Cell injury and Necrosis Flashcards
Cell injury
Plasma membrane blebbing, increased intraceullar volume, mitchondrial swelling and calcification, disagregated ribosomes, dilated vesicular ER, aggregated cytoskeletal elements
- several independent cell components are primary tagets for damaging cell stimuli: cell membranes, mitchondria, cytoskeleton, cellular DNA
- damage of one system leads to secondary damage to others
- primary impairment of mitochondrial energy production is due to the lack of oxygen and glucose and toxins like cyanide
- normal concentration of calcium in cytosol is very low, free calcium is used by secondary messenger systems to activate various cytosolic enzymes(protein kinases, phospholipases, calpain)
- calcium is rapidly removed from cytosol by ATP dependent calcium pumps and next bound to buffering proteins
- if Ca2+ is not buffered or pumped out of cells, uncontrolled enzyme activation
- in all cells, reactive oxygen metabolites are constantly generated and can be potentially damging to cells, so they ae constantly scavenged by antioxidants, glutathione peroxidase, supeoxide dismutase and catalse
- ROS is generated when oxygen is reduced to water and most are created by systems involved in electron and oxygen transport
Common causes of cellular injury
(factors of cellular injury)
-
Hypoxia and ischemia:
- Hypoxia, which refers to oxygen deficiency, and ischemia, which means reduced blood supply, are among the most common causes of cell injury. Both deprive tissues of oxygen, and ischemia and results in a deficiency of essential nutrients and a build up of toxic metabolites. The most common cause of hypoxia is ischemia resulting from an arterial obstruction, but oxygen deficiency also can result from inadequate oxygenation of the blood, as in a variety of diseases affecting the lung, or from reduction in the oxygen-carrying capacity of the blood, as with anemia of any cause, and carbon monoxide (CO) poisoning.
- Toxins. are encountered daily in the environment; these include air pollutants, insecticides, CO, asbestos, cigarette smoke, ethanol, and drugs. Many drugs in therapeutic doses can cause cell or tissue injury in a susceptible patient or in many individuals if used excessively or inappropriately. Even innocuous substances, such as glucose, salt, water and oxygen, can be toxic. Infectious agents. All types of disease-causing pathogens, including viruses, bacteria, fungi, and protozoans, injure cells.
- Immunologic reactions: Although the immune system defends the body against pathogenic microbes, immune reactions also can result in cell and tissue injury. Examples are autoimmune reactions against one’s own tissues, allergic reactions against environmental substances, and excessive or chronic immune responses to microbes . In all of these situations, immune responses elicit inflammatory reactions, which are often the cause of damage to cells and tissues.
- Genetic abnormalities. Genetic aberrations can result in pathologic changes as conspicuous as the congenital malformations associated with Down syndrome or as subtle as the single amino acid substitution in hemoglobin giving rise to sickle cell anemia. Genetic defects may cause cell injury as a consequence of deficiency of functional proteins, such as enzymes in inborn errors of metabolism, or accumulation of damaged DNA or misfolded proteins, both of which trigger cell death when they are beyond repair.
- Nutritional imbalances. Protein–calorie insufficiency among impoverished populations remains a major cause of cell injury, and specific vitamin deficiencies are not uncommon even in developed countries with high standards of living. Ironically, excessive dietary intake may result in obesity and also is an important underlying factor in many diseases, such as type 2 diabetes mellitus and atherosclerosis.
- Physical agents. Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells
What is cell death?
- inability to adapt to an environmental change leads to failure of cellular function and may result in sublethal cellular damage or death
- 2 kinds of death: necrosis and apoptosis
What is apoptosis?
- programmed cell death
- endogenous programed and energy dependent process designed to specifically switch off cells or eliminate them
- occurs when a cell dies through the activation of internally controlled suicide program
What are physiological, adaptive and pathological events in apoptosis?
- programmed destruction of cells during embryogenesis
- hormone dependent involution in the adult(endometrial cell breakdown, regression of lactating breast after weaning, prostatic atrophy after castration)
- cell deletion in proliferating cell population
- cell death in tumor
- death of neurophils
- cell death induced by cytotoxic t cells
- pathologic atrophy in parenchymal organs after duct obstruction
- cell injury in certain viral diseases(adenovirus, HIV infections)
- cell death produced by injurious stimuli, which are given in low doses, large doses of same stimuli result in necrotic cell death(heat, radiation, cytotoxic anticancer drugs, hypoxia)
What are the energy dependent cascade of molecular events for apoptosis?
- signaling pathways: transmembrane may be negative or positve determinants of apoptosis
- apoptosis is activated by caspases which exist as inactive proenzyme and must undergo enzymatic cleavage to become active
- two distinct pathways lead to caspases activation:
- mitochondrial / intrinsic pathway: Bcl-2 family of proteins- major mechanism in mammilian cells
- death receptor/extrinsic pathway: Fas-Fas ligand model, TNF receptor
- apoptotic signals result in mitochondrial permeability transitions. Formation of pores within the inner miochondrial membrane results in reduction of membrane potential, cytochrome c is releasing from mitochondria to cytosol(ativates caspases apoptosis initiating factor-AIF)
- Bcl-2 and Bcl-XL can suppress apoptosis(prevent cytochrome c release and inhibit Apaf-1 induced caspase activation
- BAX and BAK are pro-apoptotic
Apoptosis- Microsopic view
What are the phases?
- First phase priming
- normal cells are arranged in close contact and are united by cell junctions
- synthesis of enzymes can cause cell dissolution, not associated with structural changes
- in development many cells are primed for apoptosis and survive if rescued by specific trophic factor
- Second phase- cell excutioner pathway
- apoptotic cells lose surface specializations and junctions, shrinking in size, nuclear chromatin condenses but cell organelles remain normal
- endonuclease enzymes cleave chromosomes into individual nucleosome fragments
- Third phase- degradation
- splinting of cell into several fragments called apoptotic bodies
- nuclear fragmentation occurs
- each fragment contains viable mitochondria and intact organelles
- takes a few minutes
- caspases, specifically proteases are the main enzymes
- fourth phase: phagocytosis
- apoptotic fragments are recognized by adjacent cells, which inges them by phagocytosis for destuction
- some fragments degenrate extracellularly, while others are ingested by local phagocytic cells
What is oxidative stress?
- Oxidative stress refers to cellular abnormalities that are induced by ROS, which belong to a group of molecules known as free radicals.
