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Exam 1 Review (Units 1 & 2)

Cellular Adaptation

• Atrophy: Decrease in cell size.

• Hypertrophy: Increase in cell size.

• Hyperplasia: Increase in normal cell numbers.

• Metaplasia: Replacement of mature cells (adaptive mechanism).

• Dysplasia: Change in shape, size, and organization of mature cells (atypical hyperplasia). Note: Dysplasia is not considered a true adaptive mechanism.

Hypertrophy

• Characterized by an increase in cell size, often resulting from:

  • Hormonal stimulation (example: Uterine growth during pregnancy).

  • Increased functional demand (examples: Exercise, myocardial failure, increased cardiac workload).

• Hypertrophy typically results from increased cellular protein accumulation, not fluid (often seen in heart and kidneys).

• Physiological hypertrophy is reversible.

• May occur alongside hyperplasia.

• Triggers include:

  • Mechanical signals (e.g., stretch).

  • Trophic signals (e.g., growth factors, vasoactive agents).

Pathogenesis - Left Ventricular Hypertrophy

• Cardiac myocytes are terminally differentiated (unable to divide).

• Hypertension (HTN) causes increased systemic vascular resistance (SVR), thus increasing the mechanical workload of the heart muscle.

• Consequences include:

  • Left ventricular hypertrophy & cardiomegaly.

  • Myocardial structural alterations.

  • Abnormal function and increased risk of cell death.

• Question: Which cardiac ventricle undergoes hypertrophy with increased pulmonary vascular resistance (PVR)?

Metaplasia (Replacement)

• Involves reprogramming of stem cells (epithelial) or undifferentiated mesenchymal cells (connective tissue).

• Different maturation pathways are signaled by cytokines and growth factors.

• Condition is reversible unless it progresses to neoplastic changes.

• Examples include:

  • Bladder: Transitional epithelium to squamous due to kidney stones.

  • Bronchial: Ciliated columnar epithelium to stratified squamous due to smoking.

Common Biochemical Derangements of Cell Injury & Death

• Decreased ATP leads to:

  • Cellular swelling.

  • Decreased protein synthesis.

  • Impaired membrane transport.

  • Increased lipogenesis.

• Reactive Oxygen Species (ROS) leads to:

  • Destruction of cell membranes and structural components.

• Increased intracellular Ca²⁺ causes:

  • Enzyme activation resulting in mitochondrial damage (can indicate point of no return, leading to irreversible injury).

• Membrane permeability defects can release lysosomal enzymes leading to cellular digestion.

• Protein misfolding results in DNA damage and apoptosis.

Cellular Injury Mechanisms: ROS

• Free radicals: Electrically unstable molecules with unpaired electrons, disrupt chemical bonds, destroy cell membranes, and structures.

• Reactive Oxygen Species (ROS):

  • Low levels can be beneficial as byproducts of mitochondrial respiration.

  • High levels lead to apoptosis and necrosis due to lipid peroxidation, and alterations of proteins and DNA.

  • Balance between ROS and antioxidants is crucial for preventing oxidative stress.

Ischemia-Reperfusion Injury (IRI)

• Involvement of xanthine oxidase and enzyme conversion upon O₂ exposure.

• Increased ATP consumption during ischemia results in catabolites that elevate ROS during reperfusion.

• Consequences of IRI include:

  • Cellular membrane damage.

  • Loss of ATP.

  • Apoptosis and necrosis.

  • Increased oxidative stress and Ca²⁺ overload in mitochondria.

  • Inflammation with neutrophil adhesion to endothelium accelerating injury.

• Treatment options include antioxidants (to reverse neutrophil adhesion) and anti-inflammatories.

Cellular Injury Mechanisms: Burns

• Major burn injury (greater than 20% Total Body Surface Area - TBSA) causes:

  • Increased capillary permeability leading to edema, hypoalbuminemia, and hypovolemia.

  • Tissue ischemia results in decreased blood pressure (BP), acidosis, multiple organ failure (MOF/MODS), and reduced cardiac output.

  • Hypermetabolic response is characterized by heightened heart rate (HR), hyperventilation, increased body temperature, and increased blood glucose levels until wound closure, which can take approximately 24 hours post-injury to weeks or months.

  • Inflammatory/immunologic response is severe, leading to greater capillary permeability and fluid leakage from wounds.

  • Management includes fluid resuscitation, maintaining adequate electrolytes, nutrition, wound management interventions, excision & grafting, scar reduction, comfort measures, and infection control.

