Pathology: Inflammation and Repair

B This immunoglobulin deficiency prevents opsonization and phagocytosis of microbes. Deficiency of integrins and selectins, or a defect in microtubules, would prevent adhesion and locomotion of neutrophils. H2O2 production is part of the oxygen-dependent killing mechanism. This mechanism is intact in this patient because the neutrophils are able to kill bacteria when immunoglobulins in normal serum allow phagocytosis.

A 12-month-old boy with a 6-month history of repeated infections has had a fever and cough for the past 3 days. A Gram stain of sputum shows many gram-positive cocci in chains. CBC shows neutrophilia. Laboratory studies show that the patient's neutrophils phagocytose and kill organisms promptly in the presence of normal human serum, but not in his own serum. The neutrophils migrate normally in a chemotaxis assay. Which of the following is the most likely cause of this boy's increased susceptibility to infection? A Abnormality of selectin expression B Diminished opsonization C Defective neutrophil generation of hydrogen peroxide D Deficiency of integrins E Phagocytic cell microtubular protein defect

E. Naproxen, a nonsteroidal anti-inflammatory drug, targets the cyclooxygenase pathway of arachidonic acid metabolism and leads to reduced prostaglandin generation. 27Prostaglandins promote vasodilation at sites of inflammation. Chemotaxis is a function of various chemokines, and complement C3b may promote phagocytosis, but neither is affected by aspirin. Leukocyte emigration is aided by various adhesion molecules. Leukocyte release from bone marrow can be driven by the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF).

A 19-year-old woman develops a sore throat and fever during the past day. Physical examination shows pharyngeal erythema and swelling. Laboratory findings include leukocytosis. She is given naproxen. Which of the following features of the acute inflammatory response is most affected by this drug? A Chemotaxis B Emigration C Leukocytosis D Phagocytosis E Vasodilation

E. The C5a component of complement, along with TNF, leukotrienes, and bacterial products, is chemotactic for neutrophils.

A 20-year-old man has experienced painful urination for 4 days. A urethritis is suspected, and Neisseria gonorrheae is cultured. Numerous neutrophils are present in a smear of the exudate from the penile urethra. These neutrophils undergo diapedesis to reach the organisms. Release of which of the following chemical mediators is most likely to drive neutrophil exudation? A Histamine B Prostaglandin C Hageman factor D Bradykinin E Complement

B. At 1 week, wound healing is incomplete, and granulation tissue is still present. More collagen is synthesized in the following weeks. Wound strength peaks at about 80% by 3 months. Type IV collagen is found in basement membranes.

A 20-year-old woman undergoes cesarean section to deliver a term infant, and the lower abdominal incision is sutured. The sutures are removed 1 week later. Which of the following statements best describes the wound site at the time of suture removal? A Collagen degradation exceeds synthesis B Granulation tissue is still present C No more wound strength will be gained D Type IV collagen predominates E Wound strength is 80% of normal tissue

A Glucocorticoids inhibit wound healing by impairing collagen synthesis. This is a desirable side effect if the amount of scarring is to be reduced, but it results in the delayed healing of surgical wounds. Angiogenesis driven by vascular endothelial growth factor (VEGF) is not significantly affected by corticosteroids. Neutrophil infiltration is not prevented by glucocorticoids. Reepithelialization, in part driven by epidermal growth factor, is not affected by corticosteroid therapy. Serine proteinases are important in wound remodeling.

A 23-year-old woman receiving corticosteroid therapy for an autoimmune disease has an abscess on her upper outer right arm. She undergoes minor surgery to incise and drain the abscess, but the wound heals poorly over the next month. Which of the following aspects of wound healing is most likely to be deficient in this patient? A Collagen deposition B Elaboration of VEGF C Neutrophil infiltration D Reepithelialization E Serine proteinase production

E The figure shows dense collagen with some remaining dilated blood vessels, typical of the final phase of wound healing, which is extensive by the end of the first month. On day 1, the wound is filled only with fibrin and inflammatory cells. Macrophages and granulation tissue are seen 2 to 3 days postoperatively. Neovascularization is most prominent by days 4 and 5. By week 2, collagen is prominent, and fewer vessels and inflammatory cells are seen.

A 24-year-old man with acute appendicitis undergoes surgical removal of the inflamed appendix. The incision site is sutured. A trichrome-stained section representative of the site with blue appearing collagen is shown in the figure. How long after the surgery would this appearance most likely be seen? A 1 day B 2 to 3 days C 4 to 5 days D 2 weeks E 1 month

C. About 70 to 80% of the tensile strength in the scar, compared to non-wounded skin, is reached at 3 months, which is about as much as will be obtained.

A 31-year-old woman has a laparotomy performed for removal of an ovarian cyst. She recovers uneventfully, with no complications. At the time of surgery, a 12 cm long midline abdominal incision was made. The tensile strength in the surgical scar will increase so her normal activities can be resumed. Most of the tensile strength will likely be achieved in which of the following time periods? A One week B One month C Three months D Six months E One year

B One outcome of acute inflammation with ulceration is chronic inflammation. This is particularly true when the inflammatory process continues for weeks to months. Chronic inflammation is characterized by tissue destruction, mononuclear cell infiltration, and repair. In acute inflammation, the healing process of fibrosis and angiogenesis has not begun. In fibrinous inflammation, typically involving a mesothelial surface, there is an outpouring of protein-rich fluid that results in precipitation of fibrin. Granulomatous inflammation is a form of chronic inflammation in which epithelioid macrophages form aggregates. Serous inflammation is an inflammatory process involving a mesothelial surface (e.g., lining of the pericardial cavity), with an outpouring of fluid having little protein or cellular content.

