Protein Accumulation Study Materials

Chapter 4: Cellular Biology This chapter explores altered cellular and tissue biology, focusing on cellular adaptation, injury, manifestations of cellular injury, cellular death, aging, and the various types of cell death such as necrosis and apoptosis. Cellular adaptation allows cells to respond to physiological and pathological conditions, but severe or prolonged stressors can lead to cellular injury or death. Common sources of cell injury include lack of oxygen, free radicals, infections, inflammation, and metabolic derangements. Cellular aging also contributes to changes in structure and function. Bullet points Protein accumulation ● Intracellular accumulation of excess protein damages cells ● Protein excess accumulates in renal convoluted tubules and antibodyproducing B lymphocytes ● Proteinuria (excessive excretion of protein molecules in urine) indicates cellular injury or altered cellular function ● Excess protein aggregates (Russell bodies) identified in multiple myeloma, a cancer of plasma cells ● Abnormal protein folding due to mutations can lead to disease states Pigments ● Pigment accumulations may be normal or abnormal ● Endogenous pigments, produced within the body, include melanin and blood proteins ● Exogenous pigments, produced outside the body, include carbon black, mineral dusts, and dyes Melanin ● Melanin is a brown-black pigment derived from the amino acid tyrosine ● It is synthesized by melanocytes and accumulates in epithelial cells of the skin and retina ● Melanin protects the tissue from the harmful effects of prolonged exposure to sunlight ● Melanin is essential in the prevention of skin cancer Hemoproteins ● Hemoproteins include hemoglobin and oxidative enzymes ● Abnormalities involving these pigments can result in various disorders ● Excessive intracellular iron storage can lead to accumulations of hemoproteins Iron metabolism ● Iron enters the blood from tissue stores, the intestinal mucosa, and macrophages ● Iron is stored in tissue cells as ferritin or hemosiderin ● Abnormal iron metabolism can result in disorders related to iron uptake, metabolism, excretion, and storage Albinism ● Albinism is a congenital inherited disorder characterized by the absence or partial absence of melanin ● Individuals with albinism are highly predisposed to developing skin cancer ● Albinism can be inherited as an autosomal recessive or a sex-linked recessive genetic disorder ● Albinism is caused by a defect in the enzyme tyrosinase, which is responsible for melanin production Hemosiderin Accumulation ● Excess accumulation of hemosiderin occurs in the mononuclear phagocyte systems (MPSs) and other organs ● Hemosiderosis is a transient, localized deposition of iron that usually does not result in tissue damage ● Transient hemosiderin accumulation can be seen in bruising where ruptured blood vessels result in RBCs exiting the circulatory system ● The colors of bruising reflect the degradation of hemoglobin to hemosiderin Bilirubin and Jaundice ● Bilirubin is a pigment derived from hemoglobin and excess bilirubin causes jaundice ● Jaundice occurs due to various mechanisms, including destruction of RBCs, liver diseases, and bile duct obstruction Calcium Accumulation ● Calcium salts accumulate in injured and dead tissues, leading to cellular calcification ● Influx of extracellular calcium into mitochondria and excretion of acid contribute to cellular calcification ● Clustered calcium salts can interfere with the normal structure and function of cells Hypoxic Injury and Calcium ● When there is a lack of oxygen (hypoxic injury), calcium increases in the cytosol ● If the free calcium cannot be buffered or pumped out of cells, uncontrolled enzyme activation occurs, leading to further damage ● Uncontrolled entry of calcium into the cytosol is a common pathway in cell death Dystrophic Calcification ● Calcification occurs in dying or necrotic tissues ● Commonly seen in chronic pulmonary tuberculosis, lymph nodes, advanced atherosclerotic cardiovascular plaques, and injured heart valves ● Calcification in heart valves can cause a heart murmur and impede smooth opening or closing ● Found in the center of tumors over time as they experience oxygen deprivation ● Calcium salts appear as gritty, clumped granules that can become stone-like ● Psammoma bodies are laminated, calcified structures found within tumors Metastatic Calcification ● Mineral deposits in undamaged, normal tissues secondary to hypercalcemia (excess calcium in the blood) ● Causes include hyperparathyroidism, toxic levels of vitamin D, hyperthyroidism, Addison disease, and excess calcium supplementation ● Can occur in bone tumors, leukemia, disseminated cancers, and advanced renal failure with phosphate retention Urate and Gout ● Humans lack urate oxidase enzyme needed to convert uric acid to allantoin ● Urate crystals persist in dead cells and accumulate in tissues when serum urate levels are elevated ● High levels of urate crystals can cause painful disorders collectively called gout, including acute arthritis, chronic gouty arthritis, tophi, and nephritis ● Cell injury and inflammation are characteristic findings in gout-related disorders Systemic Manifestations of Cellular Injury ● Dead and injured cells initiate local inflammation and can cause systemic inflammation ● Inflammation can lead to fatigue, malaise, altered appetite, and fever ● Fever may occur due to the release of endogenous pyrogens during the inflammatory response Causes and effects of cell injury: ● Increase in oxidative metabolic processes resulting from fever ● Increase in leukocytes (leukocytosis) due to infection ● Pain caused by various mechanisms such as release of bradykinins, obstruction, pressure ● Presence of cellular enzymes released from cells in extracellular fluid Enzymes involved in cell injury: ● Lactate dehydrogenase (LDH) released from red blood cells, liver, kidney, skeletal muscle isoenzymes ● Creatine kinase (CK) released from skeletal muscle, brain, heart ● Aspartate aminotransferase (AST/SGOT) released from heart, liver, skeletal muscle, kidney, pancreas ● Alanine aminotransferase (ALT/SGPT) released from liver, kidney, heart ● Alkaline phosphatase (ALP) released from liver, bone ● Amylase released from pancreas ● Aldolase released from skeletal muscle, heart Types of cellular death: ● Necrosis: characterized by rapid loss of plasma membrane structure, organelle swelling, and lack of typical features of apoptosis ● Apoptosis: a regulated or programmed cell process, involving shrinkage of the cell and fragmentation into nucleosome-size fragments