FLS Final

Etiology

Cause of the disease, most common afflictions are multifactorial arising from effects of external trigger in genetically susceptible groups.
(1) genetic inherited mutations, disease associated genetic variants
(2) Acquired: infectious, nutritional, chemical, physical

Pathogenesis

Sequence of cellular, biochemical, molecular events following exposure to injurious agent, initial disease cause is always several steps removed from disease exposure.

Morphologic Changes

Structural alterations of cells/tissue characteristic of disease or diagnostic of etiologic process --> this is where and why we use biopsies and microscopic evaluation

Clinical Manifestations

The signs (measurable findings) and symptoms (subjective findings), clinical course and outcome of a disease. Virtually all diseases begin with molecular or structural alterations in cells, as cell injury leads to tissue and organ injury.

Cell injury occurs when

Limits of adaptive response are exceeded. Cells exposed to injurious agents/stress, cells deprived of essential nutrients, cells compromised by mutations

Hypertrophy

Increase in cell size, not an increase in cell number. Leads to increase in size of affected organ or tissue. Increase in size a result of increase in cell protein production, can be a result of physiologic change or pathologic change.

Hyperplasia

increase in number of cells in response to a stimulus and ends the stimulus is removed. Can be normal (physiologic Ex. breast enlargement in puberty), or pathologic. Frequent comorbidity with hypertrophy both resulting in increase of organ size.

Atrophy

no growth; reduction in tissue/organ size because decrease in cell size and number. Reduction in cell size can be followed by cell death if there is a prolonged adverse stimulus. Can be physiologic or pathologic.

Authophagy

Process by which cell eats its own components. Recycling of auto-digested contents in states of nutrient deprivation. Physiologic turnover of organelles. Clearance of intracellular aggregates accumulating during aging, stress or various diseases.

Metaplasia

Reversible change in which one differentiated cell type is replaced by another --> replacing cell type better suiting to alterations in local environment.

Causes of Cell injury

Hypoxia, physical agents (like trauma), chemical agents and drugs, infectious agents, immunologic reactions (autoimmunity), genetic derangements, nutritional imbalances

Necrosis

Pattern of cell death in which irreversible injury leads to:
denaturation or intracellular enzymes, loss of membrane integrity causing cell contents to leak out eliciting inflammation in surrounding tissue, necrotic cell digested by lysosomal enzymes within cell and from recruited leukocytes.

Coagulative Necrosis

Architecture of dead tissues & cells preserved for at least a few days. Area is termed an infarct; often associated with ischemia secondary to obstructed vessel

Liquefactive Necrosis

Enzymatic digestion of dead cells results in liquid viscous mass. Often seen following infectious conditions and brain infarcts.

Gangrenous Necrosis

Clinical term denoting necrosis of multiple tissue planes. Superimposed bacterial infection results in more liquefactive necrosis (wet gangrene)

Caseous Necrosis

"Cheese Like" often seen in context of tuberculosis. Associated with distinctive inflammation of granuloma.

Fibrinoid Necrosis

Usually seen in immune reaction involving blood vessels (vasculitis). Ag/Ab complexes deposit in walls of arteries together with extravasated fibrin.

Ischemia

Inadequate blood supply to organ or body part. Most common cause of cell injury in clinical medicine. Cane be caused my mechanical arterial obstruction or reduced venous drainage. Reduced flow leads to hypoxia and depletion of substrates for anaerobic glycolysis.

Ischemia repercussion Injury

Reperfusion of ischemic tissue can paradoxicaly exacerbate cell injury causing death. Increased production of ROS and NOS, intracellular calcium overload, inflammation of complement system. A sort of system overload.

Hypoxia

Deficiency in amount of O2 reaching tissues, anaerobic energy production by glycolysis can still continue.

Chemical (toxic) injury

Frequent problem in clinical medicine. Major limitation in drug therapy especially for the liver since it is the frequent target of drug toxicity due to the many drugs it metabolizes.

Apoptosis

Programmed cell death for cells destined to die. Tightly regulated suicide program - activation of intrinsic enzymes to degrade DNA and proteins. Cell breaks into app bodies that are phagocytksed without inflammation. CELL MEM STAYS INTACT

Mitochondrial Apoptosis Pathway

Major mechanism of app in mammalian cells. relative balance of pro-apop and anti app proteins of BCL-2 family influence OMM permeability.