A 37-year-old man has had midepigastric pain for the past 3 months. An upper gastrointestinal endoscopy shows a 2-cm, sharply demarcated, shallow ulceration of the gastric antrum. Microscopic examination of a biopsy from the ulcer base shows angiogenesis, fibrosis, and mononuclear cell infiltrates with lymphocytes, macrophages, and plasma cells. Which of the following terms best describes this pathologic process? A Acute inflammation B Chronic inflammation C Fibrinous inflammation D Granulomatous inflammation E Serous inflammation

B. This acute inflammatory process leads to production of acute-phase reactants, such as C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein. These proteins, particularly fibrinogen, and immunoglobulins increase RBC rouleaux formation to increase the erythrocyte sedimentation rate (ESR), which is a nonspecific indicator of inflammation. CRP production is upregulated by interleukin-6 (IL-6), whereas fibrinogen and SAA are upregulated mainly by tumor necrosis factor (TNF) and interleukin-1 (IL-1). Interferon-γ is a potent stimulator of macrophages. Nitric oxide can induce vasodilation or can assist in microbial killing within macrophages. Prostaglandins are vasodilators.

A 43-year-old man with a ventricular septal defect has had a cough and fever for the past 2 days. On examination, he has a temperature of 37.6° C and a cardiac murmur. A blood culture grows Streptococcus, viridans group. His erythrocyte sedimentation rate (ESR) is increased. Microbial cells are opsonized and cleared. Which of the following chemical mediators is most important in producing these findings? A Bradykinin B C-reactive protein C Interferon-γ D Nitric oxide E Prostaglandin F Tumor necrosis factor (TNF)

A. Epithelioid cells and giant cells are derived from activated macrophages. Tissue macrophages are derived from blood monocytes. These cells are important in the development of granulomatous inflammation in the adaptive immune response to tuberculosis.

A 43-year-old woman has had a chronic cough with fever and weight loss for the past month. A chest radiograph reveals multiple nodules from 1 to 4 cm in size, some of which demonstrate cavitation in the upper lobes. A sputum sample reveals the presence of acid fast bacilli. Which of the following cells is the most important in the development her lung lesions? A Macrophage B Fibroblast C Neutrophil D Mast cell E Platelet

E. This is a chronic inflammatory process, based upon the mononuclear inflammatory cell components present. H. pylori organisms live in the mucus above the gastric epithelium and release chemical substances that alter epithelial function and defenses, leading to gastritis. This organism does not directly infect or damage the epithelium, and its persistence leads to the chronic inflammation.

A 43-year-old woman has had nausea with vomiting persisting for the past 5 weeks. On physical examination there are no abnormal findings. She undergoes an upper GI endoscopy and gastric biopsies are obtained. The microscopic appearance of these biopsies shows mucosal infiltration by lymphocytes, macrophages, and plasma cells. Which of the following most likely caused her findings? A Staphylococcus aureus septicemia B Ingestion of chili peppers C Diabetes mellitus D Tuberculosis E Infection with Helicobacter pylori

A. This non-caseating granulomatous inflammation is typical for sarcoidosis, a non-infectious process. Granulomas are a form of type IV hypersensitivity reaction. There are cytokines such as interferon gamma produced by lymphocytes that recruit blood monocytes and stimulate macrophages to develop a granulomatous response.

A 45-year-old woman has had a chronic, non-productive cough for 3 months, along with intermittent fever. She has a chest radiograph that reveals multiple small parenchymal nodules along with hilar and cervical lymphadenopathy. A cervical lymph node biopsy is performed. Microscopic examination of the biopsy shows noncaseating granulomatous inflammation. Cultures for bacterial, fungal, and mycobacterial organisms are negative. Which of the following chemical mediators is most important in the development of her inflammatory response? A Interferon gamma B Bradykinin C Complement C5a D Histamine E Prostaglandin E2

B Myeloperoxidase is present in the azurophilic granules of neutrophils. It converts H2O2 into HOCl-, a powerful oxidant and antimicrobial agent. Degranulation occurs as phagolysosomes are formed with engulfed bacteria in phagocytic vacuoles within the neutrophil cytoplasm. Oxygen consumption with an oxidative or respiratory burst after phagocytosis is aided by glucose oxidation and activation of neutrophil NADPH oxidase, resulting in generation of 26superoxide that is converted by spontaneous dismutation to H2O2. In contrast, prostaglandin production depends on a functioning cyclooxygenase pathway of arachidonic acid metabolism.

