1ST LINE OF DEFENCE

- Threat to our homeostasis (ie. at park and steps on glass)

- Epithelial cells of the skin
- Supposed to stop pathogens/bacteria from getting in
- keratin cells (skin) are hard to penetrate
- When pathogens penetrate, they are removed by mechanical means →
sloughed off with dead skill cells (routinely replaced)
- Have low temp and pH (acidic)
- Mucous membranes
- Ear wax, sweat, mucus, saliva created by epithelial cells
- Lined with mucous and antimicrobial peptides which kill or inhibit the growth of
disease-causing bacteria, fungi, viruses (lysosomes, defensins, collectins,
mannose binding lectin)
- Respiratory tract
- Produce mucus and have cilia to trap and move pathogens upward to be
expelled through coughing or sneezing
- Linings of GI and GU tract
- Acidic, low pH
- Vomited from stomach or flushed through urine
- Normal microbiome
- Normal flora → Antibiotics suppress normal flora
- Prolonged treatment with broad spectrum antibiotics can cause the overgrowth
of normal bacteria in our body (ie. c. diff)
*microorganisms require temps near 37 oC and near neutral pH*

2ND LINE OF DEFENCE: INFLAMMATORY RESPONSE

Inflammatory response benefits

1. Prevents infection and further damage by invading microorganisms
- The inflammatory exudate dilutes toxins produced by bacteria and released from dying
cells. The activation of plasma protein systems (e.g., complement and clotting systems)
helps contain and destroy bacteria. The influx of phagocytes (e.g., neutrophils,
macrophages) destroys cellular debris and microorganisms.
2. Limits and controls the inflammatory process
 - The influx of plasma protein systems (e.g., clotting system), plasma enzymes, and cells
(e.g., eosinophils) prevents the inflammatory response from spreading to areas of
healthy tissue
3. Interacts with components of the adaptive immune system
- Elicits a more specific response to contaminating pathogens through the influx of
macrophages and lymphocytes that destroy pathogens
4. Prepares the area of injury for healing and repair
- Removes bacterial products, dead cells, and other products of inflammation (e.g., by
way of channels through the epithelium or drainage by lymphatic vessels)

The inflammatory response

1. Occurs in tissues with a blood supply (vascularized)
2. Is activated rapidly (within seconds)
3. Depends on the activity of both cellular and chemical components
4. Nonspecific: reacts the same way regardless of location
5. Contains the injury or destroys agents that can damage tissue
6. Initiate healing

Mast cells
- Release histamines to cause temporary vasoconstriction (to stop bleeding) and then vasodilation
- Causes increased blood flow and vascular permeability
- Attracts neutrophils and eosinophils

Vascular response
1. Vasodilation
2. Increased vascular permeability and leakage
3. WBC adhere to the inner walls of the vessels and migrations through the vessels (diapedesis)

Acute inflammatory response

1. Vasodilation causes slower blood velocity and increased blood flow to the injured site
2. Increased vascular permeability (blood vessels become porous because of the contraction of the
endothelial cells due to mast cells) cause leakage of fluid out of the inured site and edema
3. As plasma moves outward blood in the microcirculation becomes more viscous and slow and
increased blood flow and concentration of RBC causes erythema and warmth
4. White blood cells (leukocytes) adhere to the inner lining of vessels and migrate through the
enlarged junctions between the epithelial cells (diapedesis)

Effects of inflammation are visible in seconds : First arterioles constrict briefly to stop bleeding then
vasodilation

At the same time biochemical mediators – histamine, bradykins, leukotrienes and prostaglandins
stimulate the endothelial cells that line the capillaries and venules to contract causing spaces between
the junction of cells that allow leukocytes and plasma to enter. Leukocytes take away foreign substances

Also at the same time we have activation of the 3 plasma or complement systems – essential to an
effective inflammatory response
Cellular infiltration causes pus at site of infection
Thrombosis (blood clots) through fibrin
Stimulation of nerve endings → Prostaglandins bradykinin to cause pain
Chemokines call WBC to fight infection

Acute inflammatory response:

PLASMA PROTEIN SYSTEMS FUNCTION

Complement system
- Functions
1. The activation of inflammation
2. Opsonization: opsonins/C3b, coat the surface of bacteria and increase their
susceptibility to being phagocytized (eaten) and killed by neutrophils and macrophages
3. Chemotactic factors C5a: diffuse from inflammation site and attract phagocytes
4. Anaphylatoxin activity C5a: rapid degranulation of mast cells (release histamines that
induces vasodilation and increase capillary permeability)
5. Cell lysis: the direct killing of target cells by creating pores in the outer membranes that
permit water to enter, causing cell to die
Clotting system
- Plasma proteins (fibrin) form a blood clot that contains platelets and traps cells such as
erythrocytes, phagocytes, and microorganisms
- Purpose:
- Plug damage vessels and stop bleeding
- Trap microorganisms and prevent their spread to adjacent tissues
- Provide a framework for future repair and healing
Kinin system
- Product: Bradykinin
- Functions:
- Causes vasodilation
- Acts with prostaglandins to induce pain
- Causes smooth muscle cell contraction
- Increase vascular permeability
3RD LINE OF DEFENCE: ADAPTIVE IMMUNITY

