Pathology Exam 1

Pathology

the causes of disease and the changes in cells, tissues, and organs that are associated with the development of disease

etiology

the origin of disease including the underlying causes and modifying factors

pathogenesis

steps in disease development

even though clinical manifestations are the same the pathology can be different (similar diseases are treated very differently)

homeostasis

steady state of steady internal physical and chemical conditions

adaption

a new steady state that preserved the viability and function

reversible injury

homeostasis can and is restored

irreversible injury

leads to cell death

cellular injury response pathway

healthy cell (homeostasis) —(injurious stimulus)→ reversible injury —(severe, progressive)→ cell death (apoptosis or necrosis)

types of cellular stress

• oxidative stress

• endoplasmic reticulum stress and UPR

• disruption of calcium homeostasis

oxidative stress

• cellular damage induced by the accumulation of reactive oxygen species (ROS)

• free radicals are unstable and attack cellular components

  • peroxidation of membrane lipids

  • crosslinking and modification of proteins

  • DNA damage

causes of oxidative stress

• chemical and radiation injury

• hypoxia

• cellular aging

• tissue injury by inflammatory cells

• ischemia-reperfusion injury (hypoxia)

*Normal cellular functions can produce ROS

oxidative stress normal function vs. pathology

Normal: in the mitochondria, O₂⁺ superoxide → H₂O₂ Hydrogen Peroxide → glutathione and catalase turns it into water. Removes free radicals

Pathology: in the mitochondria, O₂⁺ superoxide → H₂O₂ Hydrogen Peroxide → HO⁺ hydroxyl radical → exits the mitochondria into the cytoplasm

1. lipid peroxidation → causes membrane (the double bonds in the fatty acid chains (stanky leg one) is disrupted by ROS)

2. protein modification → misfolds and/or destroys proteins

3. DNA damage → enters the nucleus and causes mutations and/or breaks DNA strands (disrupts the H-bonds in the DNA)

Rates of ROS

• ROS at low concentrations are needed for the signaling pathways in the cell → ROS levels are supposed to be tightly regulated

• levels of ROS are determined by production and removal

  • cleared by enzymes (glutathione peroxidase, catalase) or antioxidants

• Injuries can increase ROS by increasing production or decreasing clearance

endoplasmic reticulum stress cause

caused by the accumulation of misfolded proteins → may be caused by abnormalities that :

• increase production of misfolded proteins

• reduced ability to eliminate bad protein

mutations → misfolding, upr pathway, aging, viral infections, pH imbalance and redox state, hypoxia, or ischemia

Normal Endoplasmic Reticulum function

• during protein synthesis chaperones in the ER make sure the new proteins are folded properly

• sometimes the process fucks up and misfolded proteins happen → activate the unfolded protein response via sensor IRE1

ER stress pathology

• injuries can lead to problems with protein folding

• high levels of misfolded protein synthesis can trigger apoptosis via the mitochrondria (intrinsic pathway)

• BH3 proteins and caspases are activated to start the apoptosis pathway

Unfolded Protein Response (UPR) effects

• an adaptive response

• increases protein degradation and chaperone expression (properly fold bad proteins in mild amounts)

• deceases protein production

UPR pathway

in the ER lumen: low amounts of misfolded proteins are detected by sensors (IRE1) which increases the expression and synthesis of chaperones

pathologies caused by misfolded protein

• disease caused by deficiency of a protein → loss of function

• induced apoptosis

• gaining a toxic function

ubiquitin-proteasome system (UPS)