A 5-year-old child has a history of recurrent bacterial infections, including pneumonia and otitis media. Analysis of leukocytes collected from the peripheral blood shows a deficiency in myeloperoxidase. A reduction in which of the following processes is the most likely cause of this child's increased susceptibility to infections? A Hydrogen peroxide (H2O2) elaboration B Hydroxy-halide radical (HOCl-) formation C Failure of migration resulting from complement deficiency D Phagocytic cell oxygen consumption E Prostaglandin production

C. A transudate resembles a filtrate of plasma and has few cells with very little protein and has a clear appearance.

A 55-year-old man with a history of ischemic heart disease has worsening congestive heart failure. He has noted increasing dyspnea and orthopnea for the past 2 months. On physical examination there is dullness to percussion at lung bases. A chest x-ray shows bilateral pleural effusions. A left thoracentesis is performed, and 500 mL of fluid is obtained. Which of the following characteristics of this fluid would most likely indicate that it is a transudate? A Cloudy appearance B High protein content C <3 lymphocytes/microliter D Presence of fibrin E Large size of the effusion

D The elevated creatine kinase level indicates that myocardial necrosis has occurred. A fibrous scar gradually replaces the area of myocardial necrosis. Chronic inflammation is typically driven by ongoing stimuli such as persistent infection, autoimmunity, or irritation from endogenous or exogenous chemical agents, and it is not a feature of ischemic myocardial injury. Coagulative necrosis is typical of myocardial infarction, but after 1 month, a scar would be present. The destruction of myocardial fibers precludes complete resolution. Nodular regeneration is typical of hepatocyte injury because hepatocytes are stable cells.

A 58-year-old man had chest pain persisting for 4 hours. A radiographic imaging procedure showed an infarction involving a 4-cm area of the posterior left ventricular free wall. Laboratory findings showed serum creatine kinase of 600 U/L. Which of the following pathologic findings would most likely be seen in the left ventricular lesion 1 month later? A Chronic inflammation B Coagulative necrosis C Complete resolution D Fibrous scar E Nodular regeneration 25

E. Hydrogen peroxide is reduced by myeloperoxidase to a powerful oxidant that kills bacteria. She has an acute inflammatory response to a bacterial organism, and the majority of inflammatory cells responding will be neutrophils.

A 58-year-old woman has had a cough with fever for 3 days. A chest radiograph reveals infiltrates in the right lower lobe. A sputum culture grows Streptococcus pneumoniae. The clearance of these organisms from the lung parenchyma would be most effectively accomplished through generation of which of the following substances by the major inflammatory cell type responding to this infection? A Platelet activating factor B Prostaglandin E2 C Kallikrein D Leukotriene B4 E Hydrogen peroxide

A. Nitric oxide (NO) acts as a vasodilator. Small amounts released from endothelial cells causes vasodilation and prevents thrombosis. Macrophages release NO to kill bacteria, but large amounts released body-wide can cause hypotension and shock.

A 65-year-old woman has had a fever for the past day. On physical examination her temperature is 39°C and blood pressure 90/50 mm Hg with heart rate of 106/minute. Laboratory studies show a WBC count of 12,510/microliter and WBC differential count of 78 segs, 8 bands, 11 lymphs, and 3 monos. A blood culture is positive for Escherichia coli. Her central venous pressure falls markedly. She goes into hypovolemic shock as a result of the widespread inappropriate release of a chemical mediator derived from macrophages. She develops multiple organ failure. Which of the following mediators is most likely to produce these findings? A Nitric oxide B Bradykinin C Histamine D Prostacyclin E Complement C3a

E Bacterial infections often evoke an acute inflammatory response dominated by neutrophils. The extravasated neutrophils attempt to phagocytose and kill the bacteria. In the process, some neutrophils die, and the release of their lysosomal enzymes can cause liquefactive necrosis of the tissue. This liquefied tissue debris and both live and dead neutrophils comprise pus, or purulent exudate. Such an exudate is typical of bacterial infections that involve body cavities. Another term for purulent exudate in the pleural space is empyema. An abscess is a localized collection of neutrophils within tissues. Chronic inflammation occurs when there is a preponderance of mononuclear cells, such as lymphocytes, macrophages, and plasma cells, in a process that has gone on for more than a few days—more likely weeks or months—or that accompanies repeated bouts of acute inflammation. Edema refers to increased cellular and interstitial fluid collection within tissues, leading to tissue swelling. In fibrinous inflammation, exudation of blood proteins (including fibrinogen, which polymerizes to fibrin) gives a grossly shaggy appearance to surfaces overlying the inflammation. A serous effusion is a watery-appearing transudate that resembles an ultrafiltrate of blood plasma, with a low cell and protein content.

A 68-year-old man has had worsening shortness of breath for the past week. On physical examination, his temperature is 38.3° C. On percussion, there is dullness over the left lung fields. Thoracentesis performed on the left pleural cavity yields 800 mL of cloudy yellow fluid that has a WBC count of 2500/mm3 with 98% neutrophils and 2% lymphocytes. A Gram stain of the fluid shows gram-positive cocci in clusters. Which of the following terms best describes the process occurring in his left pleural cavity? A Abscess B Chronic inflammation C Edema D Fibrinous inflammation E Purulent exudate F Serous effusion

E. E The formation of an exudate containing a significant amount of protein and cells depends on the "leakiness" of blood vessels, principally venules. When exudation has occurred, the protein content of the extravascular space increases, and extravascular colloid osmotic pressure increases, causing extracellular fluid accumulation. Leukocytosis alone is insufficient for exudation because the leukocytes must be driven to emigrate from the vessels by chemotactic factors. The lymphatics scavenge exuded proteinaceous fluid and reduce the amount of extravascular and extracellular fluid. Sodium and water retention helps drive transudation of fluid.

