Reaction to Injury: Cell Injury, Renewal & Repair Rob Edwards, M.D., Ph.D. Department of Pathology...
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Transcript of Reaction to Injury: Cell Injury, Renewal & Repair Rob Edwards, M.D., Ph.D. Department of Pathology...
Reaction to Injury:Cell Injury,
Renewal & Repair
Rob Edwards, M.D., Ph.D.Department of Pathology and Laboratory Medicine
August 15, 2011
Outline
• The facts behind Pathology rocking…..
• Cellular responses to stress and injury
• Key vocabulary in cell injury
• Morphology of Cell injury and necrosis
• Reading:
Ground Rules for Lecture:
• 1. It’s in the (e-)book. Robbin’s 8th.http://store.vitalsource.com/show/978-1-4160-3121-5
• 2. If we’re not making sense, STOP us!
• 3. If you have a question, see #2
• 4. Come to lab! -Reinforces lecture (game situations)
Why Pathology is the finest of clinical specialties:
• Endlessly challenging (The ABMS 24)• You know every cool case in the hospital• The doctor’s doctor (Read: Pathology is a
consult service)– The 70/70 rule– People skills/communication is key– We tell surgeons what to do all day long…..
• Civilized day-to-day environment• Relatively hard to outsource
Pathology- Subdivisions
• Anatomic (Surgical) Pathology– Biopsies & Cytology (little bits of patient)– Surgicals (larger bits of patient)– Autopsies (the entire patient)– Frozen sections (intraoperative consultation)
• Clinical Pathology– Clinical Chemistry– Blood Bank/Transfusion Medicine– Microbiology/Molecular Diagnostics– Hematology/Flow Cytometry
Principle:
• Injuries occur at the molecular, cellular, tissue, organ, and organismal level
• Integration of responses to injury occur at the cellular level
• SO- We focus on cellular responses
• *Every organ system has a limited repertoire of responses:– Adaptive (maintain homeostasis)– Reversible Injury– Death
Adaptation vs. Reversible vs. Irreversible Injury:
Cellular adaptation to stress
• Hyperplasia– Increased cell number in response to ↑ demand– Reversible if stimulus is removed– Physiologic hyperplasia
• Hormonal (lactational change of the breast)• Compensatory (liver regeneration, wound repair)
– Pathologic Hyperplasia• Excessive hormone/growth factor stimulation (endometrial
hyperplasia – menorrhagia)• BPH – chronic androgenic stimulation• ‘Fertile soil’ for subsequent neoplastic transformation
Cellular adaptations to stress• Hypertrophy:
– Increased cell (& organ) size
– Physiologic:• EXAMPLE: • Skeletal muscle
of Our Governator
• Post-mitotic, respond by hypertrophy
• Each sarcomere can do more work, avoids cellular injury
Physiologic Hypertrophy
1100g; 70 g
Limits of Physiologic Hypertrophy
• Hypertrophy compensates for increased workload up to a point
• Decompensation = Cardiac failure• In cardiac failure:
– Degenerative myocyte changes/fibrosis/cell death
– Mechanism? • Insufficient vascular supply (Ischemia)• Structural alterations of sarcomeres?
Atrophy
• DEF: Shrinkage of cells due to loss of substance, after full development
• Physiologic– Post-partum uterus
• Pathologic– Decreased workload (disuse)– Loss of innervation (skeletal muscle)– Decreased blood supply– Malnutrition/aging/extrinsic compression
Disuse Atrophy:Pathologist Brain Surgeon Brain
Atrophy, Hypoplasia, Aplasia
• Atrophy: Decrease in size after full development
• Hypoplasia: Failure to develop fully
• Aplasia: Failure of primordium to develop
Metaplasia• DEF: Reversible, adaptive change in cell
type in response to stress
• Example:– Squamous metaplasia in smokers’ respiratory
tract 2o to chronic noxious stimuli– Tougher cells, but mucociliary clearance is lost
Barrett’s Metaplasia → Esophageal Cancer:
Ischemic Injury & Hypoxia
• Hypoxia = Reduced O2 availability• Switch to Glycolysis
• Ischemia = Reduced/Inadequate blood flow– Obstruction (atherosclerosis, embolus)– Hypotension
• Blood loss• Sepsis• Blocks nutrient delivery, no ox phos OR glycolysis
Question
– Which condition damages tissue faster, ischemia or hypoxia?
– Why?