Death Receptor Pathway

Extrinsic apoptotic pathway, activation of PM by death R such as TNFR, Fas receptor by cells such as T cells

Basal lamina

Anchors epithelium to underlying connective tissue. Composed of (1) lamina densa and (2) lamina propria. It is part of the basement membrane. Type IV collagen sandwiched between layers of perlecan, a proteoglycan. Made by epithelial cells.

TP53 gene

"tumor suppressor gene" encodes -53 which accumulates in cell when DNA damaged. Arrests cell cycle at G1 to allow time for DNA repair. Triggers app if damage too great.

Necroptosis

Form of cell death resembling apoptosis mechanistically, but necrosis morphologically (loss of PM integrity). Triggered by PM rupture, cell/organell sweeping and ROS generation. Does not result in caspase activation, occurs in steatohepatitis, acute pancreatitis, reperfusion injury and in some viral infections.

Steatosis (fatty change)

Abnormal intracellular accumulation of triglycerides often seen in liver (major organ for fat metabolism). In developed nations alcohol abuse, NAFLD and in context of diabetes is seen.

Xanthomas

Intracellular cholesterol accumulations within skin and tendons associated with hypercholesterolemia.

Pathologic Calcification: Dystrophic Calcification

Ca deposition in dying tissues (think atherosclerotic plaques/aging or damaged heart valves, not associated with hypercalcemia or any calcium metabolism disturbance.

Pathologic Calcification: Metastatic Calcification

Calcium deposition in normal tissues. Associated with hypercalcemia in context of metabolism disturbance (hyperparathyroidism, skeletal resorption, vitamin D related disorders, renal failure).

Functions of Basal Lamina

structure: attaches epithelium to CT
Organization: arranges PM proteins in basal membrane
Filtration: regulates movement of material between epithelium and CT
Regulation: binds growth factors that regulate cell proliferation, differentiation, and metabolism
Migration: orients movement of epithelial cells

Basement Membrane

Composed of basal lamina plus reticular lamina.

reticular lamina

different types of collagen made by connective tissue cells

Tight junctions

impermeable junction that encircles the cell. Ex: Mona occludens

Desmosomes

Anchoring junction scattered along the sides of cells. Ex. Macula adherens

Gap Junction

a junction that allows chemical substances to pass between. Contains connexons - protein channels with central pores connecting PMs

Pemphigus Vulgaris

Blistering disease in which patients make auto Ab to desmoglein proteins. Epithelial cell connections (spot desmosomes) loosen, causing fluid accumulation and superficial blisters

Bullous Pemphigoid

Blistering disease in which patients make autoantibodies to "bullies pemphigoid antigen" in hemidesmosome attachment plaques. Epithelial cells detach from basal lamina, causing fluid accumulation and blister formation.

Hemidesmosomes

Attach epithelial cells to basal lamina. Integrins attach basal portion of cell to basal lamina.

Microvilli

Projections that increase surface area for absorption or secretion. Made of actin filaments

Stereocilia

long microvilli found in parts of male reproductive system

Endothelium

considered simple squamous epithelium, but technically not epithelium, it is mesoderm derived. Lines blood and lymphatic vessels.

Mesothelium

simple squamous epithelium, it lines serous cavities (pleura, pericardium, peritoneum)

Minor Aphthous Ulceration

Most common, lease severe form of disease, younger. Occur on non-keratinized moveable mucosa such as B and L mucosa, floor of mouth, soft palate. Yellow gray ulcer surrounded by a red halo less than 10 mm in diameter, heal w/out scarring 7-10 days

Major Aphthous ulcerations

has same appearance as minor but greater than 10 mm and extremely painful, may scar and extend to keratinized areas, puberty

Herpetiform Aphthous ulcerations

most severe form, small, numerous, 1-3 mm lesions that form clusters, adults

Pseudostratified epithelium

appears stratified all cells touch BM, respiratory tract, olfactory, epididymis, vas defererns, secretion or absorption

Urothelium (previously called transitional)

stratified epithelium that distends, lower urinary tract (minor calyces of kidneys to ureter) and bladder

Merocrine

Type of exocrine gland. No loss of cytoplasm, secretion leaves by exocytosis. Sweat glands, pancreas and salivary glands most common.