- Free radical-mediated cell injury is seen in many circumstances, including chemical and radiation injury, hypoxia, cellular aging, tissue injury caused by inflammatory cells, and ischemia-reperfusion injury. In all these cases, cell death may be by necrosis, apoptosis, or the mixed pattern of necroptosis.
- Free radicals are chemical species with a single unpaired electron in an outer orbit. Such chemical states are extremely unstable, and free radicals readily react with inorganic and organic molecules; when generated in cells, they avidly attack nucleic acids as well as a variety of cellular proteins and lipids.
- In addition, free radicals initiate reactions in which molecules that react with the free radicals are themselves converted into other types of free radicals, thereby propagating the chain of damage.
The generation of free radicals is increased under several circumstances:
- The absorption of radiant energy (e.g., ultraviolet (UV) light, x-rays). Ionizing radiation can hydrolyze water into hydroxyl (•OH) and hydrogen (H•) free radicals.
- The enzymatic metabolism of exogenous chemicals (e.g., carbon tetrachloride)
- Inflammation, in which free radicals are produced by leukocytes
- Reperfusion of ischemic tissues, as already described.
Explain Generation and Removal of Reactive Oxygen Species
- The accumulation of ROS is determined by their rates of production and removal ROS are produced by two major pathways.
- ROS are produced normally in small amounts in all cells during the reduction-oxidation (redox) reactions that occur during mitochondrial respiration and energy generation. In this process, molecular oxygen is reduced in mitochondria to generate water by the sequential addition of four electrons. This reaction is imperfect, however, and small amounts of highly reactive but short-lived toxic intermediates are generated when oxygen is only partially reduced. These intermediates include superoxide (O2 • ), which is converted to hydrogen peroxide (H2O2) spontaneously and by the action of the enzyme superoxide dismutase (SOD). H2O2 is more stable than O2 • and can cross biologic membranes. In the presence of metals, such as Fe2+ , H2O2 is converted to the highly reactive hydroxyl radical •OH by the Fenton reaction.
- ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon for destroying ingested microbes and other substances during inflammation and host defense. The ROS are generated in the phagosomes and phagolysosomes of leukocytes by a process that is similar to mitochondrial respiration and is called the respiratory burst (or oxidative burst). In this process, a phagosome membrane enzyme catalyzes the generation of superoxide, which is converted to H2O2. H2O2 is in turn converted to a highly reactive compound, hypochlorite (the major component of household bleach), by the enzyme myeloperoxidase, which is present in leukocytes.
- Nitric oxide (NO) is another reactive free radical produced in macrophages and other leukocytes. It can react with O2 − to form a highly reactive compound, peroxynitrite, which also participates in cell injury
Cells have developed mechanisms to remove free radicals and thereby minimize their injurious effects. How do cells remove free radicals?
Cells have developed mechanisms to remove free radicals and thereby minimize their injurious effects. Free radicals are inherently unstable and decay spontaneously. There also are nonenzymatic and enzymatic systems, sometimes called free radical scavengers, serving to inactivate free radicals
- The rate of decay of superoxide is significantly increased by the action of superoxide dismutase (SOD).
- Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage. The most abundant member of this family, GSH peroxidase 1, is found in the cytoplasm of all cells. It catalyzes the breakdown of H2O2 by the reaction 2GSH + H2O2 → GS-SG + 2H2O. The intracellular ratio of oxidized GSH to reduced GSH is a reflection of this enzyme’s activity and thus of the cell’s ability to catabolize free radicals.
- Catalase, present in peroxisomes, catalyzes the decomposition of hydrogen peroxide (2H2O2 → O2 + 2H2O). It is one of the most active enzymes known, capable of degrading millions of molecules of H2O2 per second.
Explain generation of reactive oxygen metabolites in cell injury
- free ion
- xanthine accumulates in hypoxic tissues as a metabolite of ATP. In hypoxic conditions accumulated xanthine can be oxidized by xanthine oxidase
- following ischemia, cells become depleted of energy, but ROS does not develop because no oxygen in tissues, If tissues are reperfused, huge amounts of reactive oxygen are generated
- tissue necrosis occurs not due to cessation of blood supply but reestablishment
ROS causes cell injury by damaging which components?
ROS causes cell injury by damaging multiple components of cells:
- Lipid peroxidation of membranes. Double bonds in membrane polyunsaturated lipids are vulnerable to attack by oxygen-derived free radicals. The lipid–radical interactions yield peroxides, which are themselves unstable and reactive, and an autocatalytic chain reaction ensues. Damage to plasma membranes as well as mitochondrial and lysosomal membranes can have devastating consequences, as discussed earlier in the context of ischemia and hypoxia.
- Crosslinking and other changes in proteins. Free radicals promote sulfhydryl-mediated protein crosslinking, resulting in enhanced degradation or loss of enzymatic activity. Free radical reactions also may directly cause polypeptide fragmentation. Damaged proteins may fail to fold properly, triggering the unfolded protein response, described later.
- DNA damage. Free radical reactions with thymine residues in nuclear and mitochondrial DNA produce singlestrand breaks. Such DNA damage has been implicated in apoptotic cell death, aging, and malignant transformation of cells.
- In addition to the role of ROS in cell injury and the killing of microbes, low concentrations of ROS are involved in numerous signaling pathways in cells and thus in many physiologic reactions. Therefore, these molecules are produced normally but, to avoid their harmful effects, their intracellular concentrations are tightly regulated in healthy cells.
Calcium stores issues low chart
Free radicals flow chart
What is necrosis?
- necrosis is a common type of cell death after exogenous stimuli occuring after such stresses like ischemia after chemical injury
- oncosis is prelethal changes preceding necrotic cell death, characterized by cellular swelling and can be distinguisehd from prelethal changes in apoptosis, associated largely wit cellular shrinkage
- if damage to the cell is minimal, the cell can recover following removal of the damaged stimulus. In other situtaions, a damaging stimulus may be sublethal and cell cannot recover leading to cell death
- damaging stimulus to a cell is massive, the cell is killed immediately without passing through stages of necrosis
- Necrosis is a form of cell death in which cellular membranes fall apart, and cellular enzymes leak out and ultimately digest the cell and occurs due to underlying pathlogical process
- Necrosis elicits acute inflammation(bacterial or necrotic- MI-neutrophils)that is induced by substances released from dead cells and which serves to eliminate the debris and start the subsequent repair process.
