CAUSES OF CELL INJURY

The causes of cell injury range from the gross physical trauma of a motor vehicle accident to the single gene defect that results in a nonfunctional enzyme underlying a specific metabolic disease. Most injurious stimuli can be grouped into the following categories.
1.Oxygen Deprivation丧失
2.Chemical Agents
3.Infectious Agents
4.Immunologic Reactions
5.Genetic Factors
6.Nutritional Imbalances
7.Physical Agents
8.Aging

1. Oxygen Deprivation丧失
• Hypoxia, or oxygen deficiency, interferes with aerobic有氧的oxidative respiration and is an extremely important and common cause of cell injury and death.
• Hypoxia should be distinguished from ischemia, which is a loss of blood supply in a tissue due to impeded arterial flow or reduced venous drainage.
• Oxygen deficiency can also result from inadequate oxygenation of the blood, as in pneumonia, or from reduction in the oxygen-carrying capacity of the blood, as in blood loss anemia or carbon monoxide (CO) poisoning. (CO forms a stable complex with hemoglobin that prevents oxygen binding.)

2. Chemical Agents
• An increasing number of chemical substances that can injure cells, even innocuous 无害的substances such as glucose, salt, or even water, if absorbed or administered in excess, can so derange打乱the osmotic environment that cell injury or death results.
• Agents commonly known as poisons cause severe damage at the cellular level by altering membrane permeability, osmotic homeostasis, or the integrity of an enzyme, and exposure to such poisons can culminate达到极点in the death of the whole organism.
• Other potentially toxic agents are encountered daily in the environment; these include air pollutants, insecticides, CO, asbestos, and many drugs can cause cell or tissue injury. Even oxygen at sufficiently high partial pressures is toxic.

3. Infectious Agents
• Agents of infection range from submicroscopic viruses to meter-long tapeworms; in between are the rickettsiae, bacteria, fungi, and protozoans.

4. Immunologic Reactions
• Although the immune system defends the body against pathogenic microbes, immune reactions can also result in cell and tissue injury.
• Examples are autoimmune reactions against one’s own tissues and allergic reactions against environmental substances in genetically susceptible individuals

5. Genetic Factors遗传因素
• Genetic aberrations偏差can result in pathologic.
• 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.
• Genetic variations (polymorphisms多形性) contribute to the development of many complex diseases and can influence the susceptibility of cells to injury by chemicals and other environmental insults.

6. Nutritional Imbalances
• Nutritional deficiencies remain a major cause of cell injury.
• Protein–calorie insufficiency among underprivileged 贫困populations is only the most obvious example; specific vitamin deficiencies are not uncommon.
• Obesity markedly increases the risk for type 2 diabetes. Moreover, diets rich in animal fat are strongly implicated in the development of atherosclerosis动脉粥样硬化as well as in increased vulnerability弱点to many disorders, including cancer.

7. Physical Agents
• Trauma, extremes of temperature, radiation, electric shock, and sudden changes in atmospheric pressure all have wide-ranging effects on cells.

8. Aging
• Cellular senescence衰老leads to alterations in replicative and repair abilities of individual cells and tissues.

Cell Injury
• Cell injury underlies all diseases. When a cell is exposed to an injurious agent the possible outcomes are:
1.The cell may adapt to the situation or
2.They cell may acquire a reversible injury or
3.The cell may obtain an irreversible injury & may die.

• Which of these outcomes occur depends on both the injurious agent & on cellular factors. In other words, the result depends on the type, severity, & duration of the injury & on the type of the cell.

Types of cellular adaptation
A. Hypertrophy肥大
B. Hyperplasia增生
C. Atrophy萎缩
D. Metaplasia组织变形

A. Hypertrophy
• Hypertrophy is increase in the size of cells. Increased workload leads to increased protein synthesis & increased size & number of intracellular organelles which, in turn, leads to increased cell size. The increased cell size leads to increased size of the organ.
• Examples: the enlargement of the left ventricle in hypertensive heart disease & the increase in skeletal muscle during exercise.

B. Hyperplasia
• Hyperplasia is an increase in the number of cells. It can lead to an increase in the size of the organ. It is usually caused by hormonal stimulation.
It can be physiological as in enlargement of the breast during pregnancy or it can pathological as in endometrial hyperplasia.

C. Atrophy
• Atrophy is a decrease in the size of a cell. This can lead to decreased size of the organ. The atrophic cell shows autophagic自体吞噬vacuoles空泡which contain cellular debris from degraded organelles.

• Atrophy can be caused by:
• 1. Disuse废弃
• 2. Under nutrition
• 3. Decreased endocrine stimulation
• 4. Denervation去神经支配
• 5. Old age

D. Metaplasia
• Metaplasiais the replacement of one differentiated tissue by another differentiated tissue. There are different types of metaplasia. Examples include:

1. Squamousmetaplasia鳞片化生
2. Osseous metaplasia骨化生

1. Squamous metaplasia
• 1. Squamousmetaplasia鳞片化生：This is replacement of another type of epithelium by squamous epithelium.
•For example, the columnar epithelium of the bronchus can be replaced by squamous epithelium in cigarette smokers

2. Osseous metaplasia骨化生
• This replacement of a connective tissue by bone, for example at sites of injury.

Reversible cellular changes & accumulations
• 1. Fatty change
• 2. The accumulations of pigments

1. Fatty change
• This is accumulation of triglycerides inside cells. It is caused by an imbalance between the uptake, utilization, & secretion of fat.
• Fatty change is usually seen in the liver, heart, or kidney. Fatty liver may be caused by alcohol, diabetes, obesity, malnutrition, & poisonings.

