1. Cell Injury and Host Defenses

Etiology

bottom line cause that starts the disease process

Pathogenesis

stepwise changes that occur in disease development

Manifestations

Morphologic manifestations (changes seen in tissue due to disease), clinical manifestations (changes seen in pt due to disease): signs and symptoms

Three patterns of response to stress an noxious stimuli:

Adaptaiton

• occurs in the setting of low level but persistent stress or pathologic stimulus

• the cell has time and opportunity to change its functions in order to meet the demands of the new situation

• allows function to continue; this is a change and live strategy

• potentially reversible

Three patterns of response to stress an noxious stimuli:

Reversible injury

• occurs in several circumstances

  • when the adverse stimulus is of sudden onset and increases sharply, hence there is no time to utilize adaptive strategies

  • when no adaptive response is possible due to severity or nature of the stress

  • when the adaptive capability of the cell is exceeded

• Cell injury will compromise cell integrity and/or function

• cell injury may be reversible, leading to recovery of function, or the cell may die

Three patterns of response to stress an noxious stimuli:

Cell Death = Irreversible Injury

• Occurs when the cell cannot cope with severe acute stress that is rapid in onset and/or persistent stress

• The injury passes the point of no return

• In cell death, the injury is irreversible and there is TOTAL loss of cell function

Causes of cell injury:

Oxygen deprivation = Hypoxia

• Oxygen deficiency such that there is compromised aerobic oxidative respiration

• ischemia: hypoxia due to local loss of blood supply

• loss of oxygen supply

• lung and/or airway disease causing inadequate oxygenation of blood

• anemia: decreased oxygen- carrying capacity of the blood

Causes of cell injury:

Work overload

• metabolic demands may outstrip blood supply

• metabolic activity may create harmful intracellular contitions

Causes of cell injury:

Physical agents

• trauma

• extremes of temp

• radiation

• electrical shock

• sudden changes in atmospheric pressure

Causes of cell injury:

chemicals

• including poisons, toxins and medications

• affect vital functions of the cell in various ways such as altering cell membrane permeability or compromising enzymes

Causes of cell injury:

Infectious agents

• bacteria, viruses, fungi and parasites may all cause injury

• mechanisms of injury by biologic agents are diverse

Causes of cell injury:

Immunologic reactions

• Immune reactions to exogenous antigens, such as anaphylaxis

  • loss of self-tolerance resulting in autoimmune diseases

Causes of cell injury:

Genetic defects

• may be inherited or acquired

• may result in gross physical defects of subtle intracellular alterations

• may involve a gross defect in chromosomal material or only a point mutation at a molecular level

• tumors, both benign and malignant, arise due to genetic defects in cellular growth and differeations

Causes of cell injury:

Nutritional imbalances

• protein- calorie deficiency

• vitamin and mineral deficiencies

• nutritional excesses

Cellular adaptations to stress:

Hypertrophy

• increase in the size of cells

• increases cell size is due to larger numbers of organelles and other cellular components

• allows cell to reach new equilibrium with metabolic demands

• caused by:

  • increased functional demand (increased workload)

  • hormonal stimulation

  • growth factor stimulation

• example: cardiac hypertrophy secondary to hypertension or valve dysfunction

Cellular adaptations to stress:

Atrophy

• shrinkage in the size of a cell due to loss of cell substance

• caused by:

  • decreased workload - immobilization

  • loss of innervation

  • diminished blood supply

  • inadequate nutrition

  • loss of endocrine stimulation

• allows cell to survive in adversity by operating at a lower level of function

Cellular adaptations to stress:

Hyperplasia

• increase in the number of cells in an organ or tissue

• proliferation change

• often in response to the same physiological stresses or pathological stimuli as hypertrophy and may even occur concurrently in tissue capable of cell division

Cellular adaptations to stress:

Metaplasia

• change in cell differentiation form one adult cell type to another adult cell type

• confers better protection in the setting of a noxious environment

• most commonly involves epithelium

• ex: squamous metaplasia

  • respiratory epithelium transforms into stratified squamous epithelium in response to long term assault by cigarette smoke

  • further assault by carcinogens in smoke may transform these squamous epithelial cells into cancer cells

Cellular adaptations to stress:

Hyperkeratosis

• production of excess keratin on epithelial surfaces

• bolsters the surface barrier and protects the tissues beneath

• may also be caused by genetic damage affecting epithelial cell growth and differentiation

