9/13 Flashcards
Different types of cell cycle cells
- Labile Cells: skin, lung, GIT, GUT
Spend little time in Go cycle
Skin has stem cells at basal layer, lung stem cells are Type II pneumocytes
Cancer is common like skin, lung, prostate, leukemia, and colon
- Stable Cells: liver, renal tubules, mesenchymal tissue (except heart and skeletal muscle)
Stop dividing to sit in Go cycle, can re-enter cell cycle and proliferate to replenish damaged tissue
Cancers caused by external factors like hepatitis, know that renal tube injury can regenerate but would need dialysis in mean time
- Permanent cells: neurons, cardiac/skeletal muscle
Cancer is much less common
Granulation tissue
Part of proliferative phase of wound healing
Consists of tissue edema, inflammation, angiogenesis, and type III collagen
Tissue is weak and friable
Deposited by fibroblasts
Growth Factor
Naturally produced substance capable of stimulating cellular growth via migration, proliferation, healing, maturation, and differentiation
Act on GF receptors to initiate STP to alter gene expression, mutations in receptors are almost always oncogenic
Platelet Derived Growth Factor (PDGF)
Secreted by platelets and macrophages
Act on tyrosine kinase receptors
Activate fibroblasts to synthesize collagen, stimulate smooth muscle migration to allow angiogenic remodeling
Over stimulation involved in hypertophic scars and keloids
Atherosclerosis: macrophages activated by LDL release PDGF,stimulates smooth muscle migration and collagen deposition, smooth muscle cells go from media into intima, creates fibrous cholesterol plaque that is prone to problems
Transforming Growth Factor Beta
GF version
Stimulates angiogenesis and fibrosis
Cell cycle inhibitor (cancer therapeutic use) and inhibits inflammatory response
Acts on TGF-beta receptors with Smads that alter gene expression, use Ser/Thr kinase receptor
Released by playlets first then leukocyte, macrophages, fibroblasts, and keratinocytes
Fibroblast Growth Factor
Produced by macrophages, endothelial cells, fibroblasts, and others
Receptors have tyrosine kinase activity
Regulates embryonic development, tissue differentiation, chemotaxis, angiogenesis, cell proliferation, and tissue repair
FGF 1 and 2: stimulate angiogenesis and fibroblast activity
FGF 7: stimulates cell proliferation, for skin wounds and regeneration of hepatic stem cells
FGFR 3: achondroplasia, receptor is constitutively active, has negative regulatory effect on bone growth
Vascular Endothelial Growth Factor
Stimulates wound healing, angiogenic source for developing embryo
Forms collateral circulation, densely packed vessels that make up for chronically slowed blood flow to an area
Pathology: wet age-related macular degeneration, cancer
Bevacizumab: monoclonal antibody that inhibits VEGF, for cancers and age related macular degeneration
Epidermal Growth Factor
Stimulates cell proliferation
Erb-B1 receptor with tyrosine kinase activity, ErB receptors are proto-oncogenes
Common in lung cancer, adenocarcinoma
Erlotinib inhibits, cetuximab inhibits EGFR in cancers if no mutation in KRAS
HER2/c-neu mutation in Erb-B2 causes breast cancer
How wounds heal
Primary intention: sutured wounds, fibrin seals in 24-48 hours, short inflammatory phase, proliferative phase results in red raised scar
Secondary Intention: no effort made to approx. epithelium, prolonged inflammatory phase
Wounds close by contracture (caused by myofibroblasts), deposition of granulation tissue, progressive epithelialization from intact skin around the periphery of the wound
Tertiary Intention: infected wounds where bacterial count contradicts primary closure, wound edges approximated within 3-4 days and tensile strength develops as with primary closure
Signs of infection
Increased or new pain around wound
Discharge from wound
Unusual color of granulation tissue, unusual staining on wound dressing
Odor
General malaise
Inflammation
Not healing at expected rate
Cellulitis
Wound breakdown
Chronic wound infections
Rule out infections for wounds that are stalled for 2 weeks
50/50 shot of diagnosing wound infection based on observation
Biosy/swap: wound infection defined as x>10^5 CFU/gm tissue after debridemenet
Types of Chronic Wounds
- Venous Ulcers: stasis or varicose ulcers, improper functioning of venous valves like in the legs and esp. medial malleolus, full-thickness defect of skin
- Arterial Ulcers: occur on lower leg so similar to venous ulcers, caused by atherosclerosis, can be caused by both acute/chronic arterial insufficiency
Determining the ankle-brachial index will give an indication of patient’s ability to heal, divide the systolic BP at ankle by the systolic BP at arm
- Diabetic Ulcers: most common foot injuries leading to lower extremity amputation
