BIOL 2200 Module 1: Adaption, Inflammation, and Healing

What is the meaning of pathophysiology?

It means “the study of functional changes in cells, tissues, and organs altered by disease or injury

What is the meaning of pathology?

It means “the study of physical changes in cells and tissues associated with disease”

What underlies every disease?

An alteration in cell or tissue function

5 ways cells can be altered

Adaptation, injury, death, aging, neoplasia

What is cellular adaptation in the context of disease?

A change in the size, number, or type of cell to permit function when under stress

Atrophy

Cellular adaptation where cells decrease in size

Hypertrophy

Cellular adaptation where cells increase in size. Prevalent in skeletal and heart muscles which cannot undergo mitosis

Hyperplasia

Cellular adaptation where the number of cells increases (in tissues with cells capable of mitosis)

Metaplasia

Cellular adaptation where one mature cell type is reversibly replaced by another. E.g. undifferentiated stem cells reprogram to another cell type

Dysplasia

Cellular adaptation where size, shape, and organization of mature cells undergo abnormal changes

Atypical hyperplasia (non-cancerous)

Where rate of mitosis increases causing buildup of tissue. Increases risk of developing cancer

Intracellular accumulation

Buildup of material that the cell cannot metabolize

Endogenous intracellular accumulation

Where the cell produces substances faster than it is used

In alcoholism, what endogenous intracellular accumulation happens?

Impaired liver cannot process all fatty acids, leading to excess fat storage or fatty liver

Lipofuscin

Yellow/brown pigment formed from accumulation of undigested material during cell structure turnover

Exogenous intracellular accumulation

Intracellular accumulation from an external source, such as coal dust

Calcification

Buildup of calcium salts in tissues

Where does calcification occur in?

• Damaged tissue: From damaged/dead cells, e.g. heart valves

• Normal tissue: From excess serum calcium levels, e.g. lungs

Four major causes of cell injury

Physical agents, biological microorganisms, chemicals, nutritional imbalances

Three mechanisms of cell injury

Hypoxia, impaired calcium homeostasis, free radicals

Three mechanisms of cell injury

Hypoxia, impaired calcium homeostasis, free radicals

Hypoxia

Partial lack of oxygen for cells

Ischemia

Reduced blood flow to a part of the body, causing a shortage of oxygen and nutrientsA

Arteriosclerosis

The gradual narrowing of arteries

Embolism

Sudden blockage in blood vessels by traveling pieces of material

Anoxia

Total lack of oxygen

Why does hypoxia decrease ATP production?

Because it increases anaerobic respiration, generating less ATP than aerobic respiration

How does hypoxia reduce phospholipid synthesis?

Through reducing activity of ATP-dependent enzymes

How can hypoxia result in necrosis?

• Lysosomal membrane damage → leaks enzymes → necrosis

• Mitochondrial membrane damage → changed membrane permeability and less ATP → necrosis

• Plasma membrane damage → influx of fluids, ions, loss of cellular contents → necrosis

How does hypoxia affect the sodium/potassium pump?

It alters intracellular ion concentrations, leading to influx of intracellular sodium and cellular edema

Cellular edema

Swelling of cells caused by intracellular water accumulation

How does hypoxia raise intracellular Ca²⁺?

Through reducing activity of ATP-dependent calcium pump and releasing Ca²⁺ from damaged intracellular sources

Role of enzyme leakage in diagnosing cell injury

Leaked cell enzymes reflect disease and may help diagnose injury

Effects of high intracellular calcium

1. Activation of inappropriate enzymes

2. Increased mitochondrial permeability

3. Free radical injury

Effect of inappropriate phospholipase and protease activation in cells

Cell membrane damage

Effect of inappropriate endonuclease activation in cells

Nuclear damage

Effect of inappropriate ATPase activation in cells

Decreased atp

How does activation of inappropriate enzymes decrease ATP production?

Through increasing mitochondrial permeability

Free radical

Chemical species with an unpaired outer electron. Highly reactive and attack macromolecules, causing damage

Exogenous sources of free radicals

X-rays or UV light

Endogenous sources of free radicals

Produced by phagocytes and generated during metabolism of many drugs

Reactive oxygen species (ROS)

AKA endogenous free radicals. Drives aging and cancer. E.g. superoxide, hydrogen peroxide, and hydroxy radical

Examples of ROS scavengers

• Enzymes: superoxide dismutase (SOD)

• Antioxidants: vitamins E and C

Apoptosis

Programmed cell death caused by both normal and pathological tissue changes. E.g. endometrial cell breakdown during menstrual cycle

Process of apoptosis

Cell structures shrink → nucleus destroyed by capsaces → releases DNA fragments → membrane blebs/protrudes → apoptopic bodies pinch off → apoptopic bodies engulfed and cleared by phagocytes