Reversible cell injury:

Cellular swelling

• most common morphological pattern

• injury affects plasma membrane integrity and/ or sodium pump function of the cell membrane

• Sodium flows into cell, water follows, cytoplasm fills up with water

• whole cell swells

• many organelles within the cell may also take on excess water and swell

Reversible cell injury:

Fatty change

• much less common than cellular swelling

• occurs in cells involved in fat metabolism: liver, heart, and kidneys

• injury causes accumulation of simple lipid within cells

• may appear as small or large fat vacuoles of triglycerides

Necrosis

• cell death as the consequence of cellular injury that has become irreversible

• cell injury passes the “point of no return”

• the usual and customary mode of cell death

Necrosis = Irreversible cell injury

• a sequence of morphologic changes that accompany cell death in cells that have sustained a lethal injury

  • enzymatic digestion of the cell

  • denaturation of proteins

  • nuclear hallmarks

    • karyolysis: fading of the nucleus

    • pyknosis: shrinkage and darkening of the nucleus

    • karyorrhexis: fragmentation of a pyknotic nucleus

Coagulative Necrosis

• denaturation of proteins dominates

• basic outline of cell is preserved

• characteristic in hypoxic cell death of all tissues, except CNS

• ex: myocardial infarction: necrosis of cardiac muscle cells due to irreversible ischemic injury

Liquefactive Necrosis

• catalytic degradation of cell dominates

• characteristic of cell death due to bacterial infections

• characteristic of hypoxic death in the CNS

Apoptosis

distinctive and intentional mode of programmed cell death that is sometimes referred to as cell suicide

morphologic phases of apoptosis

• nuclear chromatin in target cells condenses and the cytoplasm turn intensely red

• the cell then dismantles into apoptotic bodies, each surrounded by intact cell membrane

• apoptotic bodies are eliminated by WBC’s via process of phagocytosis

examples of apoptosis

• programmed cell death during embryogenesis

• hormone-dependent involution of endometrial and breast tissues

• death of immune cells that are not functioning properly, such as a self-reactive lymphocytes

• programmed death of cells with damaged DNA that cannot be repaired - important in cancer prevention

exogenous pigments

colored substances which originate from outside the body

anthracosis

• carbon dust particles accumulate in macrophages of the lunges

• seen in the lungs of city dwellers, but does not cause problems

• v heavy carbon deposits may greatly reduce respiratory function, such as in “coal worker’s pneumoconiosis” = “coal miner’s lung”

Endogenous pigements

synthesized within the body as part of the normal physiologic process

• ex: hemosiderin, bilirubin (jaundice), melanin

hemosiderin

• golden yellow to brown pigment derived from hemoglobin breakdown

• form of stored iron, usually within macrophages

• ex: heart failure cells

bilirubin

• green pigment derived from hemoglobin breakdwon

• lipid soluble and carried through the bloodstream to the liver

• liver process and excretes it in bile

• jaundice is the clinical result of excess and is seen as yellow discoloration of the skin and sclerae

Innate Immunity

• systems that neutralize an offending agent without requiring prior exposure to be effective

• first line defense

  • physical barriers

  • chemical barriers or responses: mucus layer, complement

  • cellular responses: non- specific phagocytes, natural killer cells

adaptive immunity

• acquired immunity responses to a previously encountered antigen

• provided by lymphocytes

  • B cells confer humoral immunity

  • T cells confer cell-mediated immunity

• second line of defense that works in conjunction with inflammation and repair mechanisms

Humoral Immune System

• Antibody-mediated part of the immune system

• antibodies are synthesized by plasma cells

• antibodies aka immunoglobulins

  • Activation of complement (IgG and IgM)

  • Opsonization to enhance phagocytosis (IgG)

  • Mucosal immunity (IgA)

  • Neonatal immunity (maternal IgG)

  • Destruction of parasites (IgE)

• Antigen-antibody complex: when an antibody binds with its matching antigen

  • triggers complement activation via the classic pathway

Complement system

• part of innate immunity

• precursor proteins circulate in the plasma and require chemical conversion to become active

• complement is activated by the classic pathway in the presence of Ag-Ab complexes and by the the alternate pathway in the presence of microbial surfaces and polysaccharides

• end product: membrane attack complex (C5-9)

• complement cascade: kill bacteria