Cell/Tissue Injury & Chemical Mediators Flashcards Preview

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Flashcards in Cell/Tissue Injury & Chemical Mediators Deck (41)
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What are the major causes (etiologies) of cell injury?

Exposure to injurious agents, including: Physical agents - trauma, heat,Chemical and drugs - drug toxicity, poisoning,Infection - pathogenic bacteria, virus, fungi, protozoa, etc.Immunologic insults - anaphylaxis, autoimmunity, etc.Genetic derangement-phenylketonuria, cystic fibrosis, etc.Nutritional imbalance - atherosclerosis, protein and vitamin deficiency, etc.Hypoxia - cells receive too little 02. Multiple causes - primary lung disease, heart failure, shock, arterial or venous thrombosis, etc.


Understand how cell injury contributes to the pathogenesis of disease.

Every human disease results from injury or death of the fundamental unit of the body, the cell. The term “injury” refers to non-lethal, physical damage or alteration from normal of one or more components of the structure of the cell. The damage invariably perturbs normal physiology. The injured cell can not function at full capacity—metabolize nutrients, synthesize needed products, and illness results. Injury can occur “acutely”-producing effects in cells within seconds or minutes, or “chronically”-resulting in cell stress and damage that can persist days, months, or even years. Although any cell and tissue in the body can be injured, most human disease occurs from injury to epithelium.


Be able to describe major mechanisms of cell injury.

The epithelium is the tissue that first encounters injurious agents and stimuli from the environment, and it is not surprising that many important human diseases occur from epithelial injury-the major killer of adults, atherosclerosis occurs from injury to the epithelial cells (the so-called endothelium) that line arteries and >90% of all adult cancers, as another example, arise from epithelia).On the other hand, there are some very important human diseases that occur from injury to other tissue types-arthritis, leukemia/lymphoma, AIDS, lupus, etc. Injury to one tissue invariably affects the other types of tissue that are adjacent. For example, destruction of the stomach epithelium by helicobacter pylori infection (i.e., ulceration of the stomach lining), often leads to damage of the underlying connective tissue of the submucosa and smooth muscle of the muscularis propria, with intense inflammation, destruction of cells and scarring.


How can the study of morphologic change caused by cell injury explain the whys and wherefores of signs and symptoms of disease?

While cell and tissue injury leads to 1) disease symptoms (complaints voiced by the patient), and 2) disease signs (abnormal findings observed by the physician), it almost always produces a characteristic change in the appearance of the affected tissue that can be seen “grossly” (i.e. visibly by the naked eye) and/or microscopically. It is the identification of this “morphologic” change in the affected tissue that allows the pathologist to diagnose the disease process.In summary, the study of the morphologic and macromolecular change induced by injury allows the pathologist to classify and diagnose disease, and to study pathogenesis.


What are free radicals, how do they arise, and how do they produce cell injury?

A free radical is a species with an unpaired electron. Often, high levels of O2 therapy are needed to keep the patient alive. However, this causes O2 radicals to be created. Additionally, PMNs and reperfusion have enzymes that lead to the formation of free radicals. These free radicals can chemically damage proteins, DNA, RNA and trigger lipid peroxidation in cell membranes. Free radicals are generated by intrinsic oxidases (present in the ER of all cells and in PMNs) and radiation especially in the setting of high p02.


Understand how ischemia/hypoxia creates a setting where free radical damage becomes an important cause of cell injury.

Free radicals follow O2 therapy.


What are examples of free radicals and how does the body get rid of them.

O2- (superoxide) and OHe are important free radical species in the body. Fortunately, antioxidants (uric acid, vitamin E, etc.) catalase, and glutathione peroxidase serve to eliminate these radicals.


Understand how necrosis differs from apoptosis.