Cell Death: Final Common Pathways
• Two main types:– Necrosis :
• Follows from irreversible injury• Always pathologic
– Apoptosis• Pre-programmed cell death• Normal part of development• Removing ‘bad’ cells (immunity, cancer)
Morphology of Necrosis
• Results from denaturation of cell proteins• Eosinophilia due to loss of chromatin, RNA
– (-) charged PO4’s bind hematoxylin
– Acidosis neutralizes these, so loss of blue staining…
• Nuclear changes:• Karyolysis- loss of chromatin’s basophilia• Pyknosis – shrunken, raisin-like nuclei• Karyorrhexis – nuclear fragmentation
Necrosis- Subtypes• Coagulative necrosis
– Preservation of the outline of cells, (everything denatured, including all the “-ases”)
– Loss of basophilia– Characteristic of hypoxic death (except brain)
Necrosis- Subtypes• Liquefactive Necrosis:
– Complete digestion of dead cells into a gelatinous mass
– Seen in bacterial/fungal infections
– If associated with an acute inflammatory response: pus
Necrosis- Subtypes
• Gangrenous necrosis– Not technically a subtype of necrosis– Used in the context of extremities sans blood
supply– Subdivided into dry and wet gangrene
• Dry: coagulative necrosis• Wet: = Dry + bacterial infection; coag+ liquefactive
Necrosis- Subtypes• Caseous Necrosis
– Typically found in the context of TB, fungal infections
– ‘Caseous’ refers to cheesy gross appearance
– Distinct foci compsed of necrotic core surrounded by granulomatous inflammation (Sept. 16, 1-2PM)
Necrosis- Subtypes• Fat necrosis
– Again, not technically a subtype of necrosis
– Localized fat destruction due to acute pancreatitis:
• Activated enzymes autodigest membranes; fatty acids + Ca2+ = chalky deposits
• Also seen in traumatic injury to breast tissue
Apoptosis• DEF: Intentional,
programmed cell death– Tightly regulated– Cell dies from within,
fragments, membrane stays intact
– No cell guts leak out, no inflammatory response
• Eliminates unwanted/potentially harmful, or irreversibly damaged cells
MS1- Physiology PTSD:
• Baldwin- Circulatory Blood Flow
• Longhurst – Heart Failure, AMI
• Longmuir- Hypoxemias
• Vickery- Clotting Cascade
• Refresher: Robbins 111-129 (Shock to be covered specifically in CF2)
Normal Homeostasis vs. Edema
• Changes in any of these can alter homeostasis:– Vessel wall integrity/endothelial function– Intravascular pressure– Intravascular osmolarity– Balance of pro- and anti- clotting mechanisms
DEF of Edema: Excessive water in the interstitial space– Synonyms: hydrothorax, hydroperitoneum (AKA
ascites), anasarca
Categories of Edema:Inflammatory vs. Non-inflammatory
(Exudative vs Transudative)
Inflammatory: increases vascular permeability (More on that on Wednesday…) -Leads to protein rich fluid; = EXUDATE (specific gravity >1.012)
Non inflammatory: due to imbalances in hydrostatic and oncotic pressures-Leads to watery fluid; = TRANSUDATE (specific gravity < 1.012)( edema [protein]/plasma [protein] <0.5 )( Protein conc <2g/100 cc)
Things that lead to non-inflammatory edema:
• Increased hydrostatic pressure (CHF/DVT)
• Decreased plasma oncotic pressure (nephrotic syndrome, cirrhosis)
• Lymphatic obstruction (s/p mastectomy)• Sodium retention (renal insufficiency)
Figure 4.1
Morphology of Edema
Congestion/Hyperemia
Definition: Overfilling of Small Vascular Spaces in a particular tissue
• Hyperemia- Active process due to arterial dilation, increased inflow– Tissue is ‘red’ (arterial)
• Congestion: Passive: impaired venous outflow– Can be systemic (as in CHF),
or local (venous obstruction)– Tissue is ‘blue’ (venous)
Chronic Passive Congestion in CHF
-In CPG, stasis of deoxygenated blood (congestion) lead to hypoxia and cell death.
-OUTCOME: centrilobular coagulative liver necrosis.
-CLINICOPATHOLOGICAL CORRELATE: The ‘nutmeg’ liver
Hemorrhage• Definition: Extravasation of Blood due to
Rupture of Blood Vessels
• Bleeding within a tissue: Hematoma. Range from bruises to fatal)
• Little ‘uns: Petechiae (1-2 mm) – 2o to low platelet counts or function
• Bigger ‘uns: Purpura (3-10 mm) – 2o to trauma, vasculitis
• Big ‘uns: Ecchymoses (>1-2 cm) – 2o to trauma
– Color changes over time, Hb breakdown: Red- Blue- Green-Brown-Yellow
• In body cavities (hemoperitoneum, hemopericardium, hemothorax, hemarthrosis, etc.)