1. Fatty change
• Accumulation of fat in the hepatocytes (liver)

2. The accumulations of pigments
• Pigments include melanin, bilirubin, hemosiderin, & lipofuscin. These pigments can accumulate inside cells in different situations.
• a. Melanin 黑色素
• b. Bilirubin胆红素
• c. Hemosiderin血铁黄素
• d. lipofuscin脂褐素

Cell death
• Cells can die via one of the following two ways:
• 1. Necrosis坏疽
• 2. Apoptosis凋亡

Necrosis
In necrosis, excess fluid enters the cell, swells it, & ruptures its membrane which kills it.
After the cell has died, intracellular degradative降解reactions occur within a living organism.
Necrosis does not occur in dead organisms. In dead organisms, autolysis自溶& heterolysis 溶解take place.
Types of necrosis
1. Coagulative凝固物的necrosis
2. Liquefactive necrosis
3. Fat necrosis
4. Caseous干酪性necrosis
5. Gangrenous坏疽性necrosis

Apoptosis
• Apoptosis is the death of single cells within clusters of other cells. (Note that necrosis causes the death of clusters of cells.)
Apoptosis
In apoptosis, the cell shows shrinkage& increased acidophilic staining of the cell. This is followed by fragmentation of the cells. These fragments are called apoptotic bodies. Apoptosis usually occurs as a physiologic process for removal of cells during embryogenesis, menstruation, etc… It can also be seen in pathological conditions caused by mild injurious agents.

Inflammation

Definition
•Inflammation is a local response (reaction) of living tissues to endogenous内源and exogenous stimuli. Inflammation is a physiologic (protective) response to injury.

Causes of inflammation are apparently causes of diseases
 physical agents - mechanical injuries, alteration in temperatures and pressure,
radiation injuries.
 chemical agents- including the ever increasing lists of drugs and toxins.
 biologic agents (infectious)- bacteria, viruses, fungi, parasites
 immunologic disorders- hypersensitivity reactions, autoimmunity, immunodeficiency states etc
 genetic/metabolic disorders- examples gout, diabetes etc…

ACUTE INFLAMMATION
•Acute inflammation is an immediate and early response to an injurious agent and it is relatively of short duration, lasting for minutes, several hours or few days.
•It is characterized by exudation渗出 of fluids and plasma proteins and the emigration移出 of predominantly(mainly) neutrophilic嗜中性leucocytes to the site of injury.


The five basic signs of acute inflammation
1.Redness which is due to dilation of small blood vessels within damaged tissue as it occurs in cellulitis组织炎.
2.Heat which results from increased blood flow due to regional vascular dilation.
3.Swelling which is due to accumulation of fluid in the extravascular space which, in turn, is due to increased vascular permeability.
4.Pain which partly results from the stretching拉伸 & destruction破坏 of tissues due to inflammatory edema and in part from pus under pressure in as abscess cavity. Some chemicals of acute inflammation, including bradykinins血管舒缓激肽, prostaglandins前列腺素类and serotonin 5-羟色胺 are also known to induce pain.
5.Loss of function: The inflamed area is inhibited by pain while severe swelling may also physically immobilize the tissue.

Events of acute inflammation
•Acute inflammation is categorized into an early vascular and a late cellular responses.
Vascular response
The Vascular response has the following steps:
a) Immediate (momentary) vasoconstriction血管收缩in seconds due to neurogenic 神经性的 or chemical stimuli.
b) Vasodilatation血管扩张 of arterioles and venules resulting in increased blood flow.
c) After the phase of increased blood flow there is a slowing of blood flow & stasis due to increased vascular permeability. The increased vascular permeability oozes缓缓流出protein-rich fluid into extravascular血管外的 tissues. The already dilated blood vessels are now packed with red blood cells resulting in stasis. The protein-rich fluid which is now found in the extravascular space is called exudate渗出液. The presence of the exudates clinically appears as swelling.

Chemical mediators炎性介质 mediate调解 the vascular events of acute inflammation.

Cellular response
•The cellular response has the following stages:
–Migration, rolling, pavementing, & adhesion of leukocytes
–Transmigration of leukocytes
–Chemotaxis 趋化作用
–Phagocytosis 吞噬作用

Cellular response
Chemical mediators of inflammation
•Chemical mediators account for the events of inflammation.

Inflammation has the following sequence:
•Cell injury Chemical mediators 􀃆 Acute inflammation (i.e. the vascular & cellular events).

Effects of acute inflammation 

A. Beneficial effects

（1）Dilution of toxins: The concentration of chemical and bacterial toxins at the site of inflammation is reduced by dilution in the exudate渗出物 and its removal from the site by the flow of exudates from the venules through the tissue to the lymphatics.
Protective antibodies: Exudation results in the presence of plasma proteins including antibodies at the site of inflammation. Thus, antibodies directed against the causative organisms will react and promote microbial destruction by phagocytosis or complement-mediated cell lysis.
Fibrin formation: This prevents bacterial spread and enhances phagocytosis by leukocytes.
Effects of acute inflammation A. Beneficial effects

（2）Plasma mediator systems provisions准备: The complement, coagulation凝结物, fibrinolytic, & kinin激肽 systems are provided to the area of injury by the process of inflammation.
Cell nutrition: The flow of inflammatory exudates brings with it glucose, oxygen and other nutrients to meet the metabolic requirements of the greatly increased number of cells. It also removes their solute waste products via lymphatic channels.
Promotion of immunity: Micro-organisms and their toxins are carried by the exudates, either free or in phagocytes, along the lymphaics to local lymph nodes where they stimulate an immune response with the generation of antibodies and cellular immune mechanisms of defence.

B. Harmful effects
Tissue destruction: Inflammation may result in tissue necrosis and the tissue necrosis may, in turn, incite刺激 inflammation.
Swelling: The swelling caused by inflammation may have serious mechanical effects at certain locations. Examples include acute epiglottitis会厌炎 with interference in breathing; Acute meningitis and encephalitis with effects of increased intracranial pressure.
Inappropriate response: The inflammatory seen in hypersensitivity reactions is inappropriate (i.e. exaggerated).