- Leukocyte (WBC) created in bone marrow (b cells) or thymus (t cells) and produces:
- Phagocytes: Triggers the immune responses → then sends macrophages to consume
foreign cells and identify the antigen. Transmits information to lymphocytes
- Lymphocytes: “Helper” T cell (CD4) is the first to arrive and sends signals to...
- Trigger other T cells called killer cytotoxic T cells (CD8) and they can...
- Release chemicals called cytokines and will destroy the bacteria out
- Make sensitized T cells that will wait
- Or trigger B cells, once activated, it is going to make plasma cells or memory B
cells
- Plasma cells will make antibodies specific to the non-self antigen (igE)
- igE will find mast cells and attach itself making it sensitized mast cells
- Memory B cells
1. Cell mediate:
- Macrophage → helper T cells or CD4 → cytotoxic T cells → sensitized T cells and
cytokines
2. Humoral:
- Macrophage → helper T cells or CD4 → B cells → plasma cells and memory B cells
- Antibodies produced by C-cells

LOCAL AND SYSTEMIC MANIFESTATIONS OF INFLAMMATION

Local inflammation: result from vascular changes and corresponding leakage of circulating components
into the tissue.
- Heat: From vasodilation and increased blood flow
- Redness: From vasodilation and increased blood flow
- Swelling: From exudate accumulations and fluid from capillary permeability
- Pain: From pressure exerted by exudate accumulations, prostaglandins, and bradykinins
 - Loss of function: May also occur.

Systemic manifestations
- Fever
- Caused by exogenous and endogenous pyrogens
- Acts directly on the hypothalamus
- Leukocytosis
- Increased numbers of circulating leukocytes
- Left shift, increase in immature cells
- Increased plasma protein synthesis
- Acute-phase reactants
- C-reactive protein, fibrinogen, haptoglobin, amyloid A, and ceruloplasmin

DIFFERENCE BETWEEN INFLAMMATION AND INFECTION

Inflammation is a non-specific response to injury that destroys agents that could damage human tissue.
Infection refers to the invasion and multiplication of a pathogen within the body, while inflammation is
the body's protective response against infection

INNATE VS ACQUIRED IMMUNITY

Innate immunities
- Natural barriers (physical and biochemical) and inflammation
- Ie. epithelial layer
- Place at birth to prevent damage and infection by pathogenic microorganisms.
Acquired immunity
1. Active immunity: Body creates antibody to fight against own antigen
a. Active natural: Direct exposure to an antigen and development of antibody
i. ie. Antibody created to fight foreign bacteria
b. Active artificial: Introduce an antibody
i. ie. vaccine
2. Passive immunity: Transfer of antibodies
a. Passive natural: maternal antibodies (IgG) is transferred from mother to fetus across
the placenta
i. ie. Breast milk has antibodies
b. Passive artificial: injection of antibodies from a person or animal into a second person
i. ie. rabies, antivenom

CHRONIC INFLAMMATORY RESPONSE

- Last 2 weeks or longer

- Unsuccessful acute inflammatory response
PRIMARY, SECONDARY AND TERTIARY INTENTION HEALING

Primary
- Wounds that heal under conditions of minimal tissue loss (coagulation, inflammation,
proliferation, remodelling, and maturation)
- A clean incision, such as a paper cut or a sutured surgical wound, heals primarily through the
process of collagen synthesis. Because this type of wound has minimal tissue loss and close
apposition of the wound edges, very little sealing (epithelialization) and shrinkage (contraction)
are required
Secondary
- Healing of an open wound, such as a stage IV pressure ulcer, requires more tissue replacement
so that epithelialization, scar formation, and contraction take longer for healing to occur.
Healing by either primary or secondary intention may occur at different rates for different types
of tissue injury.
Tertiary
- Intentional delay in closing a wound. On occasion, wounds are left open (covered by sterile
dressing) to allow an infection or inflammation to subside. Once the wound is closed with
sutures or staples. The scarring is minimal.

