Cell Injury

Chapter 1 Cell Injury



I. Tissue Hypoxia

A. Hypoxia

1. Hypoxia refers to inadequate oxygenation of tissue.


Hypoxia: inadequate oxygenation of tissue



2. Inadequate oxygen (O2) decreases synthesis of adenosine triphosphate (ATP).

a. ATP synthesis occurs in the inner mitochondrial membrane by the process of oxidative phosphorylation (see later).

b. O2 is an electron acceptor located at the end of the electron transport chain (ETC) in the oxidative pathway.

c. A lack of O2 or a defect in oxidative phosphorylation culminates in a decrease in ATP synthesis.

3. Several types of hypoxia produce O2-related changes reported with arterial blood gas measurements (Table 1-1).


Table 1-1. Terminology Associated with Oxygen Transport and Hypoxia

image


O2 content = (Hb g/dL × 1.34) × SaO2 + Pao2 × 0.003



•. O2 diffuses down a gradient from the alveoli, to plasma (↑PaO2), and to red blood cells (RBCs), where it attaches to heme groups (↑Sao2)


Pulse oximetry is a noninvasive test for measuring Sao2. It utilizes a probe that is usually clipped over a patient’s finger. Oximetry emits light at specified wavelengths that identify oxyhemoglobin and deoxyhemoglobin, respectively. The wavelengths emitted by a pulse oximeter cannot identify dyshemoglobins such as methemoglobin (metHb) and carboxyhemoglobin (i.e., carbon monoxide bound to Hb, COHb), which normally decrease the Sao2 (see later). In the presence of these dyshemoglobins, the oximeter calculates a falsely high Sao2. Unlike the standard oximeter, a co-oximeter emits multiple wavelengths and calculates an accurate Sao2 because it identifies metHb and COHb.


4. Clinical findings of hypoxia include cyanosis (see Fig. 10-11), confusion, cognitive impairment, and lethargy.


Pulse oximeter: falsely ↑Sao2 with metHb and COHb


B. Causes of tissue hypoxia

1. Ischemia

a. Decreased arterial blood flow or venous outflow of blood

b. Examples—coronary artery atherosclerosis, decreased cardiac output, thrombosis of splenic vein


Ischemia: ↓ arterial blood inflow or venous outflow


c. Consequences of ischemia

(1) Atrophy (reduction in cell/tissue mass)

(2) Infarction of tissue (localized area of tissue necrosis)

(3) Organ dysfunction (e.g., heart failure)

2. Hypoxemia

Normal ventilation and perfusion are depicted in Figure 1-1A.

image

1-1: Ventilation (V)-perfusion (Q) defects. A, Schematic showing normal ventilation and perfusion; B, schematic showing ventilation defect; C, schematic of perfusion defect. See text for discussion. image, partial pressure of carbon dioxide in mixed venous blood; image,partial pressure of oxygen in mixed venous blood.


(From Goljan EF, Sloka KI: Rapid Review Laboratory Testing in Clinical Medicine. Philadelphia, Mosby Elsevier, 2008, p 76, Fig. 3-5.)



Hypoxemia:↓Pao2


a. Decrease in Pao2 (<40 =”0.25″/>mm Hg)

b. Causes

(1) Decreased inspired Po2 (Pio2)

• Examples—high altitude, breathing reduced %O2 mist

(2) Respiratory acidosis (hypoventilation)

(a) Carbon dioxide (CO2) retention in the lungs always produces a corresponding decrease in Pao2.

(b) Examples—depression of the medullary respiratory center (e.g., barbiturates), paralysis of the diaphragm, chronic bronchitis


↑Alveolar PCO2 = ↓ alveolar Po2 = ↓ Pao2 = ↓ Sao2


(3) Ventilation defect (Fig. 1-1B)

(a) Impaired O2 delivery to alveoli

• Example—respiratory distress syndrome (RDS) with collapse of the distal airways due to lack of surfactant

(b) No O2 exchange in lungs that are perfused but not ventilated


Ventilation defect: perfused but not ventilated; intrapulmonary shunt


(c) Diffuse disease (RDS) produces intrapulmonary shunting of blood

• Pulmonary capillary blood has the same Po2 and PCO2 as venous blood returning from tissue (i.e., a large fraction of pulmonary blood flow has not been arterialized).

