Reversible injury ‘Swelling of endoplasmic reticulum and Progressive injury Breakdown of plasma membrane, ‘organelles, and oN ae nucleus; om g. ng ea BS of contents ie: Ze p ye Inflammation © me Ae Fig. 2.3 Reversible cell injury and necrosis. The principal cellular alterations that characterize reversible cell injury and necrosis are illustrated. By conven tion, reversible injury is considered to culminate in necrosis if the injurious stimulus is not removed. Amorphous densities in mitochondriaTable 1.1 Growth Factors Involved in Regeneration and Repair Epidermal growth factor (EGF) Transforming growth factor-c. (TGF-«) Hepatocyte growth factor (HGF) (scatter factor) Vascular endothelial growth factor (VEGF) Platelet-derived growth factor (PDGF) Fibroblast growth factors (FGFs), including acidic (FGF-1) and basi (FGF-2) ‘Transforming growth factor- (TGF- ) Keratinocyte growth factor (KGF) (ie., FGF-7) Activated macrophages, salivary glands, keratinocytes, and many other cells Activated macrophages, keratinocytes, many other cell types Fibroblasts, stromal cells in the liver, endothelial cells Mesenchymal cells Platelets, macrophages, endothelial cells, smooth muscle cells, keratinocytes Macrophages, mast cells, endothelial cells, many other cell types Platelets, T lymphocytes, macrophages, endothelial cells, keratinocytes, smooth muscle cells, fibroblasts Fibroblasts Mitogenic for keratinocytes and fibroblasts; stimulates keratinocyte migration; stimulates formation of granulation tissue Stimulates proliferation of hepatocytes and many other epithelial cells Enhances proliferation of hepatocytes and other epithelial cells; increases cell motility ‘Stimulates proliferation of endothelial cells; increases vascular permeability Chemotactic for neutrophils, macrophages, fibroblasts, and smooth ‘muscle cells; activates and stimulates proliferation of fibroblasts, endothelial, and other cells; stimulates ECM protein synthesis Chemotactic and mitogenic for fibroblasts; stimulates angiogenesis and ECM protein synthesis Chemotactic for leukocytes and fibroblasts; stimulates ECM protein synthesis; suppresses acute inflammation ‘Stimulates keratinocyte migration, proliferation, and differentiation ECM, Extracellular membrane.CHAPTER 2. Cell Injury, Cell Death, and Adaptations Fig. 2.4 Morphologic changes in reversible and irreversible cell injury (necrosis). (A) Normal kidney tubules with viable epithelial cells. (B) Early (reversible) ischemic injury showing surface blebs, increased eosinophilia of cytoplasm, and swelling of occasional cells. (C) Necrotic (irreversible) injury of epithelial cells, with loss of nuclei and fragmentation of cells and leakage of contents. (Courtesy of Drs. Neal Pinckard and M.A.Venkatachalam, University of Texas Health Sciences Center, San Antonio, Texas.)x ne Tr Fig. 2.7 Liquefactive necrosis. An infarct in the brain shows dissolution of the tissue.2.6 Coagulative necrosis. (A) A wedge-shaped kidney infarct (yellow) with preservation of the outlines. (B) Microscopic view of the edge of the infarct, with normal kidney (N) and necrotic cells in the infarct (). The necrotic cells show preserved outlines with loss of nuclei, and an inflammatory infiltrate is present (difficult to discern at this magnification).i 1 Reversible : Irreversible Gai ini Ultrastructural Light cell injury oe changes microscopic changes Cell death Gross morphologic changes EFFECT DURATION OF INJURY ig. 2.5 The relationship among cellular function, cell death, and the mor- hologic changes of cell injury. Note that cells may rapidly become nonfunc- onal after the onset of injury, although they are still viable, with potentially eversible damage; with a longer duration of injury, irreversible injury and ell death may result. Note also that cell death typically precedes ultrastruc- ural, light microscopic, and grossly visible morphologic changes.Fig.2.9 Fat necrosis in acute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soap formation (saponification) at sites of lipid breakdown in the mesentery.Fig. 2.10 Fibrinoid necrosis in an artery in a patient with polyarteritis nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation. Fig. 2.8 Caseous necrosis. Tuberculosis of the lung, with a large area of» Fibrinoid necrosis is a special form