Course of acute inflammation
•Acute inflammation may end up in:
Resolution: i.e. complete restitution of normal structure and function of the tissue, eg. lobar pneumonia.
Healing by fibrosis (scar formation).
Abscess formation

CHRONIC INFLAMMATION
•Definition: Chronic inflammation can be defined as a prolonged inflammatory process (weeks or months) where an active inflammation, tissue destruction and attempts at repair are proceeding simultaneously.
Causes of chronic inflammation
•1. Persistent infections
􀃆 Certain microorganisms associated with intracellular infection such as tuberculosis, certain fungi etc characteristically cause chronic inflammation.
􀃆 These organisms are of low toxicity and evoke delayed hypersensitivity reactions.
•2. Prolonged exposure to nondegradable不可降解的 but partially toxic substances either endogenous lipid components which result in atherosclerosis 动脉粥样硬化 or exogenous substances such as silica二氧化硅, asbestos石棉.
•3. Progression from acute inflammation: Acute inflammation almost always progresses to chronic inflammation
•4. Autoimmuniy. Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis are chronic inflammations from the outset.
Cells of chronic inflammation
•Monocytes单核细胞 and Macrophages巨噬细胞 are the primary cells in chronic inflammation.
•Macrophages arise from the common precursor前驱 cells in the bone marrow, which give rise to blood monocytes. These cells are then diffusely scattered in various parts of the body, in the liver (Kupffer cells), spleen, lymph nodes (sinus histiocytes), lungs (alviolar macrophages), bone marrow, brain (microglia), skin (Langerhan’s cells), etc…. These cells constitute the mononuclear- phagocytic system.
•Macrophages are scavenger清扫工 cells of the body.

Other cells in chronic inflammation
•1. T-Lymphocytes are primarily involved in cellular immunity with lymphokine淋巴因子 production, and they are the key regulator and effector cells of the immune system.
•2. B-lymphocytes and Plasma cells produce antibody directed either against persistent antigen in the inflammatory site or against altered tissue components.
•3. Mast cells and eosinophils 嗜酸性细胞appear predominantly in response to parasitic infestations & allergic reactions.

Classification of chronic inflammation
•Chronic inflammation can be classified into the following two types based on histologic features:
•1) Nonspecific chronic inflammation: This involves a diffuse accumulation of macrophages and lymphocytes at site of injury that is usually productive with new fibrous tissue formations. E.g. Chronic cholecystitis胆囊炎.
•2) Specific inflammation (granulomatous肉芽发生inflammation):
•Definition: Granulomatous inflammation is characterized by the presence of granuloma. A granuloma is a microscopic aggregate of epithelioid cells. Epithelioid cell is an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid). The epitheloid cells can fuse with each other & form multinucleated giant cells.

Causes of granulomatious肉芽发生inflammation
•a) Bacterial: Tuberculosis, Syphilis梅毒
•b) Fungal: Coccidioidomycosis环孢子菌病
•c) Helminthic: Schistosomiasis血吸虫
•d) Protozoal: Toxoplasmosis弓浆虫病
•e) Chlamydia衣原体: Lymphogranuloma淋巴肉芽肿
•f) Inorganic material: Berrylliosis铍中毒
•g) Idiopathic: Acidosis酸中毒, Primary biliary cirrhosis肝硬化

SYSTEMIC EFFECTS OF INFLAMMATIONS
•The systemic effects of inflammation include:
1.Fever
2.Endocrine & metabolic responses
3.Autonomic responses
4.Behavioral responses
5.Leukocytosis
6.Leukopenia
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Healing

Definition of healing
•Healing, used in a pathological context, refers to the body’s replacement of destroyed tissue by living tissue.
Processes of healing
•The healing process involves two distinct processes:
•- Regeneration, the replacement of lost tissue by tissues similar in type
•- Repair (healing by scaring), the replacement of lost tissue by granulation肉芽 tissue which matures to form scar tissue. Healing by fibrosis is inevitable不可避免 when the surrounding specialized cells do not possess the capacity to proliferate增生.
•Whether healing takes place by regeneration or by repair (scarring) is determined partly by the type of cells in the damaged organ & partly by the destruction or the intactness完整无损 of the stromal 基质的 frame work of the organ. Hence, it is important to know the types of cells in the body.

Healing by regeneration
•Definition: Regeneration (generare=bring to life) is the renewal of a lost tissue in which the lost cells are replaced by identical ones.
Regeneration involves two processes:
•1. Proliferation增生 of surviving cells to replace lost tissue
•2. Migration of surviving cells into the vacant space.
Repair (Healing by connective tissue)
•Definition: Repair is the orderly process by which lost tissue is eventually replaced by a scar.
Wound contraction
•Wound contraction is a mechanical reduction in the size of the defect. The wound is reduced approximately by 70-80% of its original size. Contraction results in much faster healing, since only one-quarter to one-third of the amount of destroyed tissue has to be replaced. If contraction is prevented, healing is slow and a large ugly scar is formed.
Causes of contraction
•It is said to be due to contraction by myofibroblasts肌成纤维细胞. Myofibroblasts have the features intermediate between those of fibroblasts成纤维细胞 and smooth muscle cells.
•Two to three days after the injury they migrate into the wound and their active contraction decrease the size of the defect.

Sources of Growth Factors
Following injury, growth factors may be derived from a number of sources such as:
•1. Platelets, activated after endothelial内皮 damage,
•2. Damaged epithelial cells,
•3. Circulating serum growth factors,
•4. Macrophages巨噬细胞, or
•5. Lymphocytes recruited to the area of injury
The healing process ceases when lost tissue has been replaced.