Necrosis

Unregulated passive cell death, often causing damage to nearby tissues and elicits inflammatory response

Autolysis

Destruction or digestion of cells and tissues by their own enzymes

5 types of necrosis

Coagulative necrosis, liquefactive necrosis, caseous necrosis, fat necrosis, gangrenous necrosis

Coagulative necrosis

Necrosis caused by hypoxia, from protein denaturation. Causes the tissue to become firm and opaque. Mainly occurs in the kidneys, heart, and adrenal glands

Infarcts

Areas of ischemic necross

Liquefactive necrosis

Necrosis occurring in focal bacterial or fungal infections. Tissues soften and liquefy due to neutrophils releasing hydrolytic enzymes, forming an abscess

Caseous necrosis

Cheese-like necrosis that is a combination of coagulative and liquefactive necrosis. Often seen in lungs due to tuberculosis infections, and is often enclosed with a granuloma

Granuloma

Small cluster of immune cells that form around an infection or foreign object in the body

Fat necrosis

Areas of fat destruction, typically caused by leakage of pancreatic lipases into peritoneal cavity. Appears opaque and white, and makes “soap” (saponification)

Saponification

Combining of fatty acids with ions to make soap

Gangrenous necrosis (gangrene)

Necrosis from severe hypoxic injury, referring to large tissue areas where cells have undergone necrosis

Dry gangrene

By coagulative necrosis → skin becomes wrinkled, dry, and dark. Usually occurs in extremities due to arterial blood supply interference

Wet gangrene

By liquefactive necrosis → tissue (usually internal organs) becomes swollen, cold, and black with a foul odor (bacterial). Easily spreads to other tissues

Gas gangrene

Gangrene caused by infection of Clostridium bacteria which produces enzymes that destroy connective tissue, causing gas bubbles to form

Programmed (molecular) theory of aging

Proposes that changes occurring with aging are programmed genetically

Damaged (senescence) theory of aging

Proposes that changes result from accumulative DNA damage (e.g. free radical damage)

Purposes of inflammation

To destroy infection, limit spread and damage, initiate and promote healingF

Function of activated endothelial cells in inflammation

Loss of vascular integrity, allows leukocytes to move to sites of damage or infection, reduces antithrombotic agents, produces cytokines for further inflammatory signaling

What activates endothelial cells?

Many agents such as bacteria, cytokines, oxidative stress

Function of activated platelets in inflammation

Produces inflammatory mediators such as chemokines, cytokines, vasoactive substances (histamine)

What activates platelets?

Exposed collagen, clotting factors (tissue factor), platelet activating factor (PAF) from neutrophils and macrophages

Function of neutrophils in inflammation

Phagocytosis and activation of bactericidal mechanisms. Also produces vasoactive mediators, cytokines, and chemokines. “First on scene”

Pattern recognition receptors (PRR)

Immune receptors on neutrophils and macrophages that bind to PAMPs on microbes for phagocytosis

Pathogen Associated Molecular Patterns (PAMPs)

Molecular signatures on pathogens that PRRs detect

How do neutrophils kill bacteria?

Through producing ROS’ and proteases

Function of macrophages in inflammation

Phagocytosis, bactericidal mechanisms, AND antigen presentation. Ingests pathogens and is the dominant phagocyte later in inflammation (~48 hours). “Second on scene”

7 cells of acute inflammation

Endothelial cells, platelets, neutrophils, macrophages, mast cells, basophils, eosinophils

Function of mast cells in inflammation

Release of granules containing histamine and active agents (prostaglandins, tumor necrosis factor, platelet activating factor, leukotrienes)

What activates mast cells?

Antigens, PAMPs, physical contact, chemokines, and the complement system activates mast cells

Function of basophils in inflammation

Blood-borne functional equivalent of mast cells, releasing the same mediators. Releases histamine and other vasoactive cytokines

Function of eosinophils in inflammation

Killing of antibody-coated parasites. Important in hypersensitivity responses, by release of leukotrienes and other inflammatory mediators

Two groupings of chemicals controlling inflammation

1. Chemicals produced by the liver and always present in the plasma (in an inactive form)

2. Chemicals produced by cells (tissue/blood cells)

3 key protein systems produced by the liver

Clotting proteins/kinin systems, complement system, acute phase proteins

Clotting proteins/kinin system

Enzymatic cascade of blood proteins assisting with inflammatory response

Bradykinin

Major kinin that increases permeability and acts with other compounds to produce pain

Complement system

Cascade of reactions that activate proteins that either kill pathogens or intensify reactions of other inflammatory response components. Very potent against bacterial infection

Acute phase proteins

Blood proteins whose plasma concentrations change in response to inflammation. Promotes inflammatory response