Inflammation and Repair

Inflammation is a mechanism to protect an organism from danger, typically in the form of invading pathogens (infection) or tissue damage through other means (necrotic tissue death).
Inflammation is meant to eliminate the source of danger, limit it, and help repair the damage.
Inflammation has two main components: vascular and cellular
Based on timing and involved cells one can distinguish between acute and chronic inflammation. Response varies to a certain degree between tissues and organs. (Not all tissues are created equal)
Without Pre-existing Immunity: preformed mechanism and innate immunity are the 1st lines of defense
With Pre-existing Immunity: adaptive immunity (antibodies) facilitates activation of defense mechanisms.

Alarm the body that something is going on (swelling and pain)
Wall-off (contain) and prevent the spread of pathogens from the entrance to the blood or other tissues.
Bring “Troups” to the site of infection and DESTROY the danger
Set the stage for repair by growing blood vessels and proliferating fibroblasts

The inflammatory process should start when the offender is eliminated.
There are specific mechanisms (apoptosis) that terminate or restrict the process.
We have to eliminate the threat without destroying the host, different tissues have a different inflammatory processes.
* It is better to live with an infection than die without one.

Microbes are coated with antibodies or complement proteins
Antibodies bind complement, complement factors are cleaved, and the complement cascade is activated.
Complement factors like C3a and C5a activate other cells, like tissue mast cells.
Tissue Mast Cells release vasoactive factors (Histamine (a short-acting vasodilator that’s released early) and Bradykinin (released later and long-lasting))
Vasodilator increases blood flow into tissues, but the speed of blood flow slows down in affected areas.
Immune cells become recruited and activated (1st neutrophils then macrophages and dendritic cells ) that release factors that induce defense (Fever (CNS) and acute phase proteins (liver))

Increased blood flow = lesions turn warm and red (Rubor and Calor)
Vascular changes: the normal hypostatic blood pressure (bp) in the microcirculation (small capillaries) is 25 mmHg.
  * Plasma colloid osmotic net pressure is also 25 mmHg, so there is no NET movement into the tissues.
  * Normally the lymphatic fluid drains fluid from tissues.
  * During inflammation, the hydrostatic pressure is >25 mmHg due to increased arteriole diameter which causes more blood flow and fluid leakage into the tissues.
  * Brings antimicrobial proteins and cells.

Transudate: low in protein, Specific gravity is <1.012, clear in color, indicative of congestive heart failure, kidney disease, and Cirrhosis
Exudate: High in protein, specific gravity is >1.020, cloudy due to inflammatory cells, Typical fluid indicative of infections, pneumonia, malignancy, Tbc, PE
Edema: Transudate or exudate in tissues or body cavities
Pus: Contains many leukocytes (neutrophils, macrophages) indicative of an infection

Inflammatory and noninflammatory cells produce vasoactive factors.
Vasodilation: Histamine, Nitric Oxide, Bradykinin, prostaglandins, serotonin (primarily act on arterioles, more fluid in, less out)
Vascular Permeability: Histamine, Bradykinin, serotonin, complement factors (C3a and C5a)

Vasodilation gets acute inflammation rolling.
Mediators act on smooth muscles in vessels and relax them.
This slows down the blood flow, in an acutely inflamed area.
The slower flow of blood and increase in the demand for oxygen required by those cells (they’re working) drops in the pH (more acidic) in the inflamed region.
Inflammatory enzymes work better in an acidic environment but as you get farther away from the active area the pH gets more basic.
The slower flow of blood also creates a “turbulence” of blood cells, Marginalization (inflammatory cells leave the blood vessel and migrate into tissues), which enables blood clots to form to stop bleeding and wall off injury

Enhanced Vascular permeability: inflammatory proteins can get into injured tissues and easily migrate through vessel walls.

The complement system has over 30 proteins usually activated in a sequential order
C3a and C5a act as soluble signals (inflammation), C3 is the central molecule, and C3b sticks to the pathogen (phagocytosis) and the formation of the MAC complex (destruction)
Inflammatory cells migrate to sites of inflammation

Systematic effects of inflammation → acute phase proteins (mostly made in the liver)
Fever: is induced in the brain by endogenous pyrogens (IL-6 and TNF) that induce PGE-2 via enhancement
  * Low-grade fever: 38-39 C (99.5-102.2 F)
  * Moderate fever: 39-40 C (102.2-104 F)
  * High-grade fever: >40 C (>104 F)
  * Hyperplyrexia: >42 C (>107.6)
Acute phase proteins - antimicrobial, C-reactive protein, serum A amyloid (SAA) Fibrinogen (enhances ESR).
Leukocytosis: greater than 10,000/ul in the blood (neutrophilia, lymphocytosis, eosinophilia)
Increased pulse and enhanced blood pressure
Chills, Malaise
Very severe change → septic shock syndrome and disseminated intravascular coagulation
Acute Phase Reactants: ^^“positive” (pro-inflammation^^) (CRP, SAA, C3, C4, Fibrinogen, ESR) or $“negative” (anti-inflammatory)$ (Transferrin, albumin)

Acute Inflammation (bacterial): neutrophils, necrosis, edema, dilated vessels
Chronic inflammation (TB or Viral): Lymphocytes, fibrosis, changes in tissue architecture