(d) Inspired %O2 from 24% to 28% or greater does not significantly increase the Pao2.

• This only applies to a diffuse ventilation defect involving both lungs; smaller defects are compensated for in normally ventilated lung.

(4) Perfusion defect (Fig. 1-1C)

(a) Absence of blood flow to alveoli (e.g., pulmonary embolus)

(b) No O2 exchange in lungs that are ventilated but not perfused


Perfusion defect: ventilated but not perfused; ↑ dead space


(c) Produces an increase in dead space

• Exchange of O2 and CO2 does not occur.

(d) Inspired %O2 from 24% to 28% or greater increases the Pao2.

• Other parts of ventilated and perfused lung have normal gas exchange.

(5) Diffusion defect

(a) Decreased O2 diffusion through the alveolar-capillary interface


Diffusion defect: interstitial fibrosis, pulmonary edema


(b) Examples—interstitial fibrosis, pulmonary edema

(6) Ventilation, perfusion, and diffusion defects increase the difference in O2 concentration between alveolar Po2 (PAO2) and arterial Po2 (Pao2).

• This difference is called the alveolar-arterial (A-a) gradient (refer to Chapter 16).

3. Hemoglobin (Hb)-related abnormalities

a. Anemia

(1) Decreased Hb concentration (<7 =”0.25″/>g/dL)

(2) Causes

(a) Decreased production of Hb (e.g., iron deficiency)

(b) Increased destruction of RBCs (e.g., hereditary spherocytosis)

(c) Decreased production of RBCs (e.g., aplastic anemia)

(d) Increased sequestration of RBCs (e.g., splenomegaly)


Anemia: normal Pao2 and Sao2


(3) Normal Pao2 and Sao2

b. Methemoglobinemia

(1) Methemoglobin (metHb) is Hb with oxidized heme groups (Fe3+).


Methemoglobin is converted to the ferrous state (Fe2+) by the reduced nicotinamide adenine dinucleotide (NADH) reductase system located off the glycolytic pathway in RBCs. Electrons from NADH are transferred to cytochrome b5 and then to metHb by cytochrome b5 reductase to produce ferrous Hb. Newborns are particularly at risk for developing methemoglobinemia after oxidant stresses (see later) owing to decreased levels of cytochrome b5 reductase until at least 4 months of age.


(2) Causes

(a) Oxidant stresses

• Examples—nitrite- and sulfur-containing drugs, sepsis, local anesthetics (e.g., benzocaine)

(b) Congenital deficiency of cytochrome b5 reductase

(3) Pathogenesis of hypoxia

(a) Fe3+ cannot bind O2

MetHb: heme Fe3+; ↓ Sao2


• Normal Pao2, decreased Sao2

(b) Ferric heme groups impair unloading of O2 by oxygenated ferrous heme.

• This causes a left-shifted O2-binding curve (see later).


MetHb: Rx with IV methylene blue



Patients with methemoglobinemia have chocolate-colored blood (increased concentration of deoxyhemoglobin) and cyanosis. Clinically evident cyanosis occurs at metHb levels greater than 1.5 =”0.25″/>g/dL. Skin color does not return to normal after administration of O2. Treatment is intravenous methylene blue, which acts as an artificial electron carrier in the reduced nicotinamide adenine dinucleotide phosphate (NADPH) metHb reductase system located in the pentose phosphate shunt.


c. Carbon monoxide (CO) poisoning (also refer to Chapter 6)

(1) Leading cause of death due to poisoning

(2) Produced by incomplete combustion of carbon-containing compounds

(3) Causes include automobile exhaust, smoke inhalation, wood stoves, methylene chloride (paint thinner).

(4) Pathogenesis of hypoxia

(a) CO competes with O2 for binding sites on Hb.