Cellular Death: Apoptosis

• Defined as programmed cell death.

• Characterized by:

  • Cell shrinkage.

  • Fragmented nucleus.

  • Intact plasma membrane exhibiting altered structure.

  • Absence of inflammatory response.

• Can be categorized as physiological (normal parts of growth and development) or pathological (disease conditions).

Cellular Death: Necrosis

• Represents a consequence of unplanned irreversible cell injury or a programmed cell death.

• Characterized by:

  • Accumulation of dead cells and cellular autodigestion (autolysis).

  • Cell swelling and ruptured organelles.

  • Associated inflammatory responses.

• Common causes include prolonged hypoxia, infection, and damage to cell membranes.

• Types of necrosis include:

  • Coagulative Necrosis: Commonly seen with protein denaturation due to hypoxia, affecting organs such as the kidneys, heart, and adrenal glands.

  • Liquefactive Necrosis: Generally occurring in the brain and sigmoid colon, often associated with wet gangrene from hydrolytic enzymes.

  • Caseous Necrosis: A combination of coagulative and liquefactive necrosis (e.g., tuberculosis).

  • Fat Necrosis: Involves lipase action affecting organs such as the breast, pancreas, and abdomen.

  • Gangrenous Necrosis: Results from hypoxia and bacterial invasion, characterized by:

  • Dry gangrene: coagulative necrosis.

  • Wet gangrene: liquefactive necrosis.

  • Gas gangrene: caused by Clostridium bacteria.

Osmotic Equilibrium

• Water migrates from the intracellular fluid (ICF) to the extracellular fluid (ECF) based on osmotic gradients.

• Normal osmotic equilibrium is measured at 280 mOsm/kg.

• Examples of alterations include:

  • Addition of solute to ECF causing osmotic disequilibrium.

  • Reestablishment of osmotic equilibrium after adding free water, which creates further changes in osmolarity across compartments.

Net Filtration

• Forces involved in net filtration at the capillary:

  • Forces Favoring Filtration (at arterial end):

  • Capillary hydrostatic pressure (blood pressure pushing out).

  • Interstitial oncotic pressure (pulling water into the interstitium).

  • Forces Favoring Reabsorption (at venous end):

  • Plasma oncotic pressure (pulling water back into the capillary).

  • Interstitial hydrostatic pressure (pushing water towards the capillary).

• Capillary membrane damage can lead to protein movement into interstitial spaces, contributing to edema.

Plasma & Interstitial Water Movement

• Important pressures include:

  • Capillary hydrostatic pressure (37 mmHg at arterial end, decreases to 25 mmHg at venous end).

  • Interstitial hydrostatic pressure (approximately 2 mmHg).

  • Oncotic pressures vary with plasma oncotic pressure (20 mmHg) and interstitial fluid oncotic pressure (0 mmHg).

• Net filtration pressure can be calculated as:

  • NFP = (Capillary Hydrostatic Pressure) - (Plasma Oncotic Pressure) + (Interstitial Hydrostatic Pressure) - (Interstitial Oncotic Pressure).

Edema

• Causes of edema can result from:

  • Decreased synthesis of plasma proteins (e.g., cirrhosis, malnutrition).

  • Increased loss of plasma proteins (e.g., nephrotic syndrome).

  • Increased plasma Na⁺ and H₂O retention, leading to dilution of plasma proteins.

  • Decreased capillary oncotic pressure and increased capillary permeability (e.g., burns, inflammation).

  • Various mechanisms lead to excess fluid movement into tissues and increase tissue oncotic pressure that can result in lymph obstruction, leading to edema.

Water Balance: ADH

• Antidiuretic hormone (ADH) regulation occurs in response to:

  • Increased plasma osmolality.

  • Decreased plasma volume detected by brain osmoreceptors.

• In response to stimuli:

  • Thirst and increased fluid intake are initiated.

  • Renal retention of water occurs to increase plasma volume as part of the body’s homeostasis efforts.

Fluid Alterations

• Fluid alterations can be categorized into:

  • Hypotonic Alterations, where sodium (Na⁺) concentration decreases relative to water, resulting in cellular swelling.

  • Isotonic Alterations, where Na⁺ and water levels remain balanced.

  • Hypertonic Alterations, where Na⁺ concentration increases relative to water, leading to cellular shrinkage.

Na⁺ Regulation: RAAS

• The Renin-Angiotensin-Aldosterone System (RAAS) responds to:

  • Decreased renal perfusion.

