[ Pobierz całość w formacie PDF ]
Fibrosis: Increase of connective tissue
Accumulation of both fibrillar and basement membrane like collagens
Increase of laminen and fibronectin
Thickening of connective tissue septae
Capillarization of the sinusoids
Sclerosis: Aging of fibrotic tissue
Decrease of hyaluronic acid and heparan sulfate proteoglycans
Increase of chondroitin sulfate proteoglycans
Progressive fragmentation and disappearance of elastic fibers
Distortion of sinusoidal architecture and parenchymal damage
Cirrhosis: End-stage process of liver fibrotic degeneration
Whole liver heavily distorted by thick bands of collagen surrounding
nodules of hepatocytes with regenerative foci
470 SECTION FOUR / FUEL OXIDATION AND THE GENERATION OF ATP
Hepatocyte
Acetaldehyde
Actived
Kupffer
Kupffer
cell
Acetaldehyde-
cell
protein adducts
Respiratory burst
Lipid peroxidation
ROS
products
NO
TGF-²
Stimulated
Stellate cell
stellate cell
(Vitamin A)
Extracellular matrix Metallo
Collagen Proteases
FIBROSIS
Fig. 25.8. Proposed model for the development of hepatic fibrosis involving hepatocytes,
Kupffer cells, and stellate (Ito) cells. ROS, reactive oxygen species; NO, nitric oxide:
TGF 1, transforming growth factor 1.
(Fig.25.8). The Kupffer cells are probably activated by a product of the damaged
hepatocytes, such as necrotic debris, iron, ROS, acetaldehyde, or aldehyde products
of lipid peroxidation. Kupffer cells also may produce acetaldehyde from ethanol
internally through their own MEOS pathway.
Activated Kupffer cells produce a number of products that contribute to activation
of stellate cells. They generate additional ROS through NADPH oxidase during the
Cytokines are proteins produced
oxidative burst and NOS through inducible NO synthase (see Chapter 24). In addition,
by inflammatory cells that serve as
they secrete an impressive array of growth factors, such as cytokines, chemokines,
communicators with other cells.
prostaglandins, and other reactive molecules. The cytokine transforming growth factor
Chemokines are even smaller proteins pro-
1 (TGF 1), produced by both Kupffer cells and sinusoidal endothelial cells, is a
duced by inflammatory cells that promote
major player in the activation of stellate cells. Once activated, the stellate cells produce
migration of other inflammatory cells (e.g.,
from the blood into the site of injury). collagen and proteases, leading to an enhanced fibrotic network within the liver.
Suggested References
Lieber CS. Medical disorders of alcoholism. New England J Med 1995;33:1058 1065.
Lieber CS. Cytochrome P-4502E1: Its physiological and pathological role. Physiol Rev
1997;77:517 544.
Mezey E. Metabolic effects of alcohol. Fed Proc 1985;44:134 138.
Poli G. Pathogenesis of liver fibrosis: Role of oxidative stress. Mol Aspects Med 2000;21:49 98.
REVIEW QUESTIONS CHAPTER 25
1. The fate of acetate, the product of ethanol metabolism, is which of the following?
(A) It is taken up by other tissues and activated to acetyl CoA.
(B) It is toxic to the tissues of the body and can lead to hepatic necrosis.
(C) It is excreted in bile.
(D) It enters the TCA cycle directly to be oxidized.
(E) It is converted into NADH by alcohol dehydrogenase.
CHAPTER 25 / METABOLISM OF ETHANOL 471
2. Which of the following would be expected to occur after acute alcohol ingestion?
(A) The activation of fatty acid oxidation
(B) Lactic acidosis
(C) The inhibition of ketogenesis
(D) An increase in the NAD /NADH ratio
(E) An increase in gluconeogenesis
3. A chronic alcoholic is in treatment for alcohol abuse. The drug disulfiram is prescribed for the patient. This drug deters the
consumption of alcohol by which of the following mechanisms?
(A) Inhibiting the absorption of ethanol so that an individual cannot become intoxicated, regardless of how much he drinks
(B) Inhibiting the conversion of ethanol to acetaldehyde, which would cause the excretion of unmetabolized ethanol
(C) Blocking the conversion of acetaldehyde to acetate, which causes the accumulation of acetaldehyde
(D) Activating the excessive metabolism of ethanol to acetate, which causes inebriation with consumption of a small amount
of alcohol
(E) Preventing the excretion of acetate, which causes nausea and vomiting
4. Induction of CYP2E1 would result in which of the following?
(A) A decreased clearance of ethanol from the blood
(B) A decrease in the rate of acetaldehyde production
(C) A low possibility of the generation of free radicals
(D) Protection from hepatic damage
(E) An increase of one s alcohol tolerance level
5. Which one of the following consequences of chronic alcohol consumption is irreversible?
(A) Inhibition of fatty acid oxidation
(B) Activation of triacylglycerol synthesis
(C) Ketoacidosis
(D) Lactic acidosis
(E) Liver cirrhosis
[ Pobierz całość w formacie PDF ]