Apocrine

Type of exocrine gland where fragments of the gland go into secretion. Apex of cell pinches off. Mammary glands

Holocrine

Type of exocrine gland where whole cell becomes part of secretion which accumulates in cell, cell ruptures and dies. Sebaceous glands.

Ion Transporting Cells

deep invaginations of basal cell membranes. Zona occludens. Mitochondria in basal cytoplasm provide energy for ion transport. proximal tubules in kidney.

Serous Secretory Cells

Large rounded nucleus and abundant rough ER, Golgi, and secretory granules. Ex. pancreatic acinar cells, serous cells in salivary glands

Mucous Secretory Cells

abundant rough rough ER, Golgi, and secretory granules. Produce mucins (protective, lubricant glycoproteins). Ex. mucous cells in stomach, goblet cells in intestines, and mucous cells in salivary glands.

Neuroendocrine cells

Dense secretory granules in cytoplasm, contain polypeptides and/or amines (like epi and norepi). Scattered throughout body.

Myoepithelial Cells

Spindle shaped cells found in glandular epithelium between basal laminal and basal cytoplasm. Embrace gland acini like an octopus on a rock. Contain actin: contract and squeeze out secretory product, found mainly in breast and prostrate.

4 basic tissue types

epithelium, connective tissue, muscle, nerve

ECM and its function

A complex of macromolecules that underlies and surrounds cells and is produced by cells. Functions include structural support, embryonic development/differentiation, cell attachment, migration, proliferation, wound healing, and soft tissue repair.

Connective Tissue

cells arise from mesenchymal cells

Collagen 1

bundles of banded fibers with high tensile strength. 80% skin, 90% bone, tendons, most other organs. Most abundant form of Col and made of tropocollagen fibers that are assembled into bundles

Collagen II

thin fibrils; structural protein. Cartilage 50%, vitreous humor

Collagen III

thin fibrils; pliable. blood vessels, uterus, skin (10%)

Collagen IV

Amorphous, all basement membranes

Osteogenesis Imperfecta

Defect in formation of type I col that forms bone matrix. Mutations in col genes result in insufficient col synthesis or abnormal collagen that is unstable or unable to form helices

Scurvy

Old disease of sailors. Liver spots on skin, spongy gums, bleeding from mucous membranes, depression, immobility. Due to vitamin C deficiency which is essential for col assembly. Ascorbate needed for propel hydroxylase and Lysol hydroxyls activities

Elastin

an insoluble protein in the body. Has glycoproteins called Fibrillins, gly & pro rich but no hydroxyproline. Thinner than col with more stretch.

Fibrillin (3 forms)

large glycoproteins (~350 kDa) whose primary structures are dominated by EGF domains that in the presence of Ca adopt a rod-like structure

Elastic fibers

form a cross0linked network of random coils that can bend and contract, especially for organs that can bend and stretch

Marfan Disease and Aortic dissection

Relatively rare fibrillin defect, caused by mutation in fibrillin gene and hypertension. most common in 40-60 hypertensive males and less common in pregnancy, trauma and connective tissue disorders.

Ground Substance

a viscous gel that fills spaces between cells and fibers in CT. Functions to bind water, fills space, acts as a barrier to infection, binds fibers and anchors cells to ECM. Seen in histologic sections as clear or white space - water removed during histology preparation of tissue. Main constituents: glycosaminoglycans, proteoglycans, glycoproteins.

Glycoproteins

globular proteins with bound carbohydrates. They contain more protein than carbohydrate

Proteoglycans

consist of a protein core with bound glycosaminoglycans (polysaccharides). They contain more carbohydrate than protein.

The glycoprotein fibronectin

present throughout CT, mediates normal cell adhesion through RGD sequence (AA motif) and migration.

The glycoprotein Laminin

Present in basal lamina, helps epithelial cells stick to basal lamina and important in cell differentiation and migration.

Dense CT

fewer cells, thicker bundles of collagen, and les aground substance

Specialized Connective Tissues

Adipose tissue, bone and cartilage, Hematopoietic tissue

Adipose Tissue

MSCs differentiate into preadipocytes which then differentiate to produce White adipocytes, beige adipocytes, and brown adipocytes.

White adipocytes

large number form white adipose and a smaller form so-called beige adipocytes with cytological features and gene expressions patterns of both white and brown adipocytes. White adipocytes are unilocular with one large lipid droplet occupying most of the cytoplasm.