- The enzymes responsible for digestion of the cell are derived from lysosomes or from the dying cells or from leukocytes recruited as part of the inflammatory reaction.
- Necrosis often is the culmination of reversible cell injury that cannot be corrected.
- The mechanisms of necrosis include: failure of energy generation in the form of ATP because of reduced oxygen supply or mitochondrial damage; damage to cellular membranes, including the plasma membrane and lysosomal membranes, which results in leakage of cellular contents including enzymes; irreversible damage to cellular lipids, proteins, and nucleic acids, which may be caused by reactive oxygen species (ROS).
What are the cellular events in necrosis?
- many changes are caused by lysosomal hydrolases which are released into the cell when cell membrane integrity is lost
- intense eosinophilia of the dead cell is due to the loss of RNA and coagulation of proteins
- nuclei undergoes pyknosis, karyorrhexis, karyolysis leaving a shrunken cell devoid of a nucleus
- proteins may be liberated from the dead cells and be detected in blood in diagnosis
- Leakage of intracellular proteins through the damaged cell membrane and ultimately into the circulation provides a means of detecting tissue-specific necrosis using blood or serum samples. Cardiac muscle, for example, contains a unique isoform of the enzyme creatine kinase and of the contractile protein troponin, whereas hepatic bile duct epithelium contains the enzyme alkaline phosphatase, and hepatocytes contain transaminases. Irreversible injury and cell death in these tissues elevate the serum levels of these proteins, which makes them clinically useful markers of tissue damage.
What is coagulative necrosis?
- necrotic tissue that appears firm and pale as if cooked
- cellular outline and tissue architecture can be discerned histologically, nucleus disappears and increased eosinophilic cells that lasts for days or weeks. Cell shape and organ structure are preserved by coagulation of cellular proteins.
- Leukocytes are recruited to the site of necrosis, and the dead cells are ultimately digested by the action of lysosomal enzymes of the leukocytes. Cells have relatively few lysosmes to bring about complete breakdown of cellular proteins
- The cellular debris is then removed by phagocytosis mediated primarily by infiltrating neutrophils and macrophages.
- most common cause: occlusion of arterial supply to a tissue. Characteristic of ischemic infarction anywhere except the brain which dentaures enzymes and blocks proteolysis
- proteins liberated from the dead cell can enter the blood
- ex: MI
- Ex: area of infarcted tissue is often wedge shaped and pale(kidney). Main vessel with branching vessels and thrombus in the middle. Above occlusion is infarct
- Ex: Red infarction if blood reenters loosely organised tissue(red testicle- collapsed vein and blood reenters through a. but v. cannot take out the blood so blood builds up)
Describe acute myocardial infarction
(Coagulative necrosis)
- regional MI (90% of cases) involves one segment of ventricular wall
- Cause: thrombus formation on a complicated atheromatous plaque, if occulsion is complete then the infarct is full in thickness, if there is lysis of the thrombus or a collateral supply to the myocardium, the infarct will be limited to the subendocardial zone
- circumferential subendocardial infarction(10%) of cases involves the subendocardial zone of ventricle
- cause: hypoperfusion of the main coronary arteries (high grade atheresclerotic stenosis)
What are the 3 patterns of myocardial infarction?
- Regional Full thickness (complete persistent thrombotic occlusion, ex: full thickness of lateral wall of left v. is infarcted)
- regional subendocardial(flow reestablished after occlusion)
- circumferential subendocardial (severe reduction of lumen in main arteries, ex: the subendocardial zone around the whole circumference of left v. is infarcted and dark in color)
Describe appearances of myocardial infarction
- between 0-12 hours, an infarct is not microscopically visible, the ischemic muscle can be detected by showig a loss of oxidative enzymes(NBT)- the infarcted area appears uncolored
- between 12 and 24 hours, he infarcted area is microscopically pale, histologically infarcted muscle is brightly eosinophilic with intercellular edema
- between 24 and 72 hours, the infarcted area excites in actue inflammatory response(macro-soft and pale with a slight yellow color), histologically neutrophils infiltrate between dead cardiac muscle fibers
- between 3-10 days- organization in infarcted area (macro-hyperaemic border develops around the yellow dead muscle)- histologically - vascular granulation tissue
- after weeks or months the infarct is replaced by collagenous scar
Myocardial infarct - arteries
the coronary a. shown has narrowing of the lumen due to build up of atherosclerotic plaque. Severe narrowing can lead to angina, ischemia and infarction
Myocardial infarct- arteries
Distal portion of coronary a. shows significant narrowing. Such distal involement is typical of severe coronary atherosclerosis such as can appear with diabetes mellitus or famiial hypercholestorelemia. This makes coronary bypass operation difficult
Myocardial infarct
The left ventricular wall can have large MI. The center of the infarct contains necrotic muscle that appears yellow-tan. Surrounding this zone of red hyperemia. Remaining viable mycocardium is reddish brown
Myocardial infarct
Left ventricle of heart, extending from anterior portion and into septum is a large recent mycoardial infarction. The center is tan with surrounding hyperemia. The infarction is transmural because it extends through the full thickness of the wall
Myocardial infarct: histological
Earliest change seen in first day is contraction band necrosis. The mycoardial fibrils are beginnig to lose cross striations and the nuclei are not clear. Many irregular darker pink wavy contraction extending across the fibers
Mycardial infarct: histological
the myocardial fibers have dark red contraction bands extending across them. The myocardial cell nuclei have almost all disappeared. There is beginning of acute inflammation
Early myocardial infarction
- Acute inflammatory cell infiltrate and the myocardial fibers are so necrotic that the outlines of them are only barely visible.
- Dark red contraction bands.
- The myocardial cell nuclei have all disappeared.
Myocardial infarct
In recent MI, there is extensive hemorrhage along with myocardial fiber necrosis with contraction bands and loss of nuclei
Myocardial infarct
This myocardial infarction is 3-4 days old. There is extensive acute inflammatory cell infiltrate and myocardial fibers are so necrotic that the outlines are barely visible
Myocardial infarct
this is an intermediate MI of 1 to 2 weeks age. Remaining normal myocardial fibers at the top. Below these fibers are many macrophages along with numerous capillaries and little collagenization
Myocardial infarct
pale white collagen within intersititum between myocardial fibers. Represents an area of remote infarcion
Myocardial infarct
previous extensive transmural MI involving the free wall of LV. Thickness of mycoardial wall is normal superiorly but inferiorly is only a thin fibrous wall. Infarction was so extensive that after healing, the ventricular wall was replaced by thin band of collagen forming an aneurysm. Such an aneurysm represents non contractile tissue reduces SV and strains the remaining myocardium. The stasis of blood in aneursym pedisposes to mural thrombosis
Normal heart
External appearnce of a normal heart has smooth and glistening epicardial surface with normal epicardial fat. The left anterior descening coronary a. extends from apex root to apex.
