percentages of wbc types

• Mainly Neutrophil = bacterial infection

• Mainly lymphocytes = viral infection

Inflammatory Mediators

Chemical proteins released when inflammation occurs

Released from Plasma,

• MADE IN LIVER: Acute phase proteins, coagulation factors

Released from cells (WBC, mast cell, platlets, etc.)

• Prostaglandins: pain fever

• Leukotrienes: pain and swelling

• Histamine: sneezing, eye tearing, sinus inflammation, etc.

• Tumor necrosis factor (TNF-alpha): promotes immune response + necrosis of tumor cells

• Interleukin: IL1 producing fever

Cytokines

Inflammatory mediators released by WBCs + AMPLIFY or DAMPEN inflammation

• Tumor necrosis factor (TNF-alpha)

• Interleukins(ILs)

Acute Phase Proteins

• Inflammatory mediators made and released by LIVER

• Stimulate, modulate, deactivate reaction

  • C-reactive protein

  • Fibrinogen

  • Serum amyloid A

    • ALL INCREASE with inflammation

Lab tests for inflammation

• C-reactive protein (CRP)

• Erythrocyte sedimentation rate (ESR) (indirectly shows fibrinogen levels) (ALSO LIVER ONE, along with serum amyloid A duh)

• Leukocytosis (high WBC count)

ALL INCREASE with inflammation

Systemic Responses to inflammation (symptoms)

• Fever

• Pain

• Malaise (generalized feeling poor health)

• Lymphadenopathy (swollen lymph nodes)

• Anorexia

• Sleepy

• Anemic

• Weight loss

Fever

• Inflammatory processes activate PROSTAGLANDINS + reset HYPOTHALAMIC TEMPERATURE REGULATING CENTER (raise the level to increase total body temp)

• Higher body temp = WBC efficiency increase

Fever risks

• Fever above 102 = BAD

  • Use antipyretics (aspirin, ibuprofen, etc.)

  • Inhibit prostaglandin formation + reduce fever

Reye’s syndrome = liver failure and encephalopathy (brain dysfunction)

• Salicylate for children with viral infections

• NO APIRIN: for children as an antipyretic agent

What causes chills with fever

• Hypothalamic temperature control center is RAISED to higher baseline (normal is 98.6)

• SO, body temp is lower than NEW BASELINE = feeling cold

  • Vasoconstriction + shiver to preserve/ generate heat

Lymphadenopathy

• Enlargement of lymph nodes due to inflammation

• Lymphocytes: mature in lymph node during inflammation = swollen + tender lymph nodes

LYMPHOCYTES = WBC

Acute Inflammation Outcomes (3)

• Complete Resolution: Most desired

  • Injured cells replaced by same type

  • Vascular permeability returns

  • Mediators + debris, and WBCs are inactivated or destroyed

• Healing by Connective tissue

  • Severe tissue damage + large inflammation

  • Fibrous (scar tissue) replaces (NOT TEH SAME TYPE)

• Chronic inflammation: DOES NOT GO AWAY

Healing depends on cell type injured + severity

Cell regeneration: 3 types

• Labile: continually divide + replace eliminated cells (skin, hair, nails, GI mucosal lining, bone marrow, cancer, etc.)

• Stable: in a resting stage until STIMULATED, then enter cell cycle (bone cells, hepatocytes)

• Permanent: do NOT enter cell cycle and DONT regenerate (neurons, cardiac, myocytes)

Cell cycle phases

• G1: Synthesis of components needed for DNA

• Synthesis: DNA replication

• G2: Preparation for mitosis

• M: Mitotic phase

CIRCULAR OVERALL

G0 phase: resting phase where cells STOP dividing, can last days to decades

3 phases of wound healing

1. Inflammation

   1. Vascular phase: vasodilate + permeability

   2. Cellular phase: macrophages, phagocytes, etc.

   3. WBCs: NBELm/m

2. Proliferation, Granulation tissue formation, Epithelization

   1. Fibroblasts = extracellular matrix or growth factors

   2. Proliferation = phase following initial inflammation where new tissue is formed

   3. Granualtion tissue: highly vascularized, new CT, fibroblasts, and and extra cellular matrix (INTIAL PHASE where CT and BLOOD VESSELS froma round wound)