A 72-year-old man with severe emphysema has had worsening right ventricular failure for the past 5 years. For the past 4 days, he has had fever and increasing dyspnea. A chest radiograph shows an accumulation of fluid in the pleural spaces. Fluid obtained by thoracentesis has a specific gravity of 1.030 and contains degenerating neutrophils. The most likely cause of this fluid accumulation is due to changes in which of the following? A Colloid osmotic pressure B Leukocytic diapedesis C Lymphatic pressure D Renal sodium retention E Vascular permeability

b Viral illnesses, including those caused by common viral respiratory pathogens such as influenza, often produce chronic inflammation that is mainly interstitial in the lungs. The lack of an alveolar filling process results in the lack of a productive cough.

A 72-year-old woman did not get a 'flu' shot in the fall as recommended for older persons. In the wintertime, she became ill, as many people in her community did, with a respiratory illness that lasted for 3 weeks. During this illness, she had a fever with a non-productive cough, mild chest pain, myalgias, and headache. What was her chest radiograph most likely to have shown during this illness? A Hilar mass B Interstitial infiltrates C Hilar lymphadenopathy D Lobar consolidation E Pleural effusions

C. Endothelial cells can release nitric oxide to promote vasodilation in areas of ischemic injury. Bradykinin mainly increases vascular permeability and produces pain. Leukotriene E4, platelet-activating factor, and thromboxane A2 have vasoconstrictive properties.

A 77-year-old woman experiences a sudden loss of consciousness, with loss of movement on the right side of the body. Cerebral angiography shows an occlusion of the left middle cerebral artery. Elaboration of which of the following mediators will be most beneficial in preventing further ischemic injury to her cerebral cortex? A Bradykinin B Leukotriene E4 C Nitric oxide D Platelet-activating factor E Thromboxane A2

D. Hageman factor (factor XII as measured in the intrinsic coagulation pathway) becomes activated upon contact with injured, exposed vascular basement membrane.

A 9-year-old girl sustains a small 0.5 cm long laceration to her right index finger while playing 'Queen of Swords' with a letter opener. Which of the following substances, on contact with injured vascular basement membrane, activates both the coagulation sequence and the kinin system as an initial response to this injury? A Thromboxane B Plasmin C Platelet activating factor D Hageman factor E Histamine

B. The formation of a fluid filled cavity following an infection with S. aureus suggests that liquefactive necrosis has occurred. The cavity is filled with tissue debris and viable and dead neutrophils (pus). Localized, pus filled cavities are called abscesses. The liquified contents seek a level (air-fluid level).

A 94-year-old woman has developed a fever and cough over the past 2 days. Staphylococcus aureus is cultured from her sputum. She receives a course of antibiotic therapy. Two weeks later she no longer has a productive cough, but she still has a fever. A chest radiograph reveals a 3 cm rounded density in the right lower lobe whose liquefied contents form a central air-fluid level. There are no surrounding infiltrates. Which of the following is the best description for this outcome of her pneumonia? A Hypertrophic scar B Abscess formation C Regeneration D Bronchogenic carcinoma E Chronic inflammation F Granulomatous cavitation

D. Selectins are adhesive molecules expressed on endothelial cell surfaces and attract leukocytes, mainly neutrophils. P-selectin is expressed rapidly, while E-selectin is expressed within several hours.

A small sliver of wood becomes embedded in the finger of a 25-year-old man. He does not remove it, and over the next 3 days the area around the sliver becomes red, swollen, and tender. Neutrophils migrate into the injured tissue. Expression of which of the following substances on endothelial cells is most instrumental in promoting this inflammatory reaction? A Interferon gamma B Hageman factor C Lysozyme D E-selectin E Prostacyclin

Walled off collection of pus (neutrophils and necrotic debris) in infected tissues ◦ Area of suppuration walled off by fibrosis Requirements for abscess formation: ◦ Body cannot rid itself of inciting agent ◦ Repair and scarring more rapid Location: ◦ Any organ in the body Complications of an abscess: ◦ Pain, fever, rupture, swelling

Abscess

1. Endothelial activation -Increased expression of adhesion molecules -Increased production of mediators 2. Activation of leukocytes and other cells 3. Systemic acute phase response • Fever, cachexia and sepsis

Actions of IL-1 and TNF

E The findings here are those of strep throat with acute inflammation. Bacterial organisms often lead to fever accompanying infection through release of exogenous pyrogens that induce inflammatory cells to release endogenous pyrogens such as tumor necrosis factor (TNF) and interleukin-1 (IL-1). The pyrogens stimulate prostaglandin synthesis in the hypothalamus to "reset the thermostat," so that fever occurs as a sign of the acute inflammatory response. Hageman factor initiates the coagulation cascade. Immunoglobulin E is often increased in response to inflammatory responses with allergens and with invasive parasites. Interleukin-12 (IL-12) released by macrophages stimulates T-cell responses. Nitric oxide generated in endothelium leads to vasodilation, whereas nitric oxide produced in macrophages aids in microbial killing.