Aortic valve has three thin cusps, the coronary orifices can just be seen above, the endocardium is smooth beneath which can be seen a red brown myocardium. The aorta above the valve has smooth intima with no atherosclerosis
What are complications of myocardial infarction?
- cardiac arrythmias 75-95% of complicated cases
- left ventricular congestive failure(60%)
- pulmonary edema(60%)
- cardiogenic shock(10-15%)
- rupture of free wall, septum or papillary m.(1-5%)
- thromboembolism
- aneursyms of the heart
- epicarditis
- death of a patient
- complication of transmural myocardial infarction is rupture of the myocardium which most likely occurs in teh 1st week, 3-5 days following the initial event, when the myocardium is the softest. The white arrow maks the point of rupture in the anterior inferior MI of left ventricular free wall and septum. Dark red blood clot forms the hemopericardium which can lead to tamponade.
- In the cross section the point of rupture is seen with the white arrow, in this case there was a previous MI 3 weeks before, and another myocardial infarction occurred rupturing through the thin ventricular wall 3 days later
- there can be mural thrombus over myocardial infarct
What is Caseous necrosis?
- soft fribale necrotic tissue with white resembling cream cheese(white cottage cheese like appearance)
- combination of coagulative and liquefactive necrosis
- characteristic of granulomatous inflammation due to TB or systemic fungal infection(histoplasma and capsulatrum) and nocardia
- gross appearance of caseous necrosis in hilar lymph node affected with tuberculosis, the node has chessy tan to white appearance
- more extensive caseous necrosis, with
confluent cheesy tan granulomas in the upper
portion of this lung in a patient with tuberculosis. - The tissue destruction is so extensive that there are
areas of cavitation (cystic spaces) being formed as the
necrotic (mainly liquefied) debris drains out via the
bronchi - occurs due to macrophages that wall of the infecting microorganism leading to granular debris
- Caseous necrosis involves fragmented cells and debris surround lymphocytes and macrophages(granulomas)
- dead cells form an amorphous proteinaceous mass but in contrast to coagulative necrosis, no original architecture can be seen histlgically
- On microscopic examination, the necrotic focus appears as a collection of fragmented or lysed cells with an amorphous granular pink appearance in H&Estained tissue sections.
Caseous necrosis
Note the pink, amorphous region in the center of this granuloma at the upper right, and ringed by epithelioid cells at the left and lower areas of this photomicrograph. This is the microscopic appearance of caseous necrosis.
What is fat necrosis?
- Fat necrosis is necrotic adipose tissue with chalky white appearance due to deposition of calcium(saponification).
- Saponification is due to fatty acids release ot lipase joining with Ca. Fat necrosis refers to focal areas of fat destruction, typically resulting from the release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavity.
- can be enzymatic or non enzymatic
- Enzymatic: acute pancreatitis due to saponification of peripancreatic fat. Damaged pancreatic cells release lipase which breaks down triglycerides, liberates fatty acids and bind calcium In this disorder, pancreatic enzymes that have leaked out of acinar cells and ducts liquefy the membranes of fat cells in the peritoneum, and lipases split the triglyceride esters contained within fat cells. The released fatty acids combine with calcium to produce grossly visible chalky white areas (fat saponification), which enable the surgeon and the pathologist to identify the lesions.
- Non enzymatic: trauma to breast fat due to car accident, or sports, giant cells with calcification
- On histologic examination, the foci of necrosis contain shadowy outlines of necrotic fat cells surrounded by basophilic calcium deposits and an inflammatory reaction.
Fat necrosis
What is acute pancreatitis?
What are predisposing factors for acute pancreatitis?
- In acute pancreatitis the pancreas appears oedematous and is commonly haemorrhagic
- Pancreatic tissue becomes necrotic and sometimes semi-liquid
- Lipase relased from the pancreatic acini causes the development of foci of fat necrosis (white spots in mesenteric and retroperitoneal fat) with adjacent retroperitoneal infllammation
- Predisposing factors of acute pancreatitis
- Mechanical obstruction of pancreatic ducts (gallstones, trauma, post-operative)
- Metabolic, toxic causes (alcohol, drugs, hypercalcemia, hyperlipoproteinaemia)
- Vascular- poor perfusion (atherosclerosis, hypothermia)
- Infections (mumps)
Fat Necrosis
Acute pancreatitis
Etiology
- Acute pancreatitis is a reversible inflammatory disorder that varies in severity, from focal edema and fat necrosis to widespread hemorrhagic necrosis.
- This is a relatively common condition, with an annual incidence of 10 to 20 per 100,000 people in the Western world.
- The most common cause of acute pancreatitis in the United States is the impaction of gallstones within the common bile duct, impeding the flow of pancreatic enzymes through the ampulla of Vater (“gallstone pancreatitis”); this is closely followed by pancreatitis secondary to excessive alcohol intake.
- Overall, gallstones and alcoholism account for greater than 80% of acute pancreatitis cases, with the remaining caused by a multitude of factors (Table 17.1). These include the following:
- Non–gallstone-related obstruction of the pancreatic ducts (e.g., due to pancreatic cancer or other periampullary neoplasms, pancreas divisum, biliary “sludge,” or parasites, particularly Ascaris lumbricoides and Clonorchis sinensis)
- Medications including anti-convulsants, cancer chemotherapeutic agents, thiazide diuretics, estrogens, and more than 85 others in clinical use
- Infections with mumps virus or coxsackievirus, which can directly infect pancreatic exocrine cells
- Metabolic disorders, including hypertriglyceridemia, hyperparathyroidism, and other hypercalcemic states
- Ischemia due to vascular thrombosis, embolism, vasculitis, or shock
- Trauma, both blunt force and iatrogenic during surgery or endoscopy
- Germline mutations involving genes encoding pancreatic enzymes or their inhibitors. For example, hereditary pancreatitis is a rare autosomal dominant disease with 80% penetrance that is characterized by recurrent attacks of severe pancreatitis, usually beginning in childhood. It is caused by mutations in the PRSS1 gene, which encodes trypsinogen, the proenzyme of pancreatic trypsin. The pathogenic mutations alter the site through which trypsin cleaves and inactivates itself, abrogating an important negative feedback mechanism. This defect leads not only to the hyperactivation of trypsin, but also to the hyperactivation of many other digestive enzymes that require trypsin cleavage for their activation. As a result of this unbridled protease activity, the pancreas is prone to autodigestion and injury. Loss-of-function mutations in genes that encode protease inhibitors such as SPINK1 are less commonly associated with hereditary pancreatitis
Fat Necrosis
Acute pancreatitis
Pathogenesis
- Acute pancreatitis appears to be caused by autodigestion of the pancreas by inappropriately activated pancreatic enzymes.
