Cell Injury Pathology Study Guide

CELL INJURY
Nox4- and p22phox-dependent signaling pathways implicated in tubular cell injury triggered by p-cresyl sulfatep-cresyl sulfate accumulates in human tubular cells and promotes Nox4-dependent ROS generation via upregulation of Nox4 and p22phox. PI3-K and PKC activation mediate the stimulatory effect of p-cresyl sulfate on NADPH oxidase. Nox4-derived ROS subsequently enhance expression of inflammatory cytokines and profibrotic factors resulting in cell injury. The right panel illustrates the topology of Nox4 and the enzymatic reaction catalyzed by the enzyme. PI3-K, phosphoinositide 3-kinase; PKC, protein kinase C; OAT, organic anion transporter. Nox4 as a potential therapeutic target for treatment of uremic toxicity associated to chronic kidney disease. Gorin Y - Kidney international (2013). Not Altered. CC.

Cell Injury

Cell Injury Pathology Video

When stress exceeds a cell’s ability to adapt, cell injury may occur.

The likelihood of cellular injury occurring depends on: 

  • The type(s) of cells involved
  • The type(s) of stress
  • The severity of stress(ors)
  • The duration of the stress(ors)

Please note that neurons are extremely sensitive to ischemia.

Please note that compared to neurons, skeletal muscle cells are less sensitive to ischemia.

Acute injury can result from acute ischemia such as a stroke. 

Atrophy can result from slowly developing ischemia such as renal artery atherosclerosis leading to atrophic kidney.

Common causes of cellular injury include:

  • Inflammation
  • Nutritional deficiency
  • Nutritional excess
  • Hypoxia
  • Trauma
  • Genetic issues
Ischemic Bowel Disease
Opening the operatory specimen, the mucosa of the colon appeared totally ischemic, whilst the serosa was normal. Combination of diagnostic laparoscopy and intraoperative indocyanine green fluorescence angiography for the early detection of intestinal ischemia not detectable at CT scan. Alemanno G, Somigli R, Prosperi P, Bergamini C, Maltinti G, Giordano A, Valeri A – International journal of surgery case reports (2016). Not Altered. CC.

Hypoxia

Hypo- means low.

-oxia means oxygen.

Hypoxia means low oxygen.

Tissues are dependent on oxygen for the generation of ATP.

Hypoxia may result in low oxygen delivery to tissue.

Hypoxia is an important cause of cellular injury.

Oxygen is the final electron acceptor in the electron transport chain.

Decreased oxygen impairs oxidative phosphorylation.

Decreased oxygen results in decreased ATP production.

Lack of ATP leads to cellular injury.

Causes of hypoxia include:

  • Ischemia
  • Hypoxemia
  • Decreased oxygen carrying capacity
Infarction
Cellular interaction in the infarct demarcation zone. Infarct demarcation zone at day 7 after infarct induction (left: healthy tissue; right: infarct zone) with different stainings: H&E (A), NeuN (B), ED1 (C), anti NeuN antibody and anti-Iba1 antibody (D), GFAP (E) and VIM (F). The infarct zone was clearly demarcated (A-F) Eosinophilic coagulation (A) and neuronal degeneration (B) occurred at the infarct. ED1+ phagocytes (C) and activated microglia (D, brown) are visible within the infarct. Interactions between neurons and activated microglia occurred (D, red arrows). GFAP-positive astrocytes (E) demarcate the lesion forming an astrocytic scar in the vital tissue adjacent to the infarct border. Vimentin immunoreactivity (F) depicts proliferating astrocytes within the scar (black arrow) as well as other cell types within the infarct (green arrow). Objective: 40×; bar: 50 μm. Dynamics of neuroinflammation in the macrosphere model of arterio-arterial embolic focal ischemia: an approximation to human stroke patterns. Walberer M, Rueger MA, Simard ML, Emig B, Jander S, Fink GR, Schroeter M – Experimental & translational stroke medicine (2010). Not Altered. CC.

Ischemia

Ischemia is decreased blood flow through an organ.

Ischemia can be due to decreased arterial perfusion (e.g. atherosclerosis).

Ischemia can be due to decreased venous drainage (e.g. Budd-Chiari syndrome).