of necrosis. It usually Sar Rncteah Oneal cey) e occurs in immune reactions in which complexes of antigens and antibodies are deposited in the walls of blood vessels, but architecture is completely obliterated and cellular outlines it also may occur in severe hypertension. Deposited immuneCHAPTER 2. Cell Injury, Cell Death, and Adaptations Condensation of chromatin py) Cellular fragmentation Phagocytosis of apoptotic cells and fragments Fig. 2.11 Apoptosis. The cellular alterations in apoptosis are illustrated. ‘Contrast these with the changes that characterize necrotic cell death, shown in Fig. 23.Fig. 2.13 Morphologic appearance of apoptotic cells. Apoptotic cells (some indicated by arrows) in colonic epithelium are shown. (Some preparative regimens for colonoscopy may induce apoptosis in epithelial cells, which explains the presence of dead cells in this biopsy.) Note the fragmented nuclei with condensed chromatin and the shrunken cell bodies, some with pieces falling off. (Courtesy of Dr. Sanjay Kakar, Department of Pathology, Univer- sity of California San Francisco, San Francisco, California.)Table 2.2 Physiologic and Pathologic Conditions Associated With Apoptosis Physiologic During embryogenesis Turnover of proliferative tissues (e.g., intestinal epithelium, lymphocytes in bone marrow, and thymus) Involution of hormone- dependent tissues (e.g., endometrium) Decline of leukocyte numbers at the end of immune and inflammatory responses Elimination of potentially harmful self-reactive lymphocytes Loss of growth factor signaling (presumed mechanism) Loss of growth factor signaling (presumed mechanism) Decreased hormone levels lead to reduced survival signals Loss of survival signals as stimulus for leukocyte activation is eliminated Strong recognition of self antigens induces apoptosis by both the mitochondrial and death receptor pathways Pathologic DNA damage Accumulation of misfolded proteins Infections, especially certain viral infections Activation of proapoptotic proteins by BH3-only sensors Activation of proapoptotic proteins by BH3-only sensors, possibly direct activation of caspases Activation of the mitochondrial pathway by viral proteins Killing of infected cells by cytotoxic T lymphocytes, which activate caspasesMechanisms of Cell Injury and Cell Death Nutrient depletion 1 Autophagy OS aay L¢ Cytoplasmic organelles digestion of Fusion of vacuole contents with lysosomes Formation of autophagic vacuole Used as sources of nutrients Fig. 2.14 Autophagy. Cellular stresses, such as nutrient deprivation, activate autophagy genes, which initiate the formation of membrane-bound vesicles in which cellular organelles are sequestered, These vesicles fuse with lysosomes, in which the organelles are digested, and the products are used to provide nutrients for the cell. The same process can trigger apoptosis by mechanisms that are not well defined. MECLIARIICOMC AL CELI INI IDY ARIDCHAPTER 2° Cell Injury, Cell Death, and Adaptations Hypoxia, Multiple Mutations, cell Radiation, Infections, ischemia injurious stimuli stress, infections other insults immunologic disorders + ROS Accumulation of misfolded proteins DNA damage Inflammation + +Energy- Damage to Nucleus dependent lipids, proteins, functions nucleic acids | Toxic Cell injury Apopto: Apoptosis Necrosis or apoptosis Necrosis Fig. 2.15 The principal biochemical mechanisms and sites of damage in cell injury. Note that causes and mechanisms of cell death by necrosis and apoptosis are shown as being independent but there may be overlap; for instance, both may contribute to cell death caused by ischemia, oxidative stress, or radiation. ATP, Adenosine triphosphate; ROS, reactive oxygen species.Squamous metaplasia Basement Normal membrane columnar A epithelium caplasia of normal columnar (left) to squamous epithelium Fig. 2.23 Met nchus, shown schematically (A) and histologically (B). L (right) in a brot3 z 8 3 - & E 3 =kingaom. mT OF BACTERIA tet | Baa | eae Streptococcus sane Stn Nie io cholerae) —_ Strep throat Becta arabwacia? causes Cholera pttes causes Anthrax jicrococcus luteus "Caines arm (Helicobacter pylori) can cause stomach ulcers _ (Clostridium botulinum) (Treponema pallidurn) causes Botulism causes Syphilis Staphylococcus aure: ipgan cause sings Infect ond food poltong