- Once activated trypsin is capable of converting other zymogen forms of pancreatic enzymes to their active forms.
- Premature activation of trypsin within the substance of the pancreas can unleash these proenzymes (e.g., phospholipases and elastases), leading to tissue injury and inflammation.
- Trypsin also converts prekallikrein to its activated form, thus sparking the kinin system, and, by activation of factor XII (Hageman factor), also sets in motion the clotting and complement systems
- Three pathways can incite the initial enzyme activation that may lead to acute pancreatitis:
- Pancreatic duct obstruction. Impaction of a gallstone or biliary sludge, or extrinsic compression of the ductal system by a mass blocks ductal flow, increases intraductal pressure, and allows accumulation of an enzymerich interstitial fluid. Since lipase is secreted in an active form, local fat necrosis may result. Injured tissues, periacinar myofibroblasts, and leukocytes then release proinflammatory cytokines that promote local inflammation and interstitial edema through a leaky microvasculature. Edema further compromises local blood flow, causing vascular insufficiency and ischemic injury to acinar cells.
- Primary acinar cell injury. This pathogenic mechanism comes into play in acute pancreatitis caused by ischemia, viral infections (e.g., mumps), drugs, and direct trauma to the pancreas.
- Defective intracellular transport of proenzymes within acinar cells. In normal acinar cells, digestive enzymes intended for zymogen granules (and eventually extracellular release) and hydrolytic enzymes destined for lysosomes are transported in discrete pathways after synthesis in the endoplasmic reticulum. However, at least in some animal models of metabolic injury, pancreatic proenzymes and lysosomal hydrolases become packaged together. This results in proenzyme activation, lysosomal rupture (action of phospholipases), and local release of activated enzymes. The role of this mechanism in human acute pancreatitis is not clear.
- Alcohol consumption may cause pancreatitis by several mechanisms. Alcohol transiently increases pancreatic exocrine secretion and contraction of the sphincter of Oddi (the muscle regulating the flow of pancreatic juice through papilla of Vater). Alcohol also has direct toxic effects on acinar cells, including induction of oxidative stress in acinar cells, which leads to membrane damage (discussed later). Finally, chronic alcohol ingestion results in the secretion of protein-rich pancreatic fluid, which leads to the deposition of inspissated protein plugs and obstruction of small pancreatic ducts.
Clinical features of acute pancreatitis
- Abdominal pain is the cardinal manifestation of acute pancreatitis. Its severity varies from mild and uncomfortable to severe and incapacitating. Acute pancreatitis is diagnosed primarily by the presence of elevated plasma levels of amylase and lipase and the exclusion of other causes of abdominal pain. In 80% of cases, acute pancreatitis is mild and self-limiting; the remaining 20% develop severe disease.
- Full-blown acute pancreatitis is a medical emergency of the first order. Affected individuals usually experience the sudden calamitous onset of an “acute abdomen” with pain, guarding, and the ominous absence of bowel sounds. Characteristically, the pain is constant, intense and referred to the upper back, steatorrhea(oily smelly stools), weight loss; it must be differentiated from pain of other causes such as perforated peptic ulcer, biliary colic, acute cholecystitis with rupture, and occlusion of mesenteric vessels with infarction of the bowel.
- The manifestations of severe acute pancreatitis are attributable to systemic release of digestive enzymes and explosive activation of the inflammatory response. The initial clinical evaluation may reveal leukocytosis, disseminated intravascular coagulation, acute respiratory distress syndrome (due to diffuse alveolar damage) , and diffuse fat necrosis. Peripheral vascular collapse (shock) can rapidly ensue as a result of increased microvascular permeability and resultant hypovolemia, compounded by endotoxemia (from breakdown of the barriers between gastrointestinal flora and the bloodstream), and renal failure due to acute tubular necrosis. Laboratory findings include markedly elevated serum amylase during the first 24 hours, followed (within 72–96 hours) by rising serum lipase levels. Hypocalcemia can result from precipitation of calcium in areas of fat necrosis; if persistent, it is a poor prognostic sign. The enlarged inflamed pancreas can be visualized by computed tomography (CT) or magnetic resonance imaging (MRI). The crux of the management of acute pancreatitis is supportive therapy (e.g., maintaining blood pressure and alleviating pain) and “resting” the pancreas by total restriction of oral food and fluids. In 40% to 60% of cases of acute necrotizing pancreatitis, the necrotic debris becomes infected, usually by gram-negative organisms from the alimentary tract, further complicating the clinical course. Although most individuals with acute pancreatitis eventually recover, some 5% die from shock during the first week of illness; acute respiratory distress syndrome and acute renal failure are ominous complications. In surviving patients, sequelae include sterile or infected pancreatic “abscesses” or pancreatic pseudocysts.
- Pancreatic Pseudocysts
- A common sequela of acute pancreatitis (and in particular, alcoholic pancreatitis) is a pancreatic pseudocyst. Liquefied areas of necrotic pancreatic tissue become walled off by fibrous tissue to form a cystic space, lacking an epithelial lining (hence the designation pseudo). The cyst contents are rich in pancreatic enzymes, and a laboratory assessment of the cyst aspirate can be diagnostic. Pseudocysts account for approximately 75% of all pancreatic cysts. While many pseudocysts spontaneously resolve, they can become secondarily infected, and larger pseudocysts can compress or even perforate into adjacent structures
Fat necrosis
This is fat necrosis of the pancreas. Cellular injury to the pancreatic acini leads to release of powerful enzymes which damage fat by the production of soaps, and these appear grossly as the soft, chalky white areas seen here on the cut surfaces.
Fat necrosis
Microscopically, fat necrosis adjacent to pancreas is seen here. There are some remaining steatocytes at the left which are not necrotic. The necrotic fat cells at the right have vague cellular outlines, have lost their peripheral nuclei, and their cytoplasm has become a pink amorphous mass of necrotic material.