   4. Epithelization = Growth of EPITHELIAL CELLS over a wound

      1. Granulation b4 epithelization

3. Wound contraction + remodeling

KNOW DIAGRAM PLS

Skin Wound healing (3 processes)

• Primary intention:

  • Clean laceration requires simple re-epithelialization when edges are approximated (closed together withs stiches or som)

  • No scar tissue formed

• Secondary intention

  • Wound with LARGE GAP in tissues; some of the tissue has been gouged out (ulcer)

  • Scar tissue formed

• Tertiary intention:

  • Wound with large gap missing tissue has been CONTAMINATED + needs DRAINAGE TUBE for healing

  • MAY need skin graft

Factors for wound healing: 10

1. Nutrition: proteins, carbs, etc.

2. Oxygenation + circulation

3. Immune strength

4. Diabetes: reduces phagocytic ability + circulation

5. Corticosteroid use: anti-inflammatory delay healing

6. Immunosuppressant agents

7. Contamination

8. Surgically inserted devices

9. Obesity

10. Age

Wound complications for healing (7)

1. Keloid: hyperplasia of scar tissue

2. Contractures: inflexible shrinkage of wound tissue that pulls edges toward center

3. Dehiscence: opening wound suture line

4. Evisceration: opening of wound with extrusion of tissue + organs

5. Stricture: abnormal narrowing of tubular body passage from scar tissue

6. Fistula: abnormal connection between 2 epithelium lined organs/vessels

7. Adhesion: internal scar tissue between tissues or organs

Anaplasia

Cancer cells that divide rapidly and have little resemblance to normal cells

Neoplasm:

Abnormal mass of tissue that forms when cells grow + divide excessively instead of dying

NOT always cancerous

Benign vs Malignant Neoplasia

Benign

• Non cancerous

• Well differentiated: generally look like cells they should be replacing; but TOO MANY OF THEM

• Cell proliferation (increase in number) is EXCESSIVE

  • Can not regulate proliferation rate

Malignant:

• Cancerous

• Poorly differentiated: nonfunctional, non-resembling cells they are growing on/replacing

  • More poorly differentiated = faster growth

• Excessive cell proliferation, cant control= ANAPLASIA

Carcinogenesis (3 Phase)

• Normal cells change to cancerous cells

1. Initiation: exposure of cells to carcinogenic agent + DNA damaged

2. Promotion: start of unregulated growth (MUTATED not MALIGNANT YET)

   1. Proliferation INCREASE, Differentiation DECREASE

3. Progression: tumor cells acquire malignant phenotype (NOW MALIGNANT, becomes a tumor mass)

   1. Invade surrounding tissue

   2. GF: VEGF (Increased vascular endothelial growth factor)

   3. Alter overall tissue function

GROWTH RATE = EXPONENTIAL: because the cancerous cells keep dividing, and then those divide, and so on

Cancer Associated Gene (3)

• Proto-oncogene:

  • Genes that promote proliferation

  • When mutated, stimulate constant, unrelenting proliferation + cell cycle

• Tumor suppressor gene: stops proliferation

  • When defective/deactivated, lose ability to inhibit cell proliferation

  • Cancer then starts

  • p53 gene = tumor suppressor

• Apoptotic + anti-apoptotic gene: genes regulating apoptosis either promoting or stopping

  • Unregulated = bad duhS

LOOK AT THIS

KNOw it

Mechanism allowing viruses to cause cancer

• The initiation stage is caused by carcinogens that damage the DNA of our cells.

• Some viruses act as carcinogens by entering the body and causing cell mutations, which begins the process of carcinogenesis.

Identify several cancer causing viruses

• HPV (human papilloma viruses): causes cervical cancer

• Epstein barr virus

• Hepatitis B virus

• Human herpes virus 8