An 8-year-old girl has had difficulty swallowing for the past day. On examination, her pharynx is swollen and erythematous with an overlying yellow exudate. Laboratory studies show neutrophilia. Streptococcus pyogenes (group A streptococcus) is cultured from her pharynx. Which of the following substances is most likely to increase in response to pyrogens released by this organism? A Hageman factor B Immunoglobulin E C Interleukin-12 (IL-12) D Nitric oxide E Prostaglandins

D If inflammation is limited and brief, and the involved tissue can regenerate, then resolution is the likely outcome, without significant loss of function. In older persons this may take longer, but can still occur. Multiple bouts of acute inflammation, or ongoing inflammation, can become chronic, and there tends to be loss of some tissue function. If 28significant tissue destruction occurs, there is likely to be formation of a fibrous scar in the region of the tissue loss. Acute inflammation is not a preneoplastic event. Ulceration refers to loss of an epithelial surface with acute inflammation; if the epithelium regenerates, then there is resolution.

An 87-year-old woman has had a cough productive of yellowish sputum for the past 2 days. On examination her temperature is 37° C. A chest radiograph shows bilateral patchy infiltrates. Her peripheral blood shows leukocytosis. A week later she is afebrile. Which of the following is the most likely outcome of her pulmonary disease? A Chronic inflammation B Fibrous scarring C Neoplasia D Resolution E Ulceration

B Fibronectin is a key component of the extracellular matrix and has a structure that looks like a paper clip. Fibronectin can be synthesized by monocytes, fibroblasts, and endothelium. Dermatan sulfate, a glycosaminoglycan, forms a gel that provides resilience and lubrication. Heparin that is infused has an anticoagulant function. Hyaluronic acid binds water to form a gelatinous extracellular matrix. Procollagen produced by fibroblasts is formed into ropelike strands of collagen, which provide tensile strength.

An experiment is conducted involving cellular aspects of wound healing. Components of the extracellular matrix are analyzed to determine their sites of production and their binding patterns to other tissue components. Which of the following molecules synthesized by fibroblasts can best bind to cellular integrins and extracellular collagen and attach epidermal basal cells to basement membrane? A Dermatan sulfate B Fibronectin C Heparin D Hyaluronic acid E Procollagen

A. Mycobacterial organisms are difficult to kill, because of their lipid coat of mycolic acid. Hence a neutrophilic response has little effect. This persistent infection requires macrophage activation that leads to granuloma formation.

An inflammatory process that has continued for 3 months includes the transformation of tissue macrophages to epithelioid cells. There are also lymphocytes present. Over time, fibroblasts lay down collagen as the focus of inflammation heals. These events are most likely to occur as an inflammatory response to which of the following infectious agents? A Mycobacterium tuberculosis B Pseudomonas aeruginosa C Cytomegalovirus D Giardia lamblia E Treponema pallidum

Thin, watery exudate (liquefactive necrosis) Spreads throughout subcutaneous tissue eg. Erysipelas due to Streptococcus pyogenes

Cellulitis

Clinical features ◦ Tendency to develop repeated infections (especially Staphylococcus aureus infections) ◦ Cranial and peripheral neuropathy, hepatosplenomegaly ◦ Oculocutaneous albinism (very fair skin, white or light-colored hair, reduces pigmentation of iris) ◦ Impaired uptake of pigmented melanosomes -- pigmentation block Pathogenesis - Defects in microtubule polymerization in WBCs a) Defects in phagocytosis b) Defects in chemotaxis (impaired motility) c) Defects in degranulation (fusion of lysosomes with phagosomes prevented) Labs - Neutropenia

Chediak-Higashi Syndrome

CXC: IL-8 CC: Monocytes, eosinophils, basophils, lymphocytes C: Lymphocytes

Chemokines (CXC, CC, C)

◦ Inherited defect in NADPH oxidase ◦ Deficiency of oxygen-dependent killing ◦ Defect in respiratory burst and H2O2 bactericidal mechanisms ◦ NBT dye test is abnormal (negative)

Chronic granulomatous disease

C3a and C5a: increase vascular permeability and vasodilation. They are anaphylotoxins C5a: chemotaxis C3b: opsonins that trigger phagocytosis

Complements role in inflammation

◦ Small aggregates of modified (activated) macrophages ◦ Epithelioid cells ◦ Activated macrophages fuse → multinucleated giant cells (Langhans-type giant cells) ◦ Central necrosis may be seen ◦ Peripheral rim of lymphocytes ◦ Lymphocytes secrete factors for macrophage activation

Composition of a granuloma

D. These transformed cells are designated iPS cells because they have been induced to become pleuripotent. This transformation process gets around the problem of using embryonic stem (ES) cells derived from manipulation of human embryos, which raises ethical and religious concerns. Embryonic stem cells are totipotent, but they become pleuripotent cells that can further divide into many different cell lines, yet maintain themselves in a replicating pool. Thus pleuripotent cells are the next best thing compared to embryonic cells for deriving human cells that could replace damaged or diseased tissues. Further differentiation of pleuripotent cells gives rise to cells with more restricted developmental capacity, such as mesenchymal stem cells that can give rise to tissues such as muscle and cartilage but not to endodermal or ectodermal cells.