  • Decreased blood pressure and serum sodium.

  • Results in increased urine sodium and increased blood volume through:

  • Renin secretion.

  • Angiotensinogen conversion to Angiotensin I.

  • Conversion of Angiotensin I to Angiotensin II by angiotensin-converting enzyme (ACE) in the lungs.

  • Aldosterone release stimulating the kidneys to retain sodium and water, thus increasing extracellular fluid.

K⁺ & H⁺ Relation

• Changes in blood pH are connected with potassium (K⁺) balance:

  • Accumulation of H⁺ in the intracellular fluid (ICF) occurs during acidosis, causing K⁺ to shift extracellularly to maintain cation balance in the cytoplasm.

Membrane Excitability

• Changes in extracellular K⁺ impact membrane excitability, leading to:

  • Mild hyperkalemia causes hypopolarization of membranes, leading to neurons being more excitable.

  • Severe hyperkalemia results in inability to repolarize, marked by muscle weakness, loss of tone, and flaccid paralysis, among other symptoms.

  • ECG changes associated with hyperkalemia include peaked T waves and the potential for arrhythmias and cardiac arrest.

ECG Changes with K⁺ Levels

• Normal K⁺: Normal PR interval, normal P wave, normal QRS.

• Hypokalemia: Rounded normal T wave, possible U wave.

• Hyperkalemia: Decreased R wave, ST depression, shallow T wave, peaked T wave amplitude, prolonged PR interval, widened QRS, and depressed ST segment.

Hypocalcemia & Hypercalcemia

• Hypocalcemia: Defined as blood calcium (Ca²⁺) levels less than 8.5 mg/dL, causes:

  • Increased neuromuscular excitability (partial depolarization) resulting in muscle cramps and tetany.

  • Signs like Chvostek's and Trousseau's signs can be observed.

  • Treatment includes calcium replacement and management of phosphate levels.

• Hypercalcemia: Defined as blood calcium levels greater than 12 mg/dL, presents with:

  • Decreased neuromuscular excitability, fatigue, muscle weakness, increased propensity for bone fractures, along with kidney stones.

  • Treatment may involve the administration of fluids, or causes re-evaluation for underlying pathologies.

Acid-Base Imbalances

• Normal arterial blood pH ranges from 7.35 to 7.45, assessed through arterial blood gas (ABG) testing.

• Acidosis: Systemic increase in H⁺ ion concentration.

• Alkalosis: Systemic decrease in H⁺ ion concentration.

Acidosis & Alkalosis

• pH affects acid-base status, influenced by:

  • PaCO₂: Respiratory component (volatile).

  • HCO₃ (Bicarbonate): Metabolic component (non-volatile).

• Types of acid-base imbalances include:

  • Respiratory acidosis: Increased PaCO₂ due to ventilatory depression.

  • Respiratory alkalosis: Decreased PaCO₂ due to hyperventilation.

  • Metabolic acidosis: Decreased HCO₃ due to either an increase in acid or decrease in base.

  • Metabolic alkalosis: Increased HCO₃ due to either a decrease in acid or increase in base.

Acid-base Compensation

• pH management mechanisms:

  • Respiratory acidosis: Involves renal bicarbonate retention.

  • Respiratory alkalosis: Involves renal bicarbonate elimination.

  • Metabolic acidosis: Involves respiratory CO₂ retention.

  • Metabolic alkalosis: Involves respiratory CO₂ elimination.

The Immune System

• Innate Immunity: Immediate and non-specific defense mechanisms involving epithelial barriers, phagocytes, and natural killer (NK) cells.

• Adaptive Immunity: Longer-term, antigen-specific defense mechanisms involving B and T lymphocytes, antibodies, and effector T cell response over days to weeks.

Inflammatory Response

• Characterized by:

  • Diverse causes and nonspecific responses not reliant on the stimulus or past exposure.

  • Goals to confine damage, kill microorganisms, and clear debris.

  • Features include vasodilation (redness and heat), increased vascular permeability (leading to edema), and white blood cell (WBC) adherence and migration.

• Cardinal signs of inflammation are:

  • Local: Redness, heat, swelling, and pain.

  • Systemic: Fever, leukocytosis, and plasma protein synthesis.

Systemic Manifestations of Inflammation

• Fever: Induced by exogenous pathogens or endogenous pyrogens.

• Leukocytosis: Increased circulation of leukocytes and the 'left shift' phenomenon in neutrophils.

• Increased plasma protein synthesis resulting in acute-phase reactants such as C-reactive protein (C-RP) and fibrinogen.