• Decreases Sao2 without affecting Pao2

CO poisoning: normal Pao2, ↓Sao2


(b) CO inhibits cytochrome oxidase in the electron transport chain (ETC).

(c) CO causes a left-shifted O2-binding curve (OBC).

(5) Clinical findings

(a) Cherry-red discoloration of skin and blood

(b) Headache (first symptom at levels of 10–20%)

(c) Dyspnea, dizziness (levels of 20–30%)

(d) Seizures, coma (levels of 50–60%)

(e) Lactic acidosis due to hypoxia

(6) Treatment is O2 via nonbreather mask or endotracheal tube (100% O2)


Rx CO poisoning: O2 via nonbreather mask


d. Factors causing a left-shifted OBC

(1) Decreased 2,3-bisphosphoglycerate (BPG)

• Intermediate of glycolysis via conversion of 1,3-BPG to 2,3-BPG

(2) CO, alkalosis, metHb, fetal Hb, hypothermia

(3) These factors increase affinity of Hb for O2 with less release of O2 to tissue.

• Example—at the capillary Po2 concentration in tissue a right-shifted OBC (↑2,3-BPG, acidosis, fever) has released most of its O2 to tissue, but a left-shifted OBC still has most of its O2 attached to heme groups (Fig. 1-2).

image

1-2: Oxygen-binding curve (OBC). Note that at the Po2 in the tissue (ranges from 20 to 50 =”0.25″/>mm Hg) a left-shifted OBC still has an O2 saturation (Sao2) of 80% (only released 20% of its O2 to tissue), a normal-shifted OBC has an Sao2 of 50% (only released 50% of its O2 to tissue), and a right-shifted curve has an Sao2 of 20% (released 80% of its O2 to tissue). 2,3-Bisphosphoglycerate (BPG) improves O2 delivery to tissue by stabilizing the hemoglobin (Hb) in the taut form, which decreases O2 affinity, hence facilitating the movement of O2 from Hb into tissue by diffusion.



High altitude: ↑2,3-BPG synthesis; respiratory alkalosis



At high altitudes, the atmospheric pressure is decreased; however, the percentage of O2 in the atmosphere remains the same (i.e., 21%). Hypoxemia stimulates peripheral chemoreceptors (e.g., carotid body) causing respiratory alkalosis, which shifts the OBC to the left. However, alkalosis activates phosphofructokinase, the rate-limiting enzyme in glycolysis, causing increased production of 1,3-BPG, which is converted to 2,3-BPG. This eventually shifts the OBC to the right, leading to increased release of O2 to tissue.


C. Mitochondrial causes of ATP depletion

1. Enzyme inhibition of oxidative phosphorylation (Fig. 1-3)

image

1-3: Oxidative phosphorylation. See text for discussion.


(From Pelley J, Goljan E: Rapid Review Biochemistry, 2nd ed. St. Louis, Mosby, 2007, p 81, Fig. 5-8.)



The oxidative part of the pathway in the inner mitochondrial membrane transfers donated electrons from NADH and reduced flavin adenine dinucleotide (FADH2) derived from the energy cycles down the ETC to O2. Oxygen is a strong electron acceptor located at the end of the chain on complex IV. The transfer of electrons is coupled with the transport of protons (H+) supplied by NADH and FADH2 across the inner mitochondrial membrane into the intermembranous space, which establishes both a proton and a pH gradient. The phosphorylation part of the pathway is the synthesis of ATP. A certain amount of heat is required to synthesize ATP. ATP synthesis occurs when the protons on the cytosolic side of the inner membrane enter small channels (proton pores) within the ATP synthase molecule (complex V) and reenter the mitochondrial matrix, where ATP is synthesized. The inner mitochondrial membrane is normally impermeable to protons except through the channel in the ATP synthase molecule. This relationship is critical to the maintenance of the proton gradient. If enzymatic reactions in electron transport are inhibited (e.g., cytochrome oxidase), the formation of protons and the proton gradient are disrupted as well, leading to a decrease in ATP synthesis.


a. Synthesis of ATP is decreased.

b. CO and cyanide (CN) inhibit cytochrome oxidase in the ETC.


