Introduction to pathologylecture 6/ Cell injury

Dr H Awad

2017/18

Topics to be covered

• Autophagy

• Cellular aging

• Pathologic calcification

• Intracellular accumulation

• NOTE: there are many details in the book about these subjects, which I’m not going to cover. My aim in this lecture is to give a brief idea about each of these topics with emphasis on what is beneficial in understanding disease processes.

autophagy

• Autophagy means lysosomal digestion of the cell’s own components

• Mechanism: intracellular organelles and proteins of the cytosol are sequestered within a phagocytic vacuole which is derived from the endoplasmic reticulum. This vacuole fuses with the lysosome to form the autophagolysosome , in which lysosomal enzymes digest thcellular content.

• Aim of autophagy: to recycle cellular contents as building blocks when needed.

AUTOPHAGYauto: self; phagy: eating

➢A survival mechanism in times of nutrient deprivation

➢Involved in the clearance of misfolded proteins (in neurons and hepatocytes)

➢With inflammatory bowel disease(?!)

➢Role in cancer: tumor cells turn off autophagy at the beginning of their development in order to survive and proliferate but at times of stress like during giving chemotherapy the tumor cells use autophagy as a survival mechanism to recycle their organelles.

Roles of autophagy

• Age is one of the strongest independent risk factors for many chronic diseases, such as cancer, Alzheimer disease, and ischemic heart disease

• Cellular aging is the result of a progressive decline in the life span and functional capacity of cells.

• Several mechanisms (cumulative DNA damage, decreased cellular replication capacity, Defective protein homeostasis

CELLULAR AGING

telomeres

• Each cell has a limited replicative potential.

• This is because chromosomes have repeated nucleotide sequences at the ends of each chromosome.

• With each cell replication, telomeres shorten.. Till they become too short and the chromosomal ends fuse together which causes cell death by apoptosis.

• Stem cells have limitless replicative potential because they have telomerase enzyme which uses its RNA nucleotide sequence to replace the lost telomeres.

• Cancer cells upregulate telomerase transcription and become immortal.

Cell Senescence & Telomeres

• 1-Reduced signaling by insulin-like growth factor receptors

• 2-Reduced activation of kinases (“target of rapamycin, [TOR]).

• 3-Altered transcriptional activity.

These changes lead to improved DNA repair and protein homeostasis, enhanced immunity and inhibit aging.

• Environmental stresses may also activate proteins of the Sirtuin family, which function as protein deacetylases.

• These proteins may deacetylate DNA repair enzymes leading to their activation, thus stabilizing the DNA.

Counteracting aging

• Abnormal deposition of calcium salts, together with smaller amounts of iron, magnesium, and other mineral

• Dystrophic Calcification

• Deposition in dead/dying tissues

• Normal Ca2+ metabolism

• Exacerbated by Hypercalcemia

• Metastatic Calcification

• Deposition in normal tissues

• Almost always abnormal Ca2+ metabolism (hypercalcemia)

PATHOLOGIC CALCIFICATION

Dystrophic calcification

• Dystrophic calcification is an Incidental finding indicating insignificant past cell injury

• However it May be a cause of organ dysfunction like in calcification of heart valves.

➢1)Inadequate removal of a normal substance (fatty change in the liver)

➢2)Accumulation of an abnormal endogenous substance (α1-antitrypsin)

➢3)Failure to degrade a metabolite due to inherited enzyme deficiencies (storage diseases)

➢4)Deposition and accumulation of an abnormal exogenous substance (carbon and selica)

➢Don’t worry about the details .. Will be discussed in the relevant systems!

INTRACELLULAR ACCUMULATIONS