Healing of Skin Wounds
•A wound can be accidental or surgical.
•Healing of a wound demonstrates both epithelial regeneration (healing of the epidermis) and repair by scarring (healing of the dermis).
•Depending on the nature and size of the wound. There are two patterns of wound healing depending on the amount of tissue damage:
•1. Healing by first intention (Primary union)
•2. Healing by second intention
1. Healing by first intention (primary union)-1
•Within 24 hours, neutrophils 噬中性粒细胞 appear at the margins of the incision切口, moving toward the fibrin clot. The epidermis at its cut edges thickens as a result of mitotic 有丝分裂 activity of basal cells and
•within 24 to 48 hours, epithelial cells from the edges both migrate and grow along the cut margins of the dermis真皮 and beneath the surface scab to fuse in the midline, thus producing a continuous but thin epithelial layer.
1. Healing by first intention (primary union)-2
•By day 3, the neutrophils have been largely replaced by macrophages. Granulation tissue progressively invades the incisional切入的 space. Collagen fibers are now present in the margins of the incision. By day 5, the incisional space is filled with granulation tissue.
•The epidermis recovers its normal thickness and differentiation of surface cells yields a mature epidermal architecture with surface keratinization角质化.
1. Healing by first intention (primary union)-3
•During the second week, there is continued accumulation of collagen and proliferation of fibroblasts. Leukocytic infiltrate, edema, and increased vascularity have largely disappeared.
• By the end of the first month, the scar comprises a cellular connective tissue devoid of inflammatory infiltrate, covered now by an intact epidermis.
2. Healing by second intention (secondary union)-1
•Secondary healing differs from primary healing in several respects:
•1. Inevitably, large tissue defects initially have more fibrin and more necrotic debris and exudate that must be removed. Consequently, the inflammatory reaction is more intense.
•2. Much larger amounts of granulation tissue are formed. When a large defect occurs in deeper tissues, such as in a viscus, granulation tissue bears the full responsibility for its closure, because drainage to the surface cannot occur.
2. Healing by second intention (secondary union)-2
•3. Perhaps the feature that most clearly differentiates primary from secondary healing is the phenomenon of wound contraction, which occurs in large surface wounds.
•4. Healing by second intention takes much longer than when it occurs by first intention.
Factors that influence wound healing
•Local Factors
•• Type, size, and location of the wound
•A clean, aseptic无菌的wound produced by the surgeon’s scalpel heals faster than a wound produced by blunt trauma, which exhibits aboundant necrosis and irregular edges. Small blunt wounds heal faster than larger ones. Injuries in richly vascularized areas (e.g., the face) heal faster than those in poorly vascularized ones (e.g., the foot).
•In areas where the skin adheres to bony surfaces, as in injuries over the tibia, wound contraction and adequate apposition of the edges are difficult. Hence, such wounds heal slowly.
•• Vascular supply
•• Infection
•• Movement
Factors that influence wound healing
Systemic Factors
•Circulatory status
•Infection
•Metabolic status
•Nutritional deficiencies
–Protein deficiency
–Vitamine deficiency
–Trace element deficiency
•Hormones
•Anti-inflammatory drugs

Complications并发症 of Wound Healing
•1. Infection
•2. Deficient Scar Formation
•3. Excessive Scar Formation
•4. Excessive contraction
•5. Miscellaneous混杂的

Fibrosis in Parenchymal实质的 Organs
•Deposition of collagen is part of normal wound healing.
•The term fibrosis is used to denote the excessive deposition of collagen in a tissue. The fibrosis seen in chronic diseases such as pulmonary fibrosis is often responsible for organ dysfunction and even organ failure.

Fracture Healing(Bone Regeneration)
•Stages in Fracture Healing (Bone Regeneration)
•Stage 1: Haematoma血肿 formation. Immediately following the injury, there is a variable amount of bleeding from torn破损 vessels;
•Stage 2: Inflammation. The tissue damage excites an inflammatory response, the exudate adding more fibrin to the clot already present.
•Stage 3: Demolition损坏. Macrophages invade the clot and remove the fibrin, red cells, the inflammatory exudate, and debris.
Fracture Healing(Bone Regeneration)
•Stage 4: Formation of granulation tissue. Following this phase of demolition, there is an ingrowth of capillary loops循环 and mesenchymal间叶细胞 cells derived from the periosteum骨膜 and the endosteum骨内膜 of the bone.
•Stage 5: Woven编织 bone and cartilage formation. The mesenchymal间叶细胞 “osteoblasts破骨细胞” next differentiate to form either woven bone or cartilage.
•Stage 6: Formation of lamellar薄片 bone. The dead calcified钙化 cartilage or woven bone is next invaded by capillaries headed by osteoclasts.
•Stage 7: Remodelling. The final remodeling process involving the continued osteoclastic removal and osteoblastic laying down of bone results in the formation of a bone, which differs remarkably little from the original tissue.

Hemodynamic Disorders
局部血液循环障碍

Thromboembolismand Shock
血管栓塞 和休克

Hemostasis

•Definition: Hemostasis止血is the maintainence of the clot-free state of blood & the prevention of blood loss via the formation of hemostatic plug.
•Hemostasis depends on three general components:
•a) Vascular wall
•b) Platelets
•c) Coagulation血液凝固

Whenever a vessel is ruptured or severed切断, hemostasis is achieved by several mechanisms:
A. Vascular spasm
B. Formation of platelet plug
C. Formation blood clot as a result of blood coagulation凝结
D. Eventual growth of fibrous tissue in to the blood clot to close the hole in the vessel permanently.

Thrombosis

•Definition: Thrombosis 血栓形成 is defined as the formation of a solid or semisolid mass from the constituents of the blood within the vascular system during life.
•Pathogenesis:
There are three factors that predispose使易于 to thrombus formation.
•A: Endothelial injury
•B: Stasis or turbulence of blood flow
•C: Blood hypercoagulability

A: Endothelial injury
•It is the most important factor in thrombus formation and by itself can lead to thrombosis.
•Endothelial injury is particularly important in thrombus formation in the heart & arterial circulation.