Ischemia can be due to shock (generalized decrease perfusion of organs).

Types of shock include:

  • Hypovolemic shock
  • Neurogenic shock
  • Septic shock
  • Cardiogenic shock
  • Anaphylactic shock

Hypoxemia

Hypoxemia is technically a lower partial pressure of oxygen in the blood.

Remember from lung physiology that FiO2 -> PAO2 -> PaO2 -> SaO2.

The specific partial pressure that defines hypoxemia is:

  • PaO2 < 60 mm Hg
  • SaO2 < 90%

Hypoxemia can be caused by:

  • Hypoventilation (e.g. carbon dioxide build-up in lung -> increased PACO2)
  • V/Q mismatch
  • High altitude (e.g. FiO2 decreased)
  • Diffusion defect (e.g. thickened alveolar air sacks in interstitial fibrosis of the lung)
  • Decreased oxygen carrying capacity (e.g. anemia PaO2 & SaO2 both are normal or carbon monoxide (CO) poisoning PaO2 normal & SaO2 decreased, methemoglobinemia PaO2 normal & SaO2 decreased)

Carbon Monoxide Poisoning 

Carbon monoxide (CO) binds hemoglobin stronger than oxygen binds hemoglobin.

PaO2 normal & SaO2 decreased

Carbon monoxide poisoning can be due to:

  • Engine exhaust inhalation (e.g. suicide attempt in car)
  • Smoke inhalation from fire

Classic symptoms of carbon monoxide poisoning include:

  • Headache early on in exposure
  • Cherry red skin

Prolonged carbon monoxide exposure can lead to coma, and even death.

Methemoglobinemia

Heme contains iron.

The iron in heme can be oxidized to Fe3+.

Fe3+ cannot bind oxygen.

Patients with methemoglobinemia will have:

  • Normal PaO2
  • Decreased SaO2

Drugs that may cause methemoglobinemia are classically oxidant stresses which include:

  • Sulfa drugs
  • Nitrite drugs (e.g. “poppers”)

Newborns are at increased risk of methemoglobinemia.

Clinical signs of methemoglobin include:

  • Chocolate colored blood
  • Cyanosis

Methemoglobinemia is treated with methylene blue which is administered intravenously.

Methylene blue helps reduce Fe3+ back to the Fe2+ state.

Oxygen can bind easier to Fe2+.

Reversible Cell Injury

Hypoxia results in decreased ATP due to the oxidative phosphorylation chain being negatively impacted.

Low ATP negatively effects:

  • Na+-K+ pump
  • Ca2+ pump
  • Aerobic glycolysis

Decreased ATP results in issues with cellular function which include:

  • Cell swelling
  • Calcinosis
  • Lactic acid buildup

Cell swelling occurs due to the sodium potassium pump not having the ATP needed to function, which results in sodium accumulating in the cell.

Calcinosis occurs due to the Ca2+ pump not having the ATP needed to function.

Hypoxia causes the metabolic machinery of the cell to shift from aerobic glycolysis to anaerobic glycolysis.

Anaerobic glycolysis produces lactic acid.

Lactic acid accumulates in the cell, and lowers the cell pH, which causes denaturation of proteins.

The initial phase of hypoxic injury is reversible.

Key features of reversible cell injury includes:

  • Cellular swelling
  • Loss of microvilli
  • Membrane blebbing
  • Decreased protein synthesis

Irreversible Cell Injury

The characteristic feature of irreversible cellular injury is membrane damage, which includes:

  • Cellular membrane damage
  • Mitochondrial membrane damage
  • Lysosome membrane damage

Please note that membrane damage is the key feature of irreversible cell injury.

When the cellular membrane is damaged cytosolic enzymes are capable of leaking out of the cell into the blood and serum.

Please note that troponin testing for myocardial infarction is based on detecting intracellular components of myocardiocytes that have leaked into the blood and serum via cardiac cell membranes that were damaged due to hypoxia or ischemia.

Regarding mitochondrial membrane damage, the electron transport chain would be negatively impacted, and cytochrome C would leak out into the cytosol causing apoptotic activation.

Regarding lysosome and brain damage, hydrolytic enzymes will leak out into the cytosol and wreak havoc.

The final result of irreversible injury is cell death.

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