Brown adipocytes

Differentiate from another population of preadipocytes and remain multilocular (having many small lipid droplets) with numerous mitochondria. Mitochondrial metabolism of brown adipocytes releases heat rather than ATP.

Yellow adipose tissue

most abundant, has a wide distribution. White at birth and yellows with age. Cells have scant rings of cytoplasm surrounding single large lipid droplet; flattened nuclei. Under skin and around kidneys and eyeballs, within abdomen in breasts.

Brown adipose tissue

Found only in specific areas of body: axillae, neck and near kidneys
Cells are polygonal in shape, have a considerable volume of cytoplasm and contain multiple lipid droplets of varying size. Nuclei are round and almost centrally located. Slightly smaller and characteristically contain many small lipid droplets and central spherical nucleus. Main function is to produce heat by non-shivering thermogenesis.

Inflammation

response of vascularized tissues to infection and damage. Brings cells and molecules critical for host defense from circulation to sites where they are needed. A protective response essential for survival. Rids the host of causes of cell injury, rids host of consequences of such injury.

Cardinal Signs of Inflammation

Redness (rubor), swelling (tumor), heat (calor), pain (dolor), loss of function (functio laesa)

Causes of inflammation

Infections, tissue necrosis (death), foreign bodies (splinters, dirt, sutures), immune reactions (autoimmune, allergy)

acute inflammation

initial, rapid response to infection or tissue damage. Developes within minutes/hours, lasts for a few hours or a few days. Characterized by exudation of fluid/plasma proteins and emigration of leukocytes particularly neutrophils. Reaction subside when offending agent cleared.

Chronic Inflammation

protracted inflammation if acute inflammation cannot clear offending agent. Lymphocytes and macrophage are major cell types involved; associated with more tissue destruction and healing by deposition of connective tissue often while inflammation still occurring. Can result in fibrosis, angiogenesis, and vascular endothelial growth factor (VEGF) initiates capillary sprouting.

Exudation

The escape of fluid, proteins, and blood cells from the vascular system into the interstitial tissue or body cavities. Transudate is extravascular fluid with high protein and cell debris. Exudate is fluid with high protein content and cellular debris. Pus is exudate rich in neutrophils.

Chemokine

a cytokine with function of leukocyte recruitment

Cytokine

messenger molecules of immune system. Contribute to various local and systemic reactions of inflammation; includes TNF and interleukins.

Rolling

Period of transient attachment/detachment of leukocytes to activated endothelium. Mediated by selecting, slows leukocytes enough to give opportunity for firm adhesion.

Adhestion

Point in leukocyte recruitment where cells become firmly attached to vessel wall. Mediated by interns Cytoskeleton reorganizes and cells spread out on endothelial surfaces.

Transmigration

leukocyte movement through endothelium (diapedesis), occurs mostly in post-capillary venues. Leukocytes migrate between endothelial cells and pierce through underlying basement membrane.

Chemotaxis

process by which leukocytes move towards site of injury. Locomotion along chemical gradient, exogenous and endogenous agents act as chemoattractants.

Neutrophil extracellular traps

produced and released by neutrophils at the cost of cell survival. consist of nuclear chromatin and antimicrobial peptides. Cells go to site, release contents and die. Neutrophils die via apoptosis within a few hours of circulation.

Mediators of inflammation

Major cells that produce them are macrophages, dendritic cells, mass cells. substances that initiate and regulate inflammatory reactions. Cell derived mediators sequestered in intracellular granules for rapid secretio, synthesis de novo. Plasam derived mediators produced in liver and circulate as inactive precursors.

Arachidonic Acid

Normally present in phospholipids of cell membrane and released during inflammation. Steroids inhibit phospholipase mediated release of AA from cell membrane - the basis for steroid use in inflammatory conditions

Prostaglandins

generated by cycooxygenase (COX-1 COX-2) mediated catabolism of arachidonic acid. Important for vasodilation, pain, fever. Basis for use of COX inhibitors like NSAIDs. They are also important for platelet function in hemostasis. COX-2 expression more specifically localized to sites of inflammation than COX-1/.

Leukotrienes

generated by lipooxygenase mediated catabolism of AA. Important for chemotaxis, vascular permeability, bronchospasm. Basis of use of leukotriene receptor antagonists for asthma to limit bronchospasm.

Lipoxins

Also generated by lipooxygenase mediated catabolism of AA; suppress inflammation by inhibiting leukocyte chemotaxis.