B: Turbulence or Stasis (Alterations in normal blood flow)
•Under physiologic conditions normal blood flow is laminar流线的, that is, the cellular elements flow centrally in the vessel lumen separated from endothelium by slowing moving clear zone of plasma. Stasis & turbulence therefore:
•a. Disrupt the laminar flow and bring platelets in to contact with the endothelium
•b. Prevent dilution of activated clotting factors
•c. Retard or make a time lag in the inflow of clotting factor inhibitors and permit the build up of thrombi.

C: Hypercoagulablity
•Definition: Hypercoagulability is any alteration of the coagulation pathway that predisposes to thrombosis. Hypercoagulability is a less common cause of thrombosis , it can be divided into:
•1. Primary (Genetic)
•2. Secondary (Acquired)

Embolism

•Definition:-
•An embolus栓子is a detached intravascular solid, liquid or gaseous气态的 mass that is carried by blood to sites distant from its point of origin. After traveling via the blood, the embolus can obstruct a vessel.

•Causes of embolism:
•An embolus can arise from:
•Thrombus (99% of emboli arise from a thrombus. Such an embolus is called thromboembolus)
•Platelets aggregates
•Fragment of material from ulcerating atheromatous动脉粥样化 plaque
•Fragment of a tumour
•Fat globules小珠
•Bubbles of air
•Amniotic羊膜 fluid
•Infected foreign material
•Bits of bone marro

a) Pulmonary thromboembolism (PTE)
•PTE is refers to the impaction of an embolus in the pulumonary arteries & their branches. Such an embolus is derived from a thrombus in the systemic veins or the right side of the heart.

b) Systemic thromboembolism
•Systemic emboli arise from the left side of the heart or from thrombi & atheromatous debris in large arteries. And they impact in the systemic arteries.

Disseminated Intravascular Coagulation (DIC)

•Definition: -DIC is an acute, or chronic thrombohemorrhagic disorder occurring as a result of progressive activation of coagulation pathway beyond physiologic set point secondary to a variety of diseases resulting in failure of all components of hemostasis. Hence the other term for DIC is consumption coagoulopathy.

Shock

•Definition: Shock is a state in which there is failure of the circulatory system to maintain adequate cellular perfusion resulting in widespread reduction in delivery of oxygen & other nutrients to tissues. In shock, the mean arterial pressure is less than 60 mmHg or the systolic blood pressure is less than 90 mmHg.

Classification of shock •Shock can be divided into:
•A. Hypovolemic血容量减少 shock
•B. Cardiogenic shock
•C. Distributive分配性 shock

A. Hypovolemic shock
•Definition: This is shock caused by reduced blood volume. Reduction in circulating blood volume results in the reduction of the preload which leads to inadequate left ventricular filling, reflected as decreased left & right ventricular end diastolic volume and pressure. The reduced preload culminates in decreased cardiac out put which leads to widespread tissue perfusion (shock).

B. Cardiogenic shock
•Definition: This is shock that results from severe depression of cardiac performance. It primarily results from pump failure [myocardial failure].

C. Distributive shock
•Definition: Distributive shock refers to a group of shock subtypes caused by profound peripheral vasodilatation despite normal or high cardiac output.

Septic shock
•Definition: This is a kind of shock caused by systemic microbial infection, most commonly by gram – negative infection (endotoxic shock) but can also occur with gram – positive or fungal infections.
Clinical course of shock
•Patient with shock may manifest as having a weak and rapid pulse, cool, clammy冷湿, cyanotic skin. In septic shock, the skin will initially be warm & flushed because of peripheral vasodilation. The patient may present with confusion, restlessnes, decreased urine output, coma, and death.

Immunity Disorder

Hypersensitivity Reactions

•The purpose of the immune response is to the purpose of the immune response is to protect against invasion by foreign organisms, protect against invasion by foreign organisms, but they often lead to host tissue damage. An exaggerated immune response that results in exaggerated immune response that results in tissue injury tissue injury is broadly referred to as a is broadly referred to as a hypersensitivity reaction.

Immunologic Tolerance

Immunologic tolerance is a state in which an individual is incapable of developing an individual is incapable of developing an immune response to specific antigens. Self immune response to specific antigens. Self- tolerance refers to lack of responsiveness to tolerance refers to lack of responsiveness to an individual’s antigens.an individual’s antigens.

Autoimmune Diseases

Definition: Autoimmunity implies that an immune response has been generated against
self-antigens (Autoantigens).

Central to the concept of autoimmune diseases is a breakdown of the ability of the
immune system to differentiate between self and non-self-antigens.

Absence of other well-defined cause of disease.

Systemic Lupus Erythematosus

SLE is a systemic autoimmune disease caused by autoantibodies produced against numerous self-antigens and the formation of immune complexes.

The major autoantibodies, and the ones responsible for the formation of circulating
immune complexes, are directed against nuclear antigens. Other autoantibodies react with
erythrocytes, platelets, and various complexes of phospholipids with proteins.

Disease is a chronic remitting and relapsing often febrile illness characterized principally by
injury to the skin, joints, kidney and serosal membranes. Each and every part of the body may
be affected.

It is common among women of childbearing age and a female to male ratio of 9:1, pick on set 2nd to 4th decade.

Etiology and pathogenesis

The cause of SLE remains unknown but it appears to be a complex disorder of multifactorial origin resulting from interactions including:
1. Genetic factors
Increased familial risk, 24% concordance in monozygotic twins
2. Hormonal factors
Estrogens 雌激素 confer increased risks (10 times more common in females than males) that accelerate during pregnancy and menses.
3. Environmental factors
Drugs such as hydralazine, pencillin etc induce SLE like illness)
Ultraviolet rays
Emotional stress
Surgery
4. Immunologic factors
i ) B cell hyperactivity
ii) Autoantibodies present with reactivity to DNA, RNA

Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic, chronic inflammatory disease affecting many tissues
but principally attacking the joints to produce a nonsuppurative 非化脓 proliferative 增生性 synovitis 滑膜炎 that frequently progresses to destroy articular cartilage and underlying bone with resulting disabling arthritis.