Consequences of Hemorrhage
• Tissue destruction• Jaundice (2° to hemoglobin breakdown)• Anemia• Shock• Death
Hemostasis & Thrombosis• Normal Hemostasis: Gotta keep your blood liquid and clot-free,
UNTIL you need a rapid hemostatic clot at the site of injury!
Thrombosis- Endothelial Cell Injury
• DEF: Inappropriate, pathologic clotting of blood. Risk factors include:
– Endothelial injury (most important)- converts endothelium to prothrombotic state
– Stasis (or turbulent) blood – Anything that alters hemodynamics stresses can affect endothelial cell function.
– Hypercoagulability - Can still have thrombosis w/o endothelial disruption, ‘injury’ can lead to imbalances in coagulation states
Thrombosis-Altered Blood Flow
• Turbulent (non-laminar) blood flow OR Stasis- injures/activates endothelium
• RESULT:– 1) Allows platelet access to vessel wall
– 2) Prevents dilution of activated clotting factors
– 3) Blocks influx of clotting inhibitors
Turbulent flow contributes to thrombosis in coronary arteries, aneurysms, post AMI endocardium, valve disease
Stasis arises in hyperviscosity syndromes, SS anemia.
Thrombosis- Hypercoagulable States
• Less common but still important!• DEF: Any alteration of the coagulation
pathways that predispose to thrombosis• Primary (Genetic)
– Factor V Leiden Q506R (2-10% Caucasians, but carrier freq = 60% in pts with DVT)
• Resistant to Protein C, leads to unchecked coagulation
– Prothrombin G20210A (1-2%) – 3x risk of DVT– Hyperhomocysteinemia – thrombosis AND
atherosclerosis
Thrombosis- Hypercoagulable States
• Acquired Hypercoagulable states:– Prolonged bedrest
– AMI
– Atrial fibrillation
– Tissue damage (surgery, fracture)
– Cancer
– Heparin-Induced Thrombocytopenia- pts develop Ab’s that activate platelets, thrombosis. Rx: Lovenox
-Antiphospholipid syndrome (1o vs. 2o): Anti-cardiolipin Ab’s cause multiple thrombi, miscarriages, valve vegetations
But wait, there’s more!
• Current approach to workup of the patient with established venous thrombosis:
• http://www.uptodate.com/contents/evaluation-of-the-patient-with-established-venous-thrombosis?source=related_link
Arterial Thrombosis
• Caused by thrombogenic atherosclerotic plaques (coronaries, aorta, etc)– These can also embolize to any organ
• Also occur in akinetic segments of heart post-MI– (mural thrombi)
Venous ThrombosisVast majority occur in superficial (saphenous)/deep veins of
leg• Superficial: Congestion, pain, tenderness, rarely
embolize– Predispose to cellulitis, varicose ulcers
• Deep (femoral/popliteal/iliac) At least half are Asymptomatic– RISK OF EMBOLIZATION!
Fates of Thrombi
• Propagation, with vessel obstruction
• Embolization (dislodge and migrate)
• Dissolution (only for young thrombi)
• Organization/Recanalization
Embolism• DEF: Intravascular solid/liquid/gas that is
carried a distance from its origin. • Most are thromboemboli• Other types:
– Fat or bone marrow (trauma)– Air (diving accidents)– Tumor fragments– Amniotic fluid (s/p 1:50K deliveries – 20-40% mortality)
Targets & Sequelae of Embolization
• Lungs (Pulmonary Embolism)
-60-80% are clinically silent
-200,000 deaths per year in the US
-95% from DVT above the knee
-Often multiple/serial
-Where it embolizes depends on size
-Saddle embolus: acute Right heart failure,
(cor pulmonale), circ collapse)
-If ASD/VSD, ‘paradoxical emboli’
Infarction: The wedge on the edge!
DEF: Area of ischemic necrosis 2° to (mostly arterial) vascular occlusion
• 99% of infarcts are secondary to arterial thrombosis or embolization– Rare causes – vasospasm, extrinsic
compression by tumor, edema, torsion,
• Red (hemorrhagic) infarcts arise where:– Venous occlusion – Loose tissue with space for hemorrhage– Dual blood supplies (lung)
• White (anemic) infarcts:– Solid end-organs
Factors Influencing Infarct Severity• Nature of the blood supply
– Liver and lung = dual blood supply, fewer infarcts
– Kidney and spleen: Notsomuch…..
• Rate of vascular occlusion:– Fast = infarct- no time to
compensate/develop collaterals
• Tissue vulnerability to hypoxia (neurons>myocytes >fibroblasts
• Patient’s O2 saturation
Onward to Lab #1……