cell injury: pathologic calcification and cell aging

Learning objectives

• Pathologic calcification• Hyaline change• Cell aging!

PATHOLOGIC CALCIFICATION

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

DYSTROPHICCALCIFICATION

METASTATIC CALCIFICATION

1. Occurs locally in dead and degenerated tissues

2. Normal levels of serum calcium

3. Absence of derangements in calcium metabolism

Examples – Psammoma bodies in papillary cancers, Asbestos bodies

Can cause organ dysfunction (heart valves, Atherosclerosis)

1. Deposition in normal tissues

2. Increased levels of serum calcium

3. Disturbance in calcium metabolism

(in hyperparathyroidism, bone damage or diseases, William’s syndrome

CALCIFICATION IN DEAD TISSUES

1. Necrosis2. Infarcts3. Thrombi4. Hematomas5. Dead parasites

CALCIFICATION INDEGENERATED TISSUES

1. Dense old scars2. Atheromas3. Monckeberg’s

sclerosis4. Stroma of tumors5. Cyst walls

DYSTROPHIC CALCIFICATION

DYSTROPHIC CALCIFICATION

1. 2 Phases 1. Initiation – occurs in the mitochondria of

necrotic cells with the creation of a microcrystal 2. Propagation – accumulation of Ca+2 phosphate

salts

Although it may just be a sign of past injury it often results in organ dysfunction

Dystrophic Calcification

Dystrophic calcification in the Achilles tendon after repeated traumatic injury.

• Morphology =Basophilic, amorphous or granular appearance intracellular, extracellular or both in H & E stained sections

Pathologic calcifications

Psammoma Bodies

METASTATIC CALCIFICATION1. 4 Primary causes

1. Elevated PTH causing bone resoption1. Primary hyperparathyroidism 2. Secondary hyperparathyroidism

2. Destruction of bone3. Vitamin D related disorders intoxication, Sarcoidosis

(macrophages turn on Vita D receptor)4. Renal failure (phosphate retention so increased PTH)

2. Occurs throughout the body but favors tissues that lose acid (alkali) favoring calcium deposition (gastric mucosa, lungs, kidneys)

PATHOGENESIS

• Excessive binding of inorganic phosphate ions with the calcium ions

• Precipitation of calcium phosphates

Hyaline change

• This is an alteration• within cells or extracellular space

• Homogeneous glassy pink appearance in H& E stains

• Its just a descriptive term

• rather than a specific marker of cell injury!!

Intracellular• Mallory body • Russel body• Zenkers degeneration in

rectus muscle .. In typhoid

Extracelular• Collagenous fibrous

tissue• Change in leiomyoma• Hyaline membrane • Hyalinization in chronic

glomerulonephritis• Corpora amylaceae

Cell aging

• There is good evidence that aging-induced alterations in cells are an important component of the aging of the organism

• Cellular aging is the result of a progressive decline in cellular function and viability

– caused by genetic abnormalities &

– the accumulation of cellular and molecular damage due to the effects of exposure to exogenous influences

changes that contribute to cellular aging

• Decreased cellular replication. • Accumulation of metabolic and genetic

damage.

Telomeres and Aging:Is there a connection?

What are telomeres?

• Telomeres are…– Repetitive DNA sequences at the ends of all

human chromosomes– They contain thousands of repeats of the six-

nucleotide sequence, TTAGGG – In humans there are 46 chromosomes and

thus 92 telomeres (one at each end)

What do telomeres do?

• They protect the chromosomes.• They separate one chromosome from

another in the DNA sequence• Without telomeres, the ends of the

chromosomes would be "repaired", leading to chromosome fusion and massive genomic instability.

Telomere function, cont’.

• Telomeres are also thought to be the "clock" that regulates how many times an individual cell can divide.

• Telomeric sequences shorten each time the DNA replicates.

How are telomeres linked to aging?

• Once the telomere shrinks to a certain level, the cell can no longer divide. Its metabolism slows down, it ages, and dies.

• SENESCENCE

Telomeres & Aging

• Healthy human cells are MORTAL because they can divide only a finite number of times, growing older each time they divide. Thus cells in an elderly person are much older than cells in an infant.

What is telomerase, anyway?• Telomerase (TEE-LÓM-ER-ACE) is a

ribonucleoprotein enzyme complex (a cellular reverse transcriptase) that has been referred to as a cellular IMMORTALIZING enzyme.

• It stabilizes telomere length by adding hexameric (TTAGGG) repeats onto the telomeric ends of the chromosomes, thus compensating for the erosion of telomeres that occurs in its absence.

How Does Telomerase Work?

• Telomerase works by adding back telomeric DNA to the ends of chromosomes, thus compensating for the loss of telomeres that normally occurs as cells divide.

• Most normal cells do not have this enzyme and thus they lose telomeres with each division.

How Does Telomerase Work?

• In humans, telomerase is active in germ cells, in vitro immortalized cells, the vast majority of cancer cells and, possibly, in some stem cells.

• High telomerase activity exists in germ cells, stem cells, epidermal skin cells, follicular hair cells, and cancer cells.

HOW TO PROLONG LIFE SPAN

!!!!!!

CALORIE RESTRICTION!!!• YES!• Studies in model organisms, from yeasts

to mammals

• HOW?

• Mediated by family of proteins called SIRTUINS!

• Promotes expression of several genes whose products increase longevity

• Increase metabolism, reduce apoptosis, decrease the effects of free radicals

• constituent of red wine may activate SIRTUINS and thus increase life span!

• Relevance of these findings to aging in humans is an area of active investigation!!!!.

Thank you