PATHOGENESIS

Rheumatoid arthritis (RA) is an autoimmune disease involving complex , and still poorly
understood, interactions of genetic risk factors, environment, and the immune system.

Clinical Features
Although RA is basically a symmetric polyarticular 多关节的 arthritis, there also may be constitutional symptoms such as weakness, malaise, and low-grade fever.

Many of the systemic manifestations result from the same mediators that cause joint inflammation. The arthritis first appears insidiously, with aching and stiffness of the joints, particularly in the morning. As the disease advances, the joints become enlarged, motion is limited, and in time complete ankylosis 僵硬 may appear.

Acquired Immunodeficiency Syndrome (AIDS)

AIDS is a retroviral 逆转录病毒 disease characterized by profound immuno suppression that leads to opportunistic infections, secondary neoplasms and neurological manifestations.

Mechanisms of immune deficiency:
Loss T cells: T cell death during viral replication;

decreased thymic 胸腺的 output, functional defects

Defective macrophage
Destruction of architecture 结构 of lymphoid tissues(late)

REJECTION OF TRANSPLANTS

The major barrier to transplantation of organs from one individual to another of the same
species is immunologic rejection of the transplanted tissue.

Rejection is a complex phenomenon involving both cell and antibody mediated reactions
that destroy the graft 移植 .

The key to successful transplantation has been the development of
therapies that prevent or minimize rejection.

Neoplasia 肿瘤

Neoplasia is new, uncontrolled growth of cells that is not under physiologic control.
• A neoplasm can be benign, potentially malignant, or malignant (cancerous/cancer).

Benign refers to a condition, tumor, or growth that is not cancerous. This means that it does not spread to
other parts of the body. It does not invade nearby tissue.

Cancer /malignancy/cancerous, is an abnormal growth of cells. A term for diseases in which abnormal cells
divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the
body through the blood and lymph systems.

Characteristics of Benign and Malignant Neoplasms (Cancers)

The difference in characteristics of these neoplasms can be conveniently discussed
under the following headings:

1. Differentiation & anaplasia 退行性变
2. Rate of growth
3. Local invasion
4. Metastasis 转移

1. Differentiation and anaplasia
Differentiation refers to the extent to which parenchymal 实质的 cells resemble comparable normal cells both morphologically and functionally.

Well differentiated tumours cells resemble mature normal cells of tissue of origin.
Poorly differentiated or undifferentiated tumours have primitive 原始的 appearing, unspecialized cells.

In general, benign neoplasms are well differentiated. Malignant neoplasms in contrast.

2. Rate of growth

Most benign tumours grow slowly; most malignant tumours grow rapidly.

In general, the growth rate of neoplasms correlate with their level of differentiation, most
malignant neoplasms grow more rapidly than do benign neoplasms.

On occasions, cancers have been observed to decrease in size and even spontaneously
disappear.

3. Local invasion

Nearly all benign neoplasms grow remains localized to their site of origin and do not have the capacity to invade or metastasize to distant sites , as do malignant neoplasms.

The growth of malignant neoplasms is accompanied by progressive infiltration 渗透 , invasion
and destruction of the surrounding tissue .
Generally, they are poorly demarcated 边界清楚 from the surrounding normal tissue.

4. Metastasis

It is defined as a transfer of malignant cells from one site to another not directly connected with it.
Metastasis is the most reliable sign of malignancy. The invasiveness of cancers permits them to
penetrate in to the blood vessel, lymphatic and body cavities providing the opportunity for
spread.

Pathways of spread

1. Seeding of body cavities and surfaces
2. Lymphatic spread
3. Hematogenous (Blood) spread

1. Seeding of body cavities and surfaces ( transcoelomic spread)
•This seeding may occur wherever a malignant neoplasm penetrates into a natural “open field”.
Most often involved is the peritoneal cavity , but any other cavities such as pleural, pericardial, sub arachnoid and joint spaces may be affected.
• Particular examples are tumour arising from gastrointestinal tract, pancreas, breast, and gall
bladder may spread to one or both ovaries and the peritoneal cavities.

2. Lymphatic spread
• Lymphatic route is the most common pathway for the initial dissemination of carcinomas.
• The pattern of lymph node involvement follows the natural routes of drainage. Lymph nodes
involvement in cancers is in direct proportion to the number of tumour cell reaching the nodes.
• A clinical presence of enlarged lymph node is not necessarily synonymous with a metastasis.
Conversely, the absence of cancer cells in reseated lymph nodes does not guarantee that there is no underlying cancer.

3. Hematogenous spread
• Lung & liver cancer are common sites of metastasis Other major sites of hematogenous
spread include brain and bones.
• In the circulation, cancer cells form emboli by aggregation and by adhering to circulating
leukocytes(WBC) particularly platelets.

Clinical Features of Tumors
Effects of tumour on the host:
Both benigin and malignant neoplasms may cause problems because of
1. location and impingement 侵犯 on adjcent structures
2. functional activities such as hormone synthesis
3. bleeding and secondary infection when they ulcerate through adjacent natural surfaces
4. initiation of acute symptoms caused by either rupture 破裂 or infarction 梗塞 local and hormonal effects

Cachexia 恶病质

Cachexia is a progressive loss of body fat and lean body mass accompanied by profound weakness, anorexia 厌食 and anemia. It usually happens on the ending stage of cancer patients.

lung cancer (Carcinomas)

The four major histologic subtypes are :
•Adenocarcinomas (a cancer originating in glandulartissue. 腺癌 is most common
•Squamous cell carcinoma 鳞癌
•Small Cell Lung Carcinoma (SCLC)
•Others

Each of these is clinically and genetically distinct. SCLCs are best treated by chemotherapy, because almost all are metastatic at presentation. The other carcinomas may be curable by surgery if limited to the lung.