Peripheral neuropathy, peripheral vascular disease, and infection combine and can lead to gangrene/amputation
Stage B is infected, Stage C is ischemic
- Pressure Ulcers: usually over a bony prominence due to unrelieved pressure, problem for physically limited or bedridden elderly
Wound assessment and primary care
- Patient history and physical exam: time and mechanism of injury, neurological and vascular examination distal to injured site, check tetanus status
- Details from history and physical examination-
Thrombo-cytopenia: too few platelets
Thrombocythemia: too many platelets
Certain meds: methotrexate, anti-coagulants, transplant rejection, corticosteroids
Nutrition - Wound exploration and hemostasis: explore wound for foreign bodies and assess tissue injury, tissue lost, and degree of injury to deeper structures
Hemostasis by direct pressure, elevation, electrocautery, or suture ligation
- Debribement: remove all devitalized tissue and excise ragged edges to make a clean bleeding margin of viable tissue
- Wound closure
- Dressing
- Antibiotic Usage: can be used prophylactically, should consider location/age of wound and mechanism of injury/surgical incision to determine microbes likely for infection
3 Cornerstones of Wound Management
- Moist wound healing: dressings to maintain a moist environment, increase epithelialization, promote dermal matrix synthesis, improve patient comfort, provides optimum conditions for newly growing cells, prevents scanning and scarring
- Exudate: manage wound fluid, remove proteolytic environment and remove microorganisms, excessive exudate can inhibit wound healing, has increased levels of MMPs that inhibit wound healing, chronic wound fluid can inhibit the production of key wound healing cells
Compression, negative pressure devices and vacuum-assisted devices help wound healing, drains important in preventing exudate from accumulating in wound site
- Debridement: remove dead/dying tissues and foreign material, exposes healthy tissue and optimizes wound healing
Surgical, mechanical like hydrotherapy, autolytic through topically applied chemicals that stimulate breakdown of necrotic tissue, enzymatic like collagenase, biological like maggot therapy
Connective Tissue
Bone, tendons, ligaments, cartilage, fat, aponeuroses, blood
Architectural framework for organs, role in metabolism, immunity, ion transport, and storage
Important for wound healing, inflammation, and tumorigenesis
Key components-
- Cells
- Ground substance
- Fibers: (not for blood/lymph), collagen and elastic/reticular fibers
Loose Connective Tissue
Areolar CT
Loosely arranged fibers, many cells, and plenty of ground substance
Most abundant CT, holds organs in place, attaches epithelial tissues and glands to other tissues, found beneath epithelial linings
Lamina propria: lines tubes of GUT and GIT
Loose consistency and not very dense, appears light on microscopy
Dense Connective Tissue
- Dense Irregular: irregularly arranged fibers, few cells
Submucosa of GIT, reticular layer of dermis
- Dense Regular: densely packed organized parallel fibers, few cells like fibroblasts to maintain ground substance and make ECM
Tendons, ligaments, aponeuroses
Connective tissue cells
Permanent Cells-
1. Fibroblasts: most numerous CT cells
Secrete ground substance, MMPs, fibers, and GFs
Nuclei are present but smashed by ground substance, hard to make out borders
- Myofibroblasts: express alpha smooth muscle actin and can contract to close a wound, important in secondary intention
Secrete ground substance and MMPs
Large nucleus and nucleoli
- Macrophages (histiocytes): do innate/adaptive immunity, present antigens
Phagocytize foreign material, blood, and dead cells
Release cytokines, GFs, and enzymes that control inflammation and wound healing
- Mast cells: contain inflammatory mediators like histamine and heparin
Synthesize and release GFs, cytokines, and enzymes
Marked by tryptases
Key cell type in Type I hypersensitivity (allergy, asthma)
Infiltrating WBCs- neutrophils, T cells, B cells, eosinophils, and basophils
Ground Substance Materials
Viscous substance that occupies space between cells/fibers in CT
- Proteoglycans
- Glycosaminoglycans
- Adhesive Glycoproteins
Glycosaminoglycans
Unbranched polysaccharides, sulfate groups
Hyaluronic acid: large chain for ECM, shock absorber that regulates movement of molecules in the ECM and acts as a lubricant
Mucopolysacchsridoses- lysosomal storage disorders, heparan/dermatan sulfate buildup
- Hurler Syndrome: autosomal recessive defect in alpha -L-iduronase, developmental delay, gargoylism in hands, corneal clouding, hepatosplenomegaly
- Hunter Syndrome: X-linked recessive defect in iduronate sulfatase, aggressive behavior, normal eyes
Hunters see the X on their target and become aggressive
Proteoglycans
Core proteins attached to many GAGs and hyaluronic acid