Fat necrosis
Morphology of acute pancreatits
What are basic alterations of acute pancreatitis?
- The basic alterations in acute pancreatitis are (1) microvascular leakage causing edema, (2) necrosis of fat by lipases, (3) an acute inflammatory reaction, (4) proteolytic destruction of pancreatic parenchyma, and (5) destruction of blood vessels leading to interstitial hemorrhage.
- In mild forms, there is interstitial edema and focal areas of fat necrosis in the pancreas and peripancreatic fat (Fig. 17.2A). Fat necrosis results from enzymatic destruction of fat cells; the released fatty acids combine with calcium to form insoluble salts that precipitate in situ.
- In more severe forms, such as acute necrotizing pancreatitis, the damage also involves acinar and ductal cells, the islets of Langerhans, and blood vessels. Macroscopically, the pancreas exhibits red-black hemorrhagic areas interspersed with foci of yellow-white, chalky fat necrosis (Fig. 17.2B). Fat necrosis also can occurin extrapancreatic fat,including the omentum and bowel mesentery, and even outside the abdominal cavity (e.g., in subcutaneous fat). In most cases, the peritoneum contains a serous, slightly turbid,brown-tinged fluid with globules of fat(derived from enzymatically digested adipose tissue). In the most severe form, hemorrhagic pancreatitis, extensive parenchymal necrosis is accompanied by diffuse hemorrhage within the substance of the gland
Balser’s fatty necrosis
Foci of hard, yellow material seen in dead adipose tissue. The
reaction can occur after liberation of pancreatic enzymes into
the peritoneal cavity, following inflammation of the pancreas.
It may also be seen after trauma to fat, for example in the
breast.
Necrosis of the brain
This intermediate infarct of the frontal lobe shows
liquefactive necrosis with formation of cystic
spaces as resolution begins.
Necrosis of the brain
The neurons are the most sensitive cells to anoxic injury. Seen
here are red neurons which are dying as a result of hypoxia.
Necrosis of the brain
Resolution of the liquefactive necrosis in a cerebral infarction
leads to the formation of a cystic space.
Necrosis of the brain
Here is a large remote cerebral infarction. Resolution of the
infarction has left a huge cystic space encompassing much of
the cerebral hemisphere in this neonate.
Necrosis of the brain
The subacute (intermediate) infarct seen here at the right shows
edema with obscured structural outlines and swelling that shifts
the midline to the left. There is liquefactive necrosis with
beginning formation of cystic spaces.
Necrosis of the brain
This cerebral infarction demonstrates the presence of many
macrophages at the right which are cleaning up the lipid debris
from the liquefactive necrosis.
Encephalomalacia
- macrophages are cleaning up the lipid debris from the liquefactive necrosis
Cessation of blood flow flow chart
Uterine hypertrophy
Uterine hypertrophy is stimulated by estrogenic hormones acting on smooth muscle through estrogen receptors, eventually resulting in increased synthesis of smooth muscle proteins and an increase in cell size.
Myocardial hypertrophy
- Pressure overloaded ventricles develope concentric hypertrophy of the left ventricle, with an increased wall thickness and reduced cavity diameter
- Volume overloaded ventricles develope hypertrophy accompained by dilation with increased ventricular diameter
- Heart with both hypertrophy and dilation has occured may have increased, decreased or normal wall thickness (wall thickness not necessarily correlate with pathologic state)
- Cardiac hypertrophy constituites a tenuous balance
between adaptive characteristics (including new
sarcomers) and potentially biochemical and molecular
alterations (decrease capillary –to –myocyte ratio,
synthesis abnormal proteins) - Sustained cardiac hypertrophy often leads to cardiac
failure - Heart weigh usually ranges to 600 g, in pulmonary
hypertension to 800g, in systemic hypertension to 1000g
(sometimes more than 1000g) - Increased myocyte size is usually acompained by decrese
capillary density, increased capillary distance, and
deposition of fibrous tissue(decrease capillary –to
–myocyte ratio, synthesis abnormal proteins) - The molecular and cellular changes in hypertrophied heart ( synthesis of abnormal, dysfunctional proteins) may
contribute to development of heart failure - Loss of myocytes because of apoptosis may contribute to
progressive myocardial disfunction
Myocardial Hypertrophy
This left ventricle is very thickened (slightly over 2 cm in
thickness), but the rest of the heart is not
greatly enlarged. This is typical for
hypertensive heart disease. The hypertension creates a greater pressure load on the heart to induce the hypertrophy.
Myocardial Hypertrophy
The left ventricle is markedly thickened in this patient with
severe hypertension that was untreated for many years. The
myocardial fibers have undergone hypertrophy.
What is brown atrophy?
- In many tissues that have undergone cellular atrophy, a brown pigment called lipofuscin accumulates in a shrunken cells
- This pigment composed of a degenerate lipid material in secondary lysosomes is produced by breakdown of the cell membranes and organels through autophagy
- Lipofuscin in the atrophic myocardial fibres of eldery people, giving rise to macroscopically evident brown coloration of the myocardium- BROWN ATROPHY
- What is Lipofuscin?
The yellow-brown granular pigment seen in the hepatocytes is lipochrome (lipofuscin) which accumulates over time in cells (particularly liver and heart) as a result of “wear and tear” with aging. It is of no major consequence, but illustrates the end result of the process of autophagocytosis in which intracellular debris is sequestered and turned into these residual bodies of lipochrome within the cell cytoplasm.
- Lipofuscin, or “wear-and-tear pigment,” is an insoluble brownish-yellow granular intracellular material that accumulates in a variety of tissues (particularly the heart, liver, and brain) with aging or atrophy. Lipofuscin represents complexes of lipid and protein that are produced by the free radical–catalyzed peroxidation of polyunsaturated lipids of subcellular membranes. It is not injurious to the cell but is a marker of past free radical injury. The brown pigment (Fig. 2.25), when present in large amounts, imparts an appearance to the tissue that is called brown atrophy.
Testicular atrophy
The testis at the right has undergone atrophy and is much smaller
than the normal testis at the left.
Cerebral atrophy
Cerebral atrophy in a patient with Alzheimer disease. The gyri
are narrowed and the intervening sulci widened, particularly
pronounced toward the frontal lobe region
What is endometrial atrophy?