Dermal fibroblasts are harvested from the skin biopsy specimen of an adult man. These fibroblasts are transduced with genes encoding for transcription factors including SOX2 and MYC. Under appropriate culture conditions these cells are then able to generate endodermal, mesodermal, and ectodermal cells. Into which of the following kinds of stem cell have these fibroblasts been transformed? A Embryonic B Lineage-committed C Mesenchymal D Pleuripotent

Acute inflammatory response with neutrophils ◦ Bacterial meningitis, bronchopneumonia, abscess

Exudative inflammation

• Appearance: Finely particulate, thick fluid. • Contents of fluid: • More protein and cells than serous inflammation (exudate: Fibrinogen-rich fluid with specific gravity> 1.020). • Seen in: 1. Pericarditis associated with • Rheumatic fever • Post-myocardial infarct • Uremia • SLE • Coxsackie virus infection 2. Pleuritis associated with infarction or pneumonia

Fibrinous inflammation

TH1 cells produce cytokine IFN- γ, which activates macrophages by the classical pathway. TH2 cells secrete IL-4, IL-5, and IL-13, which activate the alternative pathway of macrophage activation. TH17 cells secrete IL-17 and other cytokines

Functions of lymphocytes

1. Phagocytosis ◦ Ingest and eliminate microbes and dead tissues 2. Initiate the process of tissue repair 3. Chemotactic factors 3. Secrete mediators of inflammation • Cytokines (TNF, IL-1), chemokines 4. Present antigens to T lymphocytes; respond to signals from T cells

Functions of macrophages

Granulomatous response predominates Slow-growing organisms ◦ Mycobacteria, Fungi, Parasites

Granulomas inflammation

C1 inhibited

Hereditary angioedema

F The COX-2 enzyme is inducible with acute inflammatory reactions, particularly in neutrophils, in synovium, and in the central nervous system. The cyclooxygenase pathway of arachidonic acid metabolism generates prostaglandins, which mediate pain, fever, and vasodilation. Ankle swelling is most likely to result from peripheral edema secondary to congestive heart failure. Increased susceptibility to bruising results from prolonged glucocorticoid administration, which also causes leukopenia. Asthma results from bronchoconstriction mediated by leukotrienes that are generated by the lipoxygenase pathway of arachidonic acid metabolism. Inhibition of histamine released from mast cells helps reduce urticaria. Fever can be mediated by prostaglandin release, not inhibition.

In a 6-month randomized trial of a pharmacologic agent, one group of patients receives a cyclooxygenase-2 (COX-2) inhibitor, and a control group does not. Both groups of adult males had mild congestive heart failure and bilateral symmetric arthritis of small joints. Laboratory measurements during the trial show no significant differences between the groups in WBC count, platelet count, hemoglobin, and creatinine. The group receiving the drug reports subjective findings different from those of the control group. Which of the following findings was most likely reported by the group receiving the drug? A Increased ankle swelling B Increased susceptibility to bruising C Increased bouts of asthma D Reduced severity of urticaria E Numerous febrile episodes F Reduced arthritis pain

C. Cell surface growth factor receptors recruit intracellular protein kinases that begin a sequence of events leading to cell division and growth.

In a clinical study, patients undergoing laparoscopic cholecystectomy are followed to document the post-surgical wound healing process. The small incisions are closed with sutures. Over the 4 weeks following surgery, the wounds are observed to regain tensile strength and there is re-epithelialization. Of the following substances, which is most likely found to function intracellularly in cells involved in this wound healing process? A Fibronectin B Laminin C Tyrosine kinase D Hyaluronic acid E Collagen

C Integrins interact with the extracellular matrix proteins (e.g., fibronectin). Engagement of integrins by extracellular matrix proteins leads to the formation of focal adhesions where integrins link to intracellular cytoskeletal elements such as actin. These interactions lead to intracellular signals that modulate cell growth, differentiation, and migration during wound healing. Epidermal growth factor stimulates epithelial cell and fibroblast proliferation. Platelet-derived growth factor (PDGF) can be produced by endothelium, macrophages, smooth muscle cells, and platelets; PDGF mediates migration and proliferation of fibroblasts and smooth muscle cells and migration of monocytes. Type IV collagen is found in basement membranes on which cells are anchored. Vascular endothelial growth factor promotes angiogenesis (capillary proliferation) through endothelial cell proliferation and migration in a healing response.

In an experiment involving observations on wound healing, researchers noted that intracytoplasmic cytoskeletal elements, including actin, interact with the extracellular matrix to promote cell attachment and migration in wound healing. Which of the following substances is most likely responsible for such interaction between the cytoskeleton and the extracellular matrix? A Epidermal growth factor B Fibronectin C Integrin D Platelet-derived growth factor E Type IV collagen F Vascular endothelial growth factor

A. The C3b fragment generated from the complement cascade serves as an effective opsonin, attaching to the bacteria so that phagocytes will find and engulf them more easily.

In an experiment, Enterobacter cloacae organisms are added to a solution containing leukocytes and blood plasma. Engulfment and phagocytosis of the microbes is observed to occur. Next a substance is added which enhances engulfment, and more bacteria are destroyed. Which of the following substances in the plasma is most likely to produce this effect? A Complement C3b B Glutathione peroxidase C Immunoglobulin M D P-selectin E NADPH oxidase

C Hepatocytes are stable cells with an extensive ability to regenerate. The ability to restore normal architecture of an organ such as the liver depends on the viability of the supporting connective tissue framework. If the connective tissue cells are not injured, hepatocyte regeneration can restore normal liver architecture. This regeneration occurs in many cases of viral hepatitis. A liver abscess associated with liquefactive necrosis of hepatocytes and the supporting connective tissue heals by scarring. The other options listed may explain the amount of liver injury, but not the nature of the response.