Negatively charged (due to GAGs) attracts water into ground substance and makes it viscous, permits nutrient diffusion while acting as a shock absorber
Adhesive Glycoproteins
- Fibronectin: cell adhesion to ECM
Binds to integrins, type IV collagen, heparin, and fibrin - Laminin: attach cells to basement membrane
Binds to integrins, type IV collagen, heparin, and fibrin - Tenascin: modulates cell adhesion in ECM
Binds to fibronectin, CAMs, heparin, and GFs - Osteopontin: binds to osteocytes and integrin receptor on osteoclasts
Binds calcium and hydroxyapatite
3 Types of Fibers
Produced by fibroblasts
- Collagen fibers: type I is most abundant, provides tensile strength,
- Reticular fibers: heavily glycosylated collagen III, abundant in LCT, support system for organs
- Elastic Fibers: elastin and fibrillin
Are purple and wavy, collagen is a lighter pinkish and in between
Main types of Collagen Fibers
I: bone, skin, tendons, late wound healing
II: cartilage
III: blood vessels, early wound healing/granulation tissue, fetus
IV: basement membrane (basal lamina)
After an ouchie you have type three, once it’s done you have type one
One: bone
Two: cartwolage
Three: bleed
Four: floor (basement membrane)
Collagen Synthesis
INTRACELLULAR
Nucleus-
1. Transcription of preprocollagen mRNA
Rough ER-
- Translation of preprocollagen alpha chains
- Hydroxylation of Pro and Lys, Vitamin C
- Glycosylation of hydroxylysine
- Formation of procollagen triple helix of alpha chains
Golgi-
6. Packaging and exocytosis of procollagen into extracellular space
EXTRACELLULAR
- Cleavage of terminal regions to form insoluble tropocollagen
- Covalent lysine-hydroxylysine cross-linking of tropocollagen molecules via lysyl oxidase to form collagen fibrils, requires copper
- Aggregation of collagen fibrils to form a collagen fiber
Collagen Pathology
Menkes Disease- defective ATP7A so less copper absorption and get less collagen cross-linking, slowed bone growth and developmental delay, “kinky hair disease”
Goodpasture’s disease: autoimmune attack on alpha-3 chain of Type IV collagen in basement membrane of lungs and kidneys
Alport Syndrome: mutation of Type IV collagen in basement membrane of inner ear, eyes, and kidneys
Get hearing loss, cataracts, and renal failure
Osteogenesis Imperfecta
Autosomal dominant mutation in collagen I, poor triple helices, inadequate type I collagen from decreased type I collagen production or mutated chains
Brittle bone disease
Multiple fractures and loose joints, hearing loss from malformed ossicles, poor dentition, blue sclera due to underlying blue vessels show through thinner sclera
Ehlers-Danlos Syndrome
Heterogenous family of disorders due to defective collagen synthesis of skin, joints, and blood vessels, mainly autosomal dominant
Classical type: Type V collagen, hyperextensible skin and joint instability
Vascular type: Type III collagen, more severe, easy bleeding and bruising, abnormal wound healing, vessel wall degeneration
Weak connective tissue in organs (from reticular fibers) makes organs fragile and prone to rupture
Prone to lethal vascular problems like valvular prolapse, rupturing aneurysms, dissections
Difference between Marfan: more prone to berry aneurysm in brain vs thoracic aneurysm, no lens subluxation or long limb/fingers, have easy bruising/bleeding and hyperlax skin
Elastic Fibers
Elastin: Insoluble, precursor is tropoelastin
Rich in Pro, Gly, and Lys but hydrophobic, little/no hydroxylated AA residues
Desmosine and isodesmosine randomly cross-link and unlink between elastin molecules outside cell
Fibrillin-1: Scaffolding around which elastin is added to, coded for by FBN1, binds TGF-beta and sequesters it
Broken down by elastase, which can be inhibited by anti-elastase
Emphysema
Loss of elasticity in lung along with destruction of connective tissue
Smoking increases elastase production
Alpha-1 antitrypsin deficiency
Mutated A1AT, an anti-elastase
Can’t stop elastase from degrading lung
Can get emphysema without smoking, get at younger age if smoke
Misfolded A1AT builds up in liver and causes cirrhosis
When have young patient with unexplained cirrhosis and shortness of breath
Marian Syndrome
Mutation in FBN1 gene for fibrillin-1, so less TGF-beta is sequestered and get less tissue elasticity
Dolichostenomelia (wingspan > height), arschnodactyly (long fingers), pectins excavatum (inverted sternum), scoliosis, hyperflexability at joints
Systemic Symptoms-
Eyes: Ectopia Lentis (lens subluxation from loss of elasticity of ciliary muscles)
Lungs: blebs of air can rupture and cause pneumothorax
Cardiovascular: aneurysm commonly in aorta, aortic dissection where vessel wall tears and blood escapes into new space created, floppy mistrial valve prolapse that leads to improper pumping