ETIOLOGY AND Clinical Course
• Smoking is the most important risk factor for lung cancer; in women and nonsmokers, adenocarcinomas are the most common cancers.
• Carcinomas of the lung are silent in the beginning. In some cases, chronic cough and expectoration call attention to still localized, resectable 可切除的 disease.
By the time hoarseness, chest pain, pericardial or pleural effusion, or persistent segmental atelectasis 肺萎陷 or pneumonitis makes its appearance, the prognosis is grim. Too often, the tumor presents with symptoms emanating from metastatic spread to the brain, liver, or bones.

Pancreatic cancer

• The pancreas, located in the abdomen, has endocrine and exocrine functions; cancer cells
can develop from both types of functional cells.
• Pancreatic cancer is highly lethal 致死的 because it grows and spreads rapidly and often is
diagnosed in its late stages.

Signs and symptoms
• Pancreatic cancer is difficult to diagnose in early stage.
• Jaundice
• Dark urine: As bilirubin levels in the blood increase, the urine becomes brown in color.
• Light colored or greasy stools: Bilirubin normally helps give stools their brown color. If the bile duct is blocked, stools might be pale or gray.
• Itchy skin: When bilirubin builds up in the skin, it can start to itch as well as turning yellow.
• Belly or back pain: Pain in the abdomen (belly) or back is common in pancreatic cancer.
• Nausea and vomiting
• Weight loss and poor appetite
• Gallbladder or liver enlargement

Pancreatic cancer Treatment
• The only curative treatment is surgical removal of all cancer and a pancreatic transplant;
however, most patients are not eligible for a pancreas transplant.
• Chemotherapy after surgery can lower the chances of the cancer returning.
• Chemotherapy for metastatic pancreatic cancer can extend life and improve the quality
of life.

Liver Cancer

• The liver shares the dubious distinction of being the visceral organs most often involved by
metastatic cancers. The most common hepatic neoplasms are metastatic carcinomas, with colon, lung, and breast.
• Primary hepatic malignancies are almost all hepatocellular 肝细胞的 carcinomas.

Etiologic associations
• Infection with HBV or HCV, alcoholic cirrhosis, and aflatoxin 黄曲霉毒素 exposure, and nonalcoholic fatty liver disease 非酒精性脂肪肝病 is increasingly becoming an important risk factor for hepatocellular cancer.
• Many variables, including age, gender, chemicals, viruses, hormones, alcohol, and nutrition, interact in the development of hepatocellular cancer.

Clinical Features
• Liver cancer may not cause any signs or symptoms in its early stages. Signs and symptoms often appear once the tumour grows and causes changes in the body, such as blocking the
bile ducts. some signs or symptoms:
• pain in the abdomen, which may move up through the right shoulder
• a lump or mass under the ribs
• Nausea / vomiting
• loss of appetite /feeling full after a small meal (called early satiety)
• Diarrhea / constipation
• weight loss
• swelling of the abdomen caused by a buildup of fluid (ascites)
• swelling in the legs and feet caused by a buildup of fluid (edema)
• Fatigue/ Weakness

Heart diseases

• HEART FAILURE
• CONGENITAL HEART DISEASE
• ISCHEMIC HEART DISEASE
• ARRHYTHMIAS

• HEART FAILURE

•Heart failure generally is referred to as congestive(充血性) heart failure (CHF). CHF is the common end point for many forms of cardiac disease.

•Heart failure can affect predominantly the left or the right side of the heart or may involve both sides.

•Left-Sided Heart Failure

•Right-Sided Heart Failure

Left-Sided Heart Failure

•Clinical Features

•Dyspnea (Difficult breath) on exertion is usually the earliest and most significant symptom of left-sided heart failure; cough also is common as a consequence of fluid transudation into air spaces.

•Other manifestations of left ventricular failure include an enlarged heart, Fast heart Rate, a third heart sound (S3), and fine rales at the lung bases.

Right-Sided Heart Failure

•Right heart failure usually is the consequence of left-sided heart failure, since any pressure increase in the pulmonary circulation inevitably produces an increased burden on the right side of the heart Isolated.

•the clinical manifestations are related to systemic and portal venous congestion, including hepatic and GI tract enlargement, peripheral edema, and ascites.

CONGENITAL HEART DISEASE

•Congenital heart diseases are abnormalities of the heart or great vessels that are present at birth.

•In most instances, congenital heart disease arises from faulty embryogenesis during gestational weeks 3 through 8, when major cardiovascular structures develop; the cause is unknown in almost 90% of cases.

•Of the known etiologic factors, environmental causes, including congenital rubella（风疹） infection, teratogens（致畸剂）, and maternal diabetes, and genetic factors are the best characterized.

•Left-to-right shunts are the most common type of congenital cardiac malformation.

•They include atrial septal defects  (ASDs), ventricular septal defects (VSDs), and patent ductus arteriosus (PDA)动脉导

•ASDs typically increase only right ventricular and pulmonary outflow volumes, while VSDs and PDAs cause both increased pulmonary blood flows and pressures.

•Manifestations of these shunts range in severity from no symptoms at all to heart failure.

ISCHEMIC HEART DISEASE

•Ischemic （缺血性的）heart disease (IHD)  is also known as coronary artery disease.

•Cholesterol plaque can build up in the arteries of the heart and cause "ischemia," which means the heart is not getting enough blood flow and oxygen.

•Several closely related syndromes caused by myocardial ischemia— an imbalance between cardiac blood supply (perfusion) and myocardial oxygen and nutritional requirements.

Angina Pectoris （心绞痛）

•Angina pectoris is an intermittent chest pain caused by transient （ 短暂的）, reversible myocardial ischemia.