On the left: thick endometrium composed of proliferative glands in an abundant stroma. On the right: the endometrium of a 75-year-old woman is thin and contains only a few atrophic and cystic glands.
What is muscle atrophy?
Some of these skeletal muscle fibers show atrophy, compared to normal fibers. The number of cells is the same as before the atrophy occurred, but the size of some fibers is reduced. This is a response to injury by “downsizing” to conserve the cell. In this case, innervation to the small, atrophic fibers was lost. A trichrome stain.
What is Metaplasia?
- Metaplasia is a change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. In this type of cellular adaptation, a cell type sensitive to a particular stress is replaced by another cell type better able to withstand the adverse environment. Metaplasia is thought to arise by the reprogramming of stem cellsto differentiate along a new pathway rather than a phenotypic change (transdifferentiation) of already differentiated cells.
- Usually induced by altered differentiation pathway of tissue stem cells (it is not result from a change in the phenotype of an already differentiated cell type);
- Metaplasia of laryngeal respiratory epithelium has occurred in a smoker. The chronic irritation has led to an exchanging of one type of epithelium (the normal respiratory epithelium) for another (the more resilient squamous epithelium).
- Metaplasia is not a normal physiologic process and may be the first step toward neoplasia.
Types of metaplasia
Esophageal metaplasia(image)
- Epithelial metaplasia is exemplified by the change that occurs in the respiratory epithelium of habitual cigarette smokers, in whom the normal ciliated columnar epithelial cells of the trachea and bronchi often are replaced by stratified squamous epithelial cells
- The rugged stratified squamous epithelium may be able to survive the noxious chemicals in cigarette smoke that the more fragile specialized epithelium would not tolerate.
- Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance of particulate matter.
- Because vitamin A(keratomalasia)is essential for normal epithelial differentiation, its deficiency also may induce squamous metaplasia in the respiratory epithelium.
- Metaplasia need not always occur in the direction of columnar to squamous epithelium; in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium(Barretts esophagus can lead to adenocarcinoma if dysplasia occurs, GERD is reversible).
- Metaplasia also may occur in mesenchymal cells, but in these situations it is generally a reaction to some pathologic alteration and not an adaptive response to stress. For example, bone is occasionally formed in soft tissues, particularly in foci of injury(myositis ossifcans). The influences that induce metaplastic change in an epithelium, if persistent, may predispose to malignant transformation.
- In fact, squamous metaplasia of the respiratory epithelium often coexists with lung cancers composed of malignant squamous cells. It is thought that cigarette smoking initially causes squamous metaplasia, and cancers arise later in some of these altered foci.
Sublethal and reversible structural abnormalities
Hydrophic degeneration
At the light microscopic the reversible changes caused by organelle swelling are reflected in cellular swelling, paleness of the cell cytoplasm, and development of the small intracellular vacuoles
Sublethal and reversible structural abnormalities
- Another manifestation of sublethal cell damage is impairment of fatty acid metabolism, affected cells acumulate lipid with cytoplasmic vacuoles, giving rise to term FATTY CHANGE.
- This is seen particulary in cells that have central roles in fatty acid metabolism (i.e. hepatocytes, sometimes in myocardium and kidney)
What is fatty change
- Fatty change, also called steatosis, refers to any accumulation of triglycerides within parenchymal cells. It is most often seen in the liver, since this is the major organ involved in fat metabolism, but also may occur in heart, skeletal muscle, kidney, and other organs. Steatosis may be caused by toxins, protein malnutrition, diabetes mellitus, obesity, or anoxia. Alcohol abuse and diabetes associated with obesity are the most common causes of fatty change in the liver (fatty liver) in industrialized nations
- The lipid vacuoles within hepatocytes. The lipid accumulates when lipoprotein transport is disrupted and/or when fatty acids accumulate(image).
Fatty change in liver
This liver is slightly enlarged and has a pale yellow appearance,
seen both on the capsule and cut surface.
Fatty change
The lipid accumulates in the hepatocytes as vacuoles. These
vacuoles have a clear appearance with H&E staining. The most
common cause of fatty change in developed nations is alcoholism.
In developing nations, kwashiorkor in children.
What is hemosiderin?
- Iron is normally caried by specific transport proteins (transferrins); in cells it is stored with association with a protein (apoferritin) to form a ferritin micelles;
- When is a local or systemic excess of iron, ferritin formes hemosiderin granules
- Hemosiderin is a hemoglobin- derived, yelow to brown granular or crystaline pigment
- This pigment is lying within the cells cytoplasm and is easily seen with a light microscope
- Hemosiderin is a hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of iron. Iron is normally stored within cells in association with the protein apoferritin, forming ferritin micelles. Hemosiderin pigment represents large aggregates of these ferritin micelles, readily visualized by light and electron microscopy; the iron can be unambiguously identified by the Prussian blue histochemical reaction. Although hemosiderin accumulation is usually pathologic, small amounts of this pigment are normal in the mononuclear phagocytes of the bone marrow, spleen, and liver, where aging red cells are normally degraded. Excessive deposition of hemosiderin, called hemosiderosis, and more extensive accumulations of iron seen in hereditary hemochromatosis
- Overload of iron could be systemic or local
Hemosiderosis
Hemosiderosis
These renal tubules contain large amounts of hemosiderin, as
demonstrated by the Prussian blue iron stain. This patient had
chronic hematuria.
What is hemochromatosis?
- The dark brown color of the liver, as well as the pancreas and lymph nodes is due to extensive iron deposition in a middle-aged man with hereditary hemochromatosis (HHC). HHC results from a mutation involving the hemochromatosis gene (HFE) that leads to increased iron absorption from the gut. The prevalence is between 1:200 and 1:500 persons in the U.S.
- The Prussian blue iron stain reveals extensive hepatic hemosiderin deposition microscopically in case of
hereditary hemochromatosis (HH). There is also cirrhosis. Excessive iron deposition in persons with HH can
affect many organs, but heart (congestive failure), pancreas (diabetes mellitus), liver (cirrhosis and hepatic failure), and joints (arthritis) are the most severely affected.
Clinical features of hemochromatosis
- Symptoms usually appear earlier in men than in women since menstrual bleeding limits the accumulation of iron until menopause.
- This results in a male-to-female ratio of clinically significant iron overload of approximately 5 :1 to 7:1. In the most common form caused by HFE mutations, symptoms usually appear in the fifth and sixth decades of life in men and later in women.