In an experiment, a group of test animals is infected with viral hepatitis. Two months later, complete recovery of the normal liver architecture is observed microscopically. A control test group is infected with bacterial organisms, and after the same period of time, fibrous scars from resolving hepatic abscesses are seen microscopically. Which of the following factors best explains the different outcomes for the two test groups? A Extent of damage to the biliary ducts B Extent of the hepatocyte injury C Injury to the connective tissue framework D Location of the lesion within the liver E Nature of the injurious etiologic agent

F The figure shows a subacute infarction with granulation tissue formation containing numerous capillaries stimulated by vascular endothelial growth factor, representing a healing response. Epidermal growth factor aids in reepithelialization of a surface wound. Interleukin-2 (IL-2) mediates lymphocyte activation. Leukotriene B4 mediates vasoconstriction and bronchoconstriction. Thromboxane A2 aids vasoconstriction and platelet aggregation. Tumor necrosis factor (TNF) induces endothelial activation and many responses that occur secondary to inflammation, including fever, loss of appetite, sleep disturbances, hypotension, and increased corticosteroid production.

In an experiment, glass beads are embolized into the coronary arteries of rats, resulting in myocardial injury. After 7 days, sections of the myocardium are studied using light microscopy. The microscopic appearance of one of these sections is shown in the figure. Which of the following mediators is most likely being expressed to produce this appearance? A Epidermal growth factor B Interleukin-2 (IL-2) C Leukotriene B4 D Thromboxane A2 E Tumor necrosis factor (TNF) F Vascular endothelial growth factor

B The respiratory, or oxidative, burst of neutrophils generates reactive oxygen species (e.g., superoxide anion) that are important in destruction of engulfed bacteria. This burst can be quantitated by flow cytometric analysis. Neutrophil attachment to endothelium is aided by adhesion molecules on both the endothelium and the neutrophil surface. These molecules include selectins and integrins. Myelopoiesis does not depend on generation of superoxide. Bacteria are opsonized by complement C3b and IgG, allowing the bacteria to be more readily phagocytosed.

In an experiment, neutrophils collected from peripheral blood are analyzed for a "burst" of oxygen consumption. This respiratory burst is an essential step for which of the following events in an acute inflammatory response? A Attachment to endothelial cells B Generation of microbicidal activity C Increased production in bone marrow D Opsonization of bacteria E Phagocytosis of bacteria

E TGF-β stimulates many steps in fibrogenesis, including fibroblast chemotaxis and production of collagen by fibroblasts, while inhibiting degradation of collagen. All of the other steps listed are unaffected by TGF-β.

In an experiment, surgical incisions are made in a study group of laboratory rats. Observations about the wounds are recorded over a 2-week period using various chemical mediators. Which of the following steps in the inflammatory-repair response is most likely affected by neutralization of transforming growth factor β (TGF-β)? A Chemotaxis of lymphocytes B Increase in vascular permeability C Leukocyte extravasation D Migration of epithelial cells E Production of collagen

D. FGF can stimulate all aspects of angiogenesis

In an experiment, surgical wound sites are observed following suturing. An ingrowth of new capillaries is observed to occur within the first week. A substance elaborated by macrophages is found at the wound site to stimulate this capillary proliferation. Which of the following substances is most likely to have this function? A Platelet-derived growth factor B Phospholipase C-gamma C Fibronectin D Fibroblast growth factor E Epidermal growth factor

B Embryonic stem (ES) cells are multipotent and can give rise to all cells, including hepatocytes. Gene targeting to produce knockout mice is done in cultures of ES cells, which are then injected into mouse blastocysts and implanted into the uterus of a surrogate mother. Mesenchymal stem cells also are multipotential, but they are not useful for gene targeting. Hematopoietic stem cells can give rise to all hematopoietic cells, but not other types of cells. Hepatocytes and oval cells within the liver can give rise only to liver cells.

In an experiment, the role of low-density lipoprotein (LDL) receptors in uptake of lipids in the liver is studied. A mouse model is created in which the LDL receptor gene is not expressed in the liver. For creating such a knockout mouse, which of the following cells would be most useful? A Adult bone marrow mesenchymal progenitor cells B Embryonic stem cells in culture C Hematopoietic stem cells D Hepatic oval cells E Regenerating hepatocytes

Immediate Transient -Post-capillary venules -Endothelial contraction mediated by histamine, bradykinin -Bee sting Immediate sustained -Arterioles, venules, capillaries -Endothelial cell necrosis mediated by bacterial enzymes -Trauma, burns, bacterial infections Delayed prolonged -Venules -Late appearing sunburn

Increase vascular permeability mechanisms

Diffuse mononuclear interstitial infiltrate Common response to viral infections ◦Interstitial pneumonitis, myocarditis (Coxsackie), viral hepatitis

Interstitial inflammation

Mutations in gene encoding for fucosyl-transferase ◦ Required for synthesis of sialyl-Lewis X on neutrophils Pathogenesis: Defective leukocyte rolling Clinical features ◦ Recurrent, but less severe and fewer infections ◦ Short stature, abnormal facies, mental retardation ◦ No delay in detachment of umbilical cord

Leukocyte Adhesion Deficiency Type II (LAD2)

Mutation in β chain of CD11/CD18 integrins, neutrophils can roll but cannot stick Recurrent bacterial infections (skin, mucous membranes)