Classic cell/tissue necrosis. This is the type of cell death usually seen following ischemia. Ischemia is hypoxic injury (meaning injury from too little oxygen) caused by a problem with the vascular blood flow to the tissue.Typically in ischemic necrosis, large portions of tissue, containing thousands of contiguous cells, die all at once. In this “classic” type of cell necrosis, the cytoplasm of the dead cell is swollen, the mitochondria and ER appear dilated, there is prominent blebbing of the plasma membrane, and loss of membrane integrity. This type of cell necrosis occurs from ischemia/anoxia and from exposure to toxins/chemicals.There is a second type of cell death-apoptosis or programmed cell death. Apoptosis, unlike necrosis, tends to affect scattered, individual cells rather than a large area of tissue. In contrast to classic cell necrosis, apoptosis is highly regulated, switched on by the binding of extracellular ligands to specific cell surface receptors (eg Fas ligand and its receptor). In the apoptotic type of dead cell, the cytoplasm is not swollen but shrunken, there are large plasma membrane blebs, and the nuclear DNA appear uniformly compacted and very dense. Eventually, the cell breaks up into small membrane bound vesicles. These are taken up by macrophages.


Understand how chronic injury leads to adaptation.

Hypertrophy - an increase in the size of the cell secondary to an increase in cell function. There is typically an increase in the number of mitochondria and ER, etc. Example: enlargement (hypertrophy) of the left ventricle secondary to severe, longstanding hypertension. With hypertension, each myocyte works harder and this causes the cell to produce more organelles.Atrophy - decrease in the size and functional capacity of the cell. Example: shrinkage (atrophy) of skeletal muscles following motor neuron loss from infection by poliovirus.Metaplasia - replacement of one type of tissue with another in response to an injury. Example: chronic reflux esophagitis leads to replacement of the stratified squamous epithelium along the distal esophagus by a columnar type of intestinal epithelium. Or replacement of the pseudostratified columnar epithelium of the bronchus by stratified squamous epithelium in response to thermal injury from tobacco smoke.Hyperplasia - an increase in the number of cells of a tissue in response to a stimulus or injury. Example: increase in the number of adrenal cortical cells secondary to a tumor that produces an ACTH- like polypeptide.


Be able to describe the major alterations in the cell membrane, mitochondrion and nucleus that occur during cell injury.

Cell membranes. The cell membrane is perhaps the most important target for both reversible and irreversible injury. The outer cell membrane because it surrounds the cell and directly interacts with the environment is usually the first cellular component to be damaged. In addition, the lipid within the membrane is easily oxidized and supports an oxidative chain reaction called lipid peroxidation. Damage to the membrane may physically break the membrane or inactivate the ion pumps that control the ionic concentrations in the cytoplasm. It is therefore not surprising that cell swelling is a morphologic change commonly seen in nearly all types of injury.Mitochondria. Mitochondrial swelling, due to the accumulation of H20 in the matrix compartment, is a morphologic change that occurs very soon after many types of cell injury, especially in those cases where the supply of oxygen to the cell is interrupted. This swelling results from a decrease in the 02- dependent synthesis of ATP required to fuel the ion pumps of the mitochondrial membrane.Nucleus. In most types of reversible injury, there are alterations in the appearance of the nucleolus. These changes are not well characterized but there is probably some effect on the synthesis of rRNAs, again causing a decrease in protein synthesis.All 3 of these are reversible if the bad stimulus is removed


Understand the four major types of necrosis seen in human disease.

Coagulative necrosis - dead cell remains a ghost-like remnant of its former self. Classically seen in the heart following a myocardial infarction (infarction" means "necrosis" secondary to vascular insufficiency). Liquefactive necrosis - dead cell dissolves away as lysosomal hydrolases digest cellular components. Commonly seen in the brain and spleen and with acute infection.Caseous necrosis - seen only in tuberculosis. The central portion of an infected lymph node is necrotic (attributed to toxic affects of mycobacteria) and has a chalky white appearance not unlike the milk protein casein.Fat necrosis - refers to necrotic adipose tissue typically following acute pancreatitis or trauma. In fat necrosis fats are hydrolyzed into free fatty acids which precipitate with Ca++ producing a peculiar chalky gray material characteristic of "fat necrosis"."