Eosinophils

• Involved in allergic responses.

• Primary defense against helminthic (parasitic) infections.

• Limited phagocytic activity.

• Regulate vascular mediators released by mast cells via mechanisms such as Eosinophil Chemotactic Factor of Anaphylaxis (ECF-A).

Phases of Inflammation

• Acute Inflammation:

  • Duration: 8-10 days.

  • Immediate response, vascular site of action, characterized by neutrophils and platelets.

  • Leads to minimal scarring.

• Chronic Inflammation:

  • Duration: Beyond 2 weeks.

  • Prolonged response mostly in connective tissue with lymphocytes and macrophages leading to fibrotic changes and granuloma formation.

Acute Inflammation Process

• Involves activation of various plasma systems, including:

  • Complement system (helping with opsonization and cytotoxicity).

  • Clotting system (to address vascular injury).

  • Kinin system (contributing to vasodilation and increased permeability).

The Membrane Attack Complex (MAC)

• This forms a tubular structure leading to pore formation in target cell membranes that disrupts cellular integrity.

Inflammatory Mediators

• Various cytokines serve roles in regulating the responses:

  • Inflammatory: Prostaglandins, histamines, and NO enhance vasodilation and permeability.

  • Inhibitory: IL-10 and TGF-B work to limit inflammation.

Wound Healing Processes

• Resolution (Regeneration) vs. Repair (Scar Tissue): Involves three main phases:

  • Fill, seal, and shrink.

• Involves:

  • Inflammation.

  • Proliferation.

  • Remodeling processes with fibroblasts, growth factors, and structural proteins playing critical roles.

Functionality and Dysfunctionality in Wound Healing

• Timeline of wound healing effectiveness from initial injury to full repair varies significantly, indicating the complexity of physiological responses across time.

Innate vs. Adaptive Immune Response

• Innate immune responses are rapid, nonspecific, and short-lived, occurring immediately upon infection.

• Adaptive immune responses are slower, antigen-specific, and create a memory for future infections.

Clonal Diversity & Selection

• Involves the production of a wide array of lymphocytes with unique receptors (clonal diversity) and the selection of those that can specifically respond to a given antigen (clonal selection).

• This enables the body to mount effective immune responses by producing both cellular and humoral immunity.

Antigen Processing & Presentation

• Effective immune responses require:

  • Proper processing of antigens by Antigen-Presenting Cells (APCs).

  • Activation of helper T cells which are crucial for the activation and proliferation of B lymphocytes and cytotoxic T cells.

Active vs. Passive Immunity

• Active Immunity:

  • Antibodies or T cells developed post exposure or vaccination; provides long-term immunity.

• Passive Immunity:

  • Transfer of pre-formed antibodies or lymphocytes; provides immediate but transient immunity.

Hypersensitivity Reactions

• Altered immunologic responses to antigens can lead to tissue damage or exaggerated immune responses:

  • Types include immediate (Type I, such as anaphylaxis) and delayed (Type IV, thymocyte-mediated) reactions.

Hypersensitivity – Type I

• Mediated by IgE and involves mast cells responding to allergens leading to rapid and extreme reactions.

• Symptoms: Itching, urticaria, conjunctivitis, gastrointestinal issues, dyspnea, shock.

• Treatment involves epinephrine for severe reactions, antihistamines, or desensitization therapy.

Hypersensitivity – Type II

• Tissue-specific; involves antibody binding to specific tissue antigens leading to complement activation, resulting in cell membrane damage.

• Examples include autoimmune conditions like Graves’ disease.

Hypersensitivity – Type III

• Immune complex-mediated where antigen-antibody complexes form and can deposit in tissues leading to inflammation and possible damage.

• Examples include conditions such as systemic lupus erythematosus (SLE).

Systemic Lupus Erythematosus (SLE)

• Chronic autoimmune disorder characterized by the formation and deposition of immune complexes leading to systemic inflammation affecting various tissues.

• Clinical manifestations include fatigue, joint pain, and renal implications.

Hypersensitivity – Type IV

• Cell-mediated response orchestrated by T lymphocytes, resulting in destruction of target tissues.

• Example conditions: Graft rejection, tuberculin response, and some types of dermatitis.

Conclusion

• The notes provided cover the first two units crucial for understanding cell biology, adaptation, immune responses, and physiological balance.

• Emphasis is placed on detailed mechanisms and clinical implications relevant to human health and disease. Good luck on Exam 1!