Leukocyte adhesion deficiency 1

1. Margination, rolling (selectins) and adhesion (pavementing, integrins) of leukocytes to endothelium 2. Transmigration across the endothelium and vessel wall (diapedesis), Movement between endothelial cells via integrin attachment and adherence to PECAM-1. Emigration is facilitated by Leukocyte-derived collagenases (i.e. type IV collagen) 3. Migration in interstitial tissues towards a chemotactic stimulus

Leukocyte delivery

Infiltration with mononuclear cells ◦ Macrophages, lymphocytes, plasma cells Tissue destruction ◦ Induced by persistent offending agent or by inflammatory cells Attempts at healing -Fibrosis

Morphological features of chronic inflammation

Myeloperoxidase • Responsible for peroxidase activity of azurophilic granules in neutrophils • Greenish color of pus •Myeloperoxidase deficiency • Mild to moderate defect in bacterial killing • Marked defect in fungal killing

Myeloperoxidase Deficiency

Marked tissue necrosis and hemorrhage Eg. Many virulent organisms -like anthrax, herpes simplex encephalitis

Necrotising inflammation

Defect in DAF RBC lysis and anemia

Paroxysmal Nocturnal hemoglobinuria

1. Recognition and attachment 2. Engulfment: Bacteria are internalized within a phagosome. Phagosome fuses with lysosomes (degranulation) containing myeloperoxidase (MPO) → phagolysosomes 3. Killing or degradation: A. Reactive oxygen species (ROS) or reactive oxygen intermediates (ROI) B. Reactive nitrogen species derived from nitric oxide (NO) C. Lysosomal enzymes

Phagocytosis

Toxin-induced superficial mucosal damage Shaggy membrane compose of necrotic tissue formed along a mucosal surface 1. Pseudomembrane of diphtheria • associated with Corynebacterium diphtheriae 2. Pseudomembranous colitis • associated with Clostridium difficile

Pseudo-membranous inflammation

•Appearance: Pus (thick, white-yellow fluid). •Contents of fluid: Neutrophils, protein, and necrotic cells (i.e., an exudate). •Seen in: Bacterial (staphylococci, streptococci, gram negative bacilli) and fungal infections

Purulent inflammation

◦ Release of energy from this reaction requires ◦ Oxygen and activation of NADPH oxidase ◦ Converts O2 to superoxide, OH- radicals, H2O2 ◦ Detected by Nitro-blue tetra-zolium (NBT) dye test

Respiratory burst-kill

Appearance: ◦ Relatively clear, thin, watery fluid. Contents of fluid: ◦ Few cells ◦ Mainly transudate (protein-poor fluid with a specific gravity < 1.012). Seen in: ◦ Viral infections ◦ Blister fluid in second-degree burns

Serous inflammation

Loss of mucosa and deeper tissues Microscopic morphology of an ulcer: ◦ 4 layers, from superficial to deep, are fibrin, neutrophils, granulation tissue, and fibrosis. Location: GIT (most common) ◦ Predisposing factors : NSAIDS, Zollinger-Ellison syndrome Complications of an ulcer: ◦ Pain ◦ Hemorrhage, if ulcer involves a vessel ◦ Perforation ---- hemorrhage within a cavity or lumen of GIT ◦ Seeding of peritoneal cavity with GIT contents --- peritonitis

Ulcer

1. Infections ◦ Bacterial, viral, fungal, parasitic and microbial toxins 2. Tissue necrosis ◦ Ischemia (eg. myocardial infarct) ◦ Physical and chemical injury (e.g., thermal injury, as in burns or frostbite; irradiation; exposure to environmental chemicals). 3. Foreign bodies ◦ Splinters, dirt, sutures 4. Immune reactions (or hypersensitivity reactions) Cardinal Signs: redness and heat (vasodilation, induced by histamine), swelling, pain (PGE2, bradykinin)

What are the causes and cardinal signs of inflammation?

LTB4, C5a, IL-8, bacterial products

What are the key mediators that attract neutrophils?

DAF inhibits C3 Convertase CD59 inhibits MAC formation

What does DAF and CD59 inhibit?

Focal accumulation of activated macrophages ◦ Activated macrophages become enlarged and flattened (Epithelioid macrophages) ◦ Interferon-gamma (IFN-γ) transforms macrophages (enlarged cell with abundant pink cytoplasm)

What is a granuloma?

-Systemic effects of inflammation ◦ Mediated by cytokines ◦ IL-6 (CRP, fibrinogen) ◦ IL-1, TNF (SAA) -Hepatic synthesis of acute phase proteins • C-reactive protein (CRP), serum amyloid protein (SAA), complement, fibrinogen --- Rouleaux formation of RBCs - ↑ ESR, prothrombin, α-1 anti-trypsin, α-2 macroglobulin, ferritin, ceruloplasmin -Synthesis of adhesion molecules -Neutrophil granulation

What is an acute phase response?

Platelet aggregation, release and broncho-constriction • Vasodilation and increased vascular permeability • Increased leukocyte adhesion and chemotaxis

What is the function of Platelet Activating Factor

LTB4, TNF, IL-1, chemokines, C3a, C5a

What mediators are involved with chemotaxis, leukocyte recruitment and activation

IL-1, TNF, Prostaglandins

What mediators are involved with fever

PGE2 and bradykinin

What mediators are involved with pain

Histamine, serotonin, C3a, C5a, leukotrienes C,D,E

What mediators increase vascular permeability?