Myocardial Infarction （心肌梗死）

•Myocardial infarction (MI), also commonly referred to as “heart attack,” is necrosis of heart muscle resulting from ischemia.

Clinical Features

•The classic MI is heralded by severe, crushing substernal chest pain (or pressure) that can radiate to the neck, jaw, epigastrium, or left arm. In contrast to angina pectoris, the associated pain typically lasts several minutes to hours, and is not relieved by nitroglycerin or rest.

•However, in a substantial minority of patients (10% to 15%), MIs have atypical signs and symptoms and may even be entirely asymptomatic. Such “silent” infarcts are particularly common in patients with diabetes and in elderly persons.

•The pulse generally is rapid and weak.

ARRHYTHMIAS

•The heart contains specialized conduction system that regulate the rate and rhythm of cardiac contraction and are 

essential for normal cardiac function.

Heart  conduction system

(1) the sinoatrial (SA) node pacemaker (located at the junction of the right atrial and superior vena cava)

(2) the atrioventricular (AV) node (located in the right atrium along the atrial septum)

(3) the bundle of His, connecting the right atrium to the ventricular septum, and the subsequent divisions.

 (4) the right and left bundle branches that stimulate their respective ventricles

•Arrhythmias can be caused by ischemic or structural changes in the conduction system or by myocyte肌细胞 electrical instability.

•In structurally normal hearts, arrhythmias more often are due to mutations突变基因 in ion channels.

•Atelecatasis 肺不张(Collapse)

•Chronic Bronchitis

•Asthma

•Pulmonary Infections(Pneumonias)

•Lung Abscess

Atelecatasis肺不张(Collapse)

•Atelectasis, also known as collapse, is loss of lung volume caused by inadequate expansion of air spaces.

•It results in shunting of inadequately oxygenated blood from pulmonary arteries into veins, thus giving rise to a ventilation perfusion imbalance and hypoxia.

ATELECTASIS (COLLAPSE) is classified into three forms

Resorption atelectasis • Resorption atelectasis occurs when an obstruction prevents air from reaching distal airways. The air already present gradually becomes absorbed, and alveolar collapse follows. Depending on the level of airway obstruction, an entire lung, a complete lobe, or one or more segments may be involved. • The most common cause of resorption collapse is obstruction of a bronchus by a mucous or mucopurulent plug. This frequently occurs postoperatively, chronic bronchitis, tumor, or foreign body aspiration, particularly in children.

Compression atelectasis

• Compression atelectasis (sometimes called passive or relaxation atelectasis) is usually associated with accumulation of fluid, blood, or air within the pleural cavity, which mechanically collapses the adjacent lung. This is a frequent occurrence with pleural effusion, caused most commonly by congestive heart failure (CHF). Leakage of air into the pleural cavity. Pneumothorax气胸 also leads to compression atelectasis.

Contraction atelectasis

• Contraction (or cicatrization瘢痕形成) atelectasis occurs when either local or generalized fibrotic changes in the lung or pleura hamper expansion and increase elastic recoil during expiration.

Symptoms and signs

• May have no signs and symptoms or they may include:

• cough, but not prominent;

• chest pain (not common);

• breathing difficulty (fast and shallow);

• pleural effusion (transudate渗出液type);

• Cyanosis紫绀(late sign);

• increased heart rate.

Chronic Bronchitis

Chronic bronchitis is one type of COPD (chronic obstructive pulmonary disease). The inflamed bronchial tubes produce a lot of mucus. This leads to coughing and difficulty breathing. Cigarette smoking is the most common cause. Breathing in air pollution, fumes, or dust over a long period of time may also cause it.

Clinical Features

• Cough.

• Production of mucus (sputum), which can be clear, white, yellowish-gray or green in color.

• Fatigue. • Shortness of breath.

• Slight fever and chills.

 • Chest discomfort.

• Chronic bronchitis is defined as persistent productive cough for at least 3 consecutive months in at least 2 consecutive years.

Asthma

• Asthma is a chronic inflammatory disorder in which the airways narrow and swell and produce extra mucus. This can causes recurrent episodes of breathing difficult and trigger coughing, wheezing chest tightness and shortness of breath.

Causes

• It isn't clear why some people get asthma and others don't, but it's probably due to a combination of environmental and genetic (inherited) factors.

• Asthma triggers:

• Exposure to various irritants and substances that trigger allergies (allergens) can trigger signs and symptoms of asthma. Asthma triggers are different from person to person and can include:

• Respiratory infections, such as the common cold

• Physical activity (exercise-induced asthma)

• Cold air • Airborne substances and Air pollutants and irritants

• Certain medications

• Strong emotions and stress

Clinical Features

• An attack of asthma is characterized by severe dyspnea with wheezing; the chief difficulty lies in expiration. The victim labors to get air into the lungs and then cannot get it out, so that there is progressive hyperinflation of the lungs with air trapped distal to the bronchi, which are constricted and filled with mucus and debris. In the usual case, attacks last from 1 to several hours and subside either spontaneously or with therapy

Pulmonary Infections (Pneumonias)

Pneumonia is an infection that inflames the air sacs in one or both lungs. The air sacs may fill with fluid or pus (purulent material). A variety of organisms, including bacteria, viruses and fungi, can cause pneumonia.

Clinical Features

• Cough, which may produce phlegm

• Chest pain when breathe or cough

• Shortness of breath

• Fatigue

• Fever, sweating and chills

• Nausea, vomiting or diarrhea

Lung Abscess

• Lung abscess refers to a localized area of suppurative necrosis within the pulmonary tissue, resulting in the formation of one or more large cavities.

Clinical Features

Prominent cough that usually yields copious amounts of foul-smelling, purulent, or bloody sputum. Fever and chest pain are common. Being sick for several weeks or months. General feeling of poor health. Loss of appetite and weight loss. Deep cough that may produce foul-tasting.