Know which morphologic and biochemical alterations during hypoxic injury are reversible and which are irreversible.

Hypoxia leads to ischemic injury, probably the single must important type of injury seen in clinical medicine. Different cells vary in the ability to tolerate hypoxia. Neurons can tolerate only 3 to 5 minutes of hypoxia while fat cells and skeletal muscle cells survive many hours.Reversible changes: 1) ↓ ATP 2) ↓ Na pump (cell swelling) 3) ↑ glycolysis, ↓ pH 4) ↓ protein synthesisIrreversible changes: 1) activation of lysosomal enzymes 2) DNA, protein degradation 3) ↑ Ca 2+ influx


Name examples of etiologic processes (neoplastic and non-neoplastic) that incite an inflammatory response.

Neoplastic: primary, hematopoeitic, metastaticNon-neoplastic: bugs, dead tissue, foreign materials, immune complexes


Discuss the role that inflammatory mediators play in cell-to-cell communication.

Inflammatory cells lack junctions and synapses. Cell-to cell communication mechanism includes near-range (autocrine, paracrine) and distant range (endocrine-like) signals. These are predominantly receptor-mediated.


Cell derived mediators:HistamineClass, Action(s)

Pre-formed, vasoactive amineVasodilation, Increase vascular permeability, constriction of bronchial smooth muscle, chemotaxis of WBCs


Cell derived mediators:SeratoninClass, Action(s)

Pre-formed, vasoactive amineIncreases vascular permeability


Cell derived mediators:ProstaglandinsClass, Action(s)

Eicosanoid (lipid)Vasodilation (PG12), Platelet activation and clotting (+/-), bronchial smooth muscle constriction, fever, pain (PGE2, PG12)


Cell derived mediators:Leukotrienes (LT, C4, D4, E4)Class, Action(s)

Eicosanoid (lipid)Increase vasc perm, constrict bronchial smooth muscle, vasoconstriction


Cell derived mediators:Leukotrienes B4 (LTB4)Class, Action(s)

Eicosamoid lipidWBC chemotaxis 


Cell derived mediators:Thromboxanes (TXA2)Class, Action(s)

Eicosanid lipidVasoconstriction, platelet aggregation and clotting


Cell derived mediators:Platelet Activating Factor (PAF)Class, Action(s)

LipidVasoconstricts, WBC Chemotaxis, Platelet aggregation and clotting, bronchial smooth muscle contractionLow []: vasodilates, inc vasc perm


Cell derived mediators:Reactive Oxygen SpeciesClass,Action(s)

O2 basedTissue and microbe damage


Cell derived mediators:Nitric Oxide (NO)Class, Action(s)

Made of Nitrogen and Oxygen (snap!)Vasodilation, WBC chemotaxis/activation (+/-), bronchial smooth muscle relaxations, tissue and microbe damage


Cell derived mediators:Tumor Necrosis Factor (TNF)Class, Action(s)

CytokineWBC recruitment, fever 


Cell derived mediators:Interleukins (IL-1,6)Class, Action(s)

CytokineWBC recruitment, fever


Cell derived mediators:ChemokinesClass, Action(s)

CytokinesWBC recruitment


Cell derived mediators:Cytoplasmic granule contentClass, Action(s)

Pre-formed enzymesWBC chemotaxis, Tissue and microbe damage


Cell derived mediators:Substance PClass, Action(s)

NeuropeptideMade in nerve fibersPain, inc vasc perm


Plasma derived mediators:C3a, C5aClassActions

Complement cascadeMast cell stimulation, increases vascular permeability, WBC chemotaxis, MAC complex formed to damage tissue and microbesmade in liver 


Plasma derived mediators: BradykininClassActions

KininsVasodilation, increase vasc perm, contract SM airways, painMade in liver