WOUND HEALING

Regeneration
- Most favourable
- Damaged tissues are replaced with healthy tissue → regrowth
- Occurs in epithelia of skin, intestines and some organs (liver)
Resolution
- Returning injured tissue to the original structure and function
Repair
- Occurs if extensive damage is present
- Scar tissue replaces destroyed tissue
- Scar tissue is composed of collagen that fills the lesions and restores the strength but cannot
carry the physiologic functions of the destroyed tissue ∴ loss of function

Phase I: Inflammation
- Coagulation and infiltration
- Platelets, neutrophils, macrophages
- Fibrin mesh of blood clot acts as scaffold
- Platelets release growth factors.
- Neutrophils and macrophages clean the wound.
- Debridement occurs.
- Blood vessels and lymph drain away debris.
- Vascular dilation and permeability reverse.
Phase II: Reconstruction
- Wound begins to heal
 - Healing begins 3–4 days after the injury and continues for 2 weeks.
- Fibroblast proliferation occurs.
- Collagen synthesis by fibroblasts.
- Epithelialization—cells from healthy tissue grow into wounds.
- Wound contracts through the actions of myofibroblasts.
- Cellular differentiation occurs.
Phase III: Remodelling and Maturation
- Healed wound is remodelled.
- This phase begins several weeks after injury and may last for 2 years.
- Cellular differentiation continues.
- Scar tissue forms.
- Scar remodelling occurs

DYSFUNCTIONAL WOUND HEALING

Causes: ischemia, excessive bleeding, obesity, excessive fibrin deposition, a predisposing disorder such
as diabetes mellitus, wound infection, inadequate nutrients, numerous medications, and tobacco smoke

Dysfunctional collagen synthesis

- Hypertrophic scar: is raised but remains in the boundaries of the wound, regress over
time
- Keloid scar: raised scar that extends beyond original boundaries
- Caused by excessive synthesis of collagen at suture sites
Wound disruption
- Dehiscence (risk of infection)
Impaired contraction
- Contracture: scarred skin become nonelastic, limiting ROM

HIV
Clinical manifestations
- Acute Infection
- The development of HIV specific antibodies (sero-conversion) is usually accompanied by flu-like
symptoms
- Fever, swollen lymph glands, sore throat, headache, malaise, nausea, muscle and joint
pain, diarrhea, diffuse rash
- Occurs 1 to 3 weeks after infection and is termed acute retroviral syndrome
- There are increased viral load & CD4 T-cell count drops then returns to Normal
Diagnosis
- Everyone exposed to HIV has a window period: time from which antibodies against the virus
starts to show in the blood. Not detecting the virus, but detecting the antibodies
- Usually takes 4-6 months to detect the antibodies but can start prophylactic (intended to
prevent disease) once you have suspicion
- Window time: the time between the entry of the virus to when the antibodies appear in blood
- Infectious disease doctor will follow up once confirmed of HIV or AIDS to check:
- HIV: Western Blot or ELISA test to check for serum antibodies
 - AIDS: CD4 count (less than 200) and Viral load (increase) (amount of virus)
Treatment
- Which med will block enzyme protease = nevirapine (viramune)
- In combination with other antiretroviral drugs, nevirapine reduces HIV viral loads and increases
CD4 counts, thereby retarding or preventing the damage to the immune system and reducing
the risk of developing AIDS

MODES AND VARIABLES IN THE TRANSMISSION OF HIV

- Transmitted only through contact with body fluids
- Blood, semen, vaginal secretions, breast milk

HIV ANTIVIRAL THERAPY

GLUCOCORTICOIDS
- A natural hormone released by adrenal cortex
- Suppresses every component of inflammatory response
- Glucocorticoids have the ability to suppress histamine release and inhibit the synthesis of
prostaglandins by COX-2. In addition, they can inhibit the immune system by suppressing certain
functions of phagocytes and lymphocytes. These multiple actions markedly reduce
inflammation, making glucocorticoids the most effective medications available for the treatment
of severe inflammatory disorders.

PREDNISONE
- Prevent inflammation, reduce risk of bronchospasm in patients with asthma or certain cancers;
immunosuppressive at higher dose
 - Decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration
to sites of inflammation
- Adverse effects: Cushing’s syndrome (long-term), fluid retention

DEXAMETHASONE
- Synthetic glucocorticoid
- Used for inflammation
- Decreases inflammation by suppressing migration of polymorphonuclear leukocytes, fibroblasts,
reversing increased capillary permeability and lysosomal stabilization, suppresses normal
immune response, no mineralocorticoid effects

NSAIDs → IBUPROFEN
- Inhibit cyclooxygenase (COX), an enzyme responsible for the formation of prostaglandins →
inflammation and pain are reduced
- Act by inhibiting pain mediators at the nociceptor level
- When tissue is damaged, chemical mediators, including histamine, potassium ion, hydrogen ion,
bradykinin, and prosta-glandins, are released locally. Bradykinin is associated with the sensory
impulse of pain. Prostaglandins can induce pain through the formation of free radicals

CELECOXIB
- Mild to mod pain
- Inflammation due to RA, OA, etc
- Blocks COX-2 without inhibiting COX-1
- Analgesic, anti-inflammatory, antipyretic effects without causing platelet aggregation or
GI irritation