- With population screening, it has become clear that homozygosity for the most common HFE mutation (C282Y) shows variable penetrance; thus disease development is not inevitable, presumably because other genetic and environmental factors influence the rate of iron accumulation.
- The principal manifestations include hepatomegaly, abdominal pain, skin pigmentation (particularly in sunexposed areas), deranged glucose homeostasis or frank diabetes mellitus due to destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis.
- In some patients, the presenting complaint is hypogonadism (e.g., amenorrhea in the female, impotence and loss of libido in the male). As noted, clinically apparent disease is more common in males and rarely becomes evident before 40 years of age.
- Death may result from cirrhosis or cardiac disease. In those with untreated disease, the risk for HCC is increased 200-fold, presumably because of ongoing liver damage and the genotoxic effects of oxidants generated by iron in the liver.
- Fortunately, hemochromatosis can be diagnosed long before irreversible tissue damage has occurred. Screening of family members of probands is important. Heterozygotes also accumulate excessive iron, but not to a level that causes significant tissue damage.
- Currently most patients with hemochromatosis are diagnosed in the subclinical, precirrhotic stage due to routine serum iron measurements (as part of another diagnostic workup).
- Regular phlebotomy results in steady removal of excess tissue iron, and with this simple treatment life expectancy is normal.
What is dystrophic calcification?
- Formation of crystalline calcium phosphate mineral; the process has two phases: initiation and propagation
- It occurs in changed, injured cells
- Intracellular initiation- occurs in mitochondria of dead or dying cells
- Extracellular initiation- include phospholipids found in membrane- bound vesicles which are derived from degenerating or ageing cells
- Propagation of crystal formation depends of the concentration of Ca +2 and PO 4 and the presence of inhibitors
- Is encountered in areas of necrosis, whether they are of
coagulative, caseous or liquefactive type and in foci of
enzymatic necrosis of fat. - Occurs in atheromas of advanced atherosclerosis
- Developes in ageing or damaged heart valves
- Macroscopically- white granules or clumps, offten felt as
gritty deposites. - Sometimes –tuberculous lymph node is virtually converted to stone
- This is dystrophic calcification in the wall of the stomach. At the far left is an artery with calcification in its wall. There are also irregular bluish-purple deposits of calcium in the submucosa.
What is metastatic calcification?
“metastatic calcification” in the lung of a patient with a very high
serum calcium level (hypercalcemia).
- Metastatic calcification- may occur in normal tissue whenever there is hypercalcemia
- Increased secretion of parathyroid hormone (parathyroid tumors or ectopic secretion of PTH)
- Destruction of bone tissue (primary tumors or metastasis, immobilization)
- Vitamine D related disorders
- Renal failure (retention of phosphate leading to secondary hyperparathyroidism)
- Mainly affects the interstitial tissues of the gastric mucosa,
kidneys, lungs, systemic arteries, pulmonary veins - All of these tissues loss acid and therefore have an internal alkaline compartment that predisposes them to metastatic calcification
- Morphologicaly- noncrystalline amorphous deposites or
hydroxyapatite crystals
Pneumoconiosis
The black streaks seen between lobules of lung beneath the pleural surface are due to accumulation of anthracotic pigment. This anthracosis of the lung is not harmful and comes from the
carbonaceous material breathed in from dirty air typical of
industrialized regions of the planet. Persons who smoke would have even more of this pigment.
Pneumoconiosis
Anthracotic pigment in macrophages in a hilar lymph node.
Pathogenesis
The reaction of the lung to mineral dusts depends on many variables, including the size, shape, solubility, and reactivity of the particles. For example, particles greater than 5 to 10 µm are unlikely to reach distal airways, whereas particles smaller than 0.5 µm move into and out of alveoli, often without substantial deposition and injury. Particles that are 1 to 5 µm in diameter are the most dangerous, because they get lodged at the bifurcation of the distal airways. Coal dust is relatively inert, and large amounts must be deposited in the lungs before lung disease is clinically detectable. Silica, asbestos, and beryllium are more reactive than coal dust, resulting in fibrotic reactions at lower concentrations. Most inhaled dust is entrapped in the mucus blanket and rapidly removed from the lung by ciliary movement. However, some of the particles become impacted at alveolar duct bifurcations, where macrophages accumulate and engulf the trapped particulates. The pulmonary alveolar macrophage is a key cellular element in the initiation and perpetuation of inflammation, lung injury and fibrosis. Following phagocytosis by macrophages, many particles activate the inflammasome and induce production of the pro-inflammatory cytokine IL-1 as well as the release of other factors, which initiates an inflammatory response that leads to fibroblast proliferation and collagen deposition. Some of the inhaled particles may reach the lymphatics either by direct drainage or within migrating macrophages and thereby initiate an immune response to components of the particulates and/ or to self-proteins that are modified by the particles. This then leads to an amplification and extension of the local reaction. Tobacco smoking worsens the effects of all inhaled mineral dusts, more so with asbestos than other particles.
Pneumoconiosis
Anthracotic pigment ordinarily is not fibrogenic, but in massive
amounts (as in “black lung disease” in coal miners) a fibrogenic
response can be elicited to produce the “coal worker’s
pneumoconiosis” seen here.
Pneumoconiosis
- By polarized light microscopy can be seen the etiology for most pneumoconioses (even those in coal miners)–silica crystals.
- Bright white crystals of varying sizes. The silica induces a fibrogenic response by macrophages to produce the nodular foci of collagen deposition.
What is silicosis?
(histologically)
- Silicotic nodule is composed mainly of bundles of interlacing pink collagen(second image). There is a minimal inflammatory reaction.
- The greater the degree of exposure to silica and increasing length of exposure determine the amount of silicotic nodule formation and the degree of restrictive lung disease.
- Silicosis increases the risk for lung carcinoma about 2-fold.
- Anthracosilicosis(1st image)
What is asbestosis?
(Histologically)
- The asbestos fiber becomes coated with iron and calcium, which is why it is often referred to as a “ferruginous body” -iron stain. Ingestion of these fibers by macrophages sets off a fibrogenic response via release of growth factors that promote collagen deposition by fibroblasts.
- Another gross lesion typical for pneumoconioses, and asbestosis in particular, is a fibrous pleural plaque. Seen here on the pleural side of the diaphragmatic leaves are several tan-white pleural plaques.
Asbestosis
(Histologically)
Microscopically, the fibrous pleural plaque is composed of
dense layers of collagen.