CO and CN: inhibit cytochrome oxidase


c. CN poisoning (also refer to Chapter 6)

(1) It may result from drugs (e.g., nitroprusside) and combustion of polyurethane products in house fires.

(2) It produces an initial central nervous system and cardiovascular stimulation followed by CNS depression and death.


CO and CN poisoning: house fires


(3) It produces lactic acidosis due to hypoxia.

(4) It produces increased venous Po2 and saturation.

• Tissue cannot extract O2.

(5) Treatment involves two stages.


Rx CN poisoning: amyl nitrite, thiosulfate


• Amyl nitrite (produces metHb which combines with CN to form cyanmetHb) followed by thiosulfate (CN converted to thiocyanate)

2. Uncoupling of oxidative phosphorylation

a. Uncoupling proteins carry protons in the intermembranous space through the inner mitochondrial membrane into the mitochondrial matrix without damaging the membrane.

(1) Bypass of ATP synthase causes decreased synthesis of ATP.


Uncouplers: thermogenin, dinitrophenol


(2) Examples—thermogenin (natural uncoupler in brown fat in newborns), dinitrophenol used in synthesizing nitroglycerin

b. Heat normally used to synthesize ATP raises the core body temperature.

(1) There is a danger of developing hyperthermia with dinitrophenol.

(2) Thermogenin is useful in stabilizing body temperature in newborns.


Mitochondrial toxins: alcohol, salicylates



Agents such as alcohol and salicylates act as mitochondrial toxins. They damage the inner mitochondrial membrane, causing protons to move into the mitochondrial matrix. As with dinitrophenol, hyperthermia is a common complication in alcohol and salicylate poisoning.


D. Tissues susceptible to hypoxia

1. Watershed areas between terminal branches of major arterial blood supplies


Watershed areas: cerebral vessels, mesenteric arteries


a. The blood supply from the two vessels does not overlap.

b. Examples

(1) Area between the distribution of the anterior and middle cerebral arteries (Fig. 1-4)

(2) Area between the distribution of the superior and inferior mesenteric arteries (i.e., splenic flexure)

2. Subendocardial tissue

a. Coronary vessels penetrate the epicardial surface.

b. Subendocardial tissue receives the least amount of O2.

image

1-4: Watershed infarction showing a wedge-shaped hemorrhagic infarction at the junction of the anterior and middle cerebral arteries.


(From Damjanov I, Linder J: Anderson’s Pathology, 10th ed. St. Louis, Mosby, 1996, p 375, Fig. 17-16.)



ST-segment depression ECG: subendocardial ischemia



Factors decreasing coronary artery blood flow (e.g., coronary artery atherosclerosis) produce subendocardial ischemia, which is manifested by chest pain (i.e., angina) and ST-segment depression in an electrocardiogram (ECG). Increased thickness of the left ventricle (i.e., hypertrophy) in the presence of increased myocardial demand for O2 (e.g., exercise) can also produce subendocardial ischemia.


3. Renal cortex and medulla


Cortex: proximal tubule most susceptible to hypoxia


a. In the cortex, the straight portion of the proximal tubule is most susceptible to hypoxia.

• Primary site for reclaiming bicarbonate and reabsorbing sodium

b. In the medulla, the Na+-K+-2 Cl− symporter cotransport channel in the thick ascending limb is most susceptible to hypoxia.


Medulla: thick ascending limb most susceptible to hypoxia


• Primary site for regenerating free water, which is necessary for normal dilution and concentration of urine.

4. Neurons in the central nervous system


Neurons: most adversely affected cell in tissue hypoxia


a. Examples—Purkinje cells in cerebellum, neurons in layers 3, 5, and 6 of the cerebral cortex

b. Irreversible damage occurs ∼︀5 minutes after global hypoxia.

5. Hepatocytes located around the central vein


In the portal triads, hepatic artery tributaries carrying oxygenated blood and portal vein tributaries carrying unoxygenated blood empty their blood into the liver sinusoids (mixed oxygenated and unoxygenated blood), which drain blood into the central veins (terminal hepatic venules). The central veins become the hepatic vein, which empties into the inferior vena cava. Hepatocytes closest to the portal triads (zone I) receive the most oxygen and nutrients, and those farthest from the portal triads (zone III around the central vein) receive the least amount of oxygen and nutrients. Production of free radicals from drugs (e.g., acetaminophen, see later), tissue hypoxia (e.g., shock, CO poisoning), and alcohol-related fatty change of the liver initially damage zone III hepatocytes.



Zone III hepatocytes: most susceptible to hypoxia


E. Consequences of hypoxic cell injury

1. Decreased synthesis of ATP

2. Anaerobic glycolysis is used for ATP synthesis and is accompanied by several changes—

a. Activation of phosphofructokinase

• Caused by low citrate levels and increased adenosine monophosphate

b. Net gain of 2 ATP


Anaerobic glycolysis: primary source ATP in hypoxia; lactic acidosis


c. Decrease in intracellular pH caused by an excess of lactate

(1) Also accumulates in blood producing lactic acidosis

(2) Denatures structural and enzymic proteins

d. Impaired Na+/K+-ATPase pump

(1) Diffusion of Na+ and H2O into cells causes cellular swelling.

(2) Potentially reversible with restoration of O2

3. Decreased protein synthesis

• Due to detachment of ribosomes (potentially reversible)

4. Irreversible cell changes


↑Ca2+ in cytosol: “point of no return”; activates enzymes


a. Impaired calcium (Ca2+)-ATPase pump

• Normal function of the pump is to keep Ca2+ out of the cytosol.

b. Increased cytosolic Ca2+ has two lethal effects.

(1) Enzyme activation

(a) Phospholipase increases cell and organelle membrane permeability.

(b) Proteases damage the cytoskeleton.

(c) Endonucleases cause fading of nuclear chromatin (karyolysis).

(2) Reentry of Ca2+ into mitochondria

(a) Increases mitochondrial membrane permeability


Cytochrome c in cytosol: activates apoptosis (cell death)


(b) Release of cytochrome c into the cytosol activates apoptosis (see later)

II. Free Radical Cell Injury

A. Definition of free radicals

• Unstable chemical compounds with a single unpaired electron in their outer orbital

B. Formation, function, types of free radicals (FRs)

1. Produced by—

a. Ionizing radiation

• Produces hydroxyl FRs


Hydroxyl FRs: most destructive FRs


b. Damaged mitochondria

• Produce superoxide FRs

c. High concentration of O2

(1) Produces superoxide and hydroxyl FRs

(2) Produces hydrogen peroxide (H2O2)

• A reactive oxygen species that produces hydroxyl and peroxide FRs.

d. Oxidase reactions


Oxidase reactions: produce superoxide FRs


(1) NADPH oxidase in the neutrophil and monocyte cell membrane

(a) Myeloperoxidase in a phagolysosome combines hydrogen peroxide with chloride to form bleach (hypochlorous acid).

(b) Hypochlorous acid is a reactive oxygen species that can generate FRs.

(2) Xanthine oxidase acting upon xanthine (degradation product of ATP)

• Produces superoxide FRs

e. Drugs (e.g., acetaminophen)


Acetaminophen: drug FRs formed in liver


• Converted to acetaminophen FRs in the liver

f. Carbon tetrachloride

• Converted to CCl3 FRs in the liver

g. Cigarette smoke

(1) Produces quinone/hydroquinone FRs produced from tar

(2) Produces nitric oxide (NO), an FR gas

• NO reacts with other reactive species (e.g., isoprene) to produce additional FRs.

h. Pollution

• Nitrogen dioxide in car exhaust and ozone produce nitrate FRs.

i. Metals (e.g., iron, copper)


Iron, copper: generate hydroxyl FRs

Related posts:

  1. Skin Disorders
  2. Vascular Disorders
  3. Genetic and Developmental Disorders
  4. Red Blood Cell Disorders

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Jun 25, 2017 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Cell Injury

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