inflammation and repair reading objectives

33. Summarize the roles that Transforming growth factor-β and Platelet-derived growth factor play in tissue repair and scar formation.

*TGF-beta and PDGF recruit and activate fibroblasts*. TGF-beta triggers production of collagen, fibronectin, and proteoglycan and inhibits collagen degradation by decreasing proteinase and increasing tissue inhibitors of proteinases, TiMPs. TGF-beta is also anti-inflammatory because it inhibits leukocyte proliferation. PDGF is stored in platelets and released when platelets are activated. It causes migration and proliferation of of fibroblasts and smooth muscle cells and may contribute to migration of macrophages too.

19. Further explain the role of the *complement system* in inflammation and identify the key complement components. Differentiate between the classical, alternative, and lectin pathways. Define the membrane attack complex (MAC) and explain how it is formed. Identify which complement components are considered anaphylatoxins. Show how C1 inhibitor, decay-accelerating factor, and Factor H regulate the complement system.

*complement system* consists of plasma proteins that play an important role in host defense (immunity) and inflammation. contributes to the inflammatory response by *increasing permeability and leukocyte chemotaxis*. *MAC=membrane attack complex* that *forms pores* in the membranes of invading microbes; initiated by complement activation. classical, alternative, and lectin pathways all result in cleavage of C3 by different mechanisms. *classical pathway* is triggered by *C1 fixing to antigen-antibody complexes*. The *alternative pathway* is triggered by *bacterial polysaccharides* and other microbial cell wall components and *uses plasma proteins like properdin and factors B and D*. The lectin pathway occurs when *plasma lectin binds to mannose* residues on the pathogen and activates early component in the classical pathway, *without the presence of antibodies*. *anaphylatoxins are C3a and C5a* because they mimic the action of mast cells (which cause anaphylaxis) *C1 inhibitor, decay-accelerating factor, and factor H regulate the complement system*; all protect normal cells from damage during reactions against microbes. C1 inhibitor blocks activation of C1. Decay-accelerating factor limits the formation of C3 and C5 convertases. Factor H is a plasma protein that almost limits convertase formation.

27. Define the 2 types of stem cells and identify 2 important properties of these cells.

*embryonic stem cells* are the most undifferentiated stem cell. present in inner cell mass of blastocyst and can renew. they can be maintained in culture for over a year without differentiating. can be induced to form specialized cells of all three germ layers including neurons, cardiac muscle, liver cells, and pancreatic islet cells. adult stem cells/tissue stem cells are less undifferentiated and found among differentiated cells within an organ or tissue. They have self-renewal capacity, but it's more limited. their lineage potential is also restricted to some or all of the differentiated cells of the tissue or organ they're found in.

9. Compare and contrast an exudate and a transudate. Identify which one would be seen during an inflammatory response.

*exudate=protein-rich* accumulation in *extravascular* tissues from *increased osmotic pressure*. This is the one that is seen in an *inflammatory response* *transudate=interstitial fluid* accumulations from *increased hydrostatic pressure* (usually from decreased venous return). usually doesn't have much protein or many blood cells in it

35. Compare and contrast healing by first and second intention.

*healing by 1st intention*: healing of clean *surgical incision*. it causes only focal disruption of epithelial basement membrane continuity and death of relatively few epithelial and CT cells. Epithelial regeneration is the principal mechanism of repair. *Small scar with minimal wound contraction*. *healing by second intention*: when cell or tissue loss is more extensive, the repair process involves a *combo of regeneration and scarring*. the inflammatory reaction is more intense and there is *lots of granulation tissue* with accumulation of ECM and formation of a large scar with wound contraction mediated by myofibroblasts. It has a larger clot/scab rich in fibrin and fibronectin forms at surface of the wound. inflammation if more intense so there is more necrotic debris, exudate, and fibrin. greater volume of granulation and greater mass of scar tissue. within 6 weeks, large skin defects may be reduced largely by contraction.

7. State how cells of the human body recognize harmful agents such as microbes and dead cells. Identify examples.

*phagocytes, DCs*, and many other cells *express receptors, called PRRs*, that are designed to *sense the presence of infectious pathogens* and substances released from dead cells two types of PRRs: *TLRs and inflammasomes*. *TLRs* are microbial sensors found in *plasma membranes and endosomes* that detect extracellular and digested microbes. *inflammasomes are cytoplasmic* complexes that recognize products of dead cells and trigger the inflammatory response via caspase1.

5. List the steps of the inflammatory response. ("five R's")

1. Recognition of the injurious agent 2. Recruitment of leukocytes 3. Removal of agent 4. Regulation (control) of the response 5. Resolution (repair)

2. List the external manifestations (cardinal signs) of inflammation. Describe why each manifestation occurs.

1. heat (calor) 2. redness (rubor) 3. swelling (tumor) 4. pain (dolor) 5. loss of function (functio laesa) these all occur because of the vascular changes (vasodilation, increased vascular permeability) and leukocyte recruitment and activation (emigration of leukocytes from circulation to site of injury, activation of leukocytes) that occur in inflammation

28. Review the 3 main types of plasma membrane receptors involved in signal transduction pathways.

1. receptors with intrinsic kinase activity: binding of ligand causes dimerization and phosphorylation of receptor subunits. the receptor can then bind other intracellular proteins and stimulate downstream signals leading to cell proliferation or other transcription programs. 2. g-protein coupled receptors: 7 transmembrane alpha helix segments. after ligand binds, the receptor associates with intracellular GTP-binding proteins (G proteins) that contain GDP. binding of G proteins causes exchange of GDP with GTP, leading to activation of proteins. 3. receptors without intrinsic enzymatic activity: monomereic transmemrbrane molecules. when ligand binds there is conformational change that allows association with intracellular JAK. phosphorylation of JAK activates transcription factors, STATs, which shuttle into the nucleus and induce transcription of target genes.

12. Summarize the 3 steps of phagocytosis and the process of opsonization and list some important opsonins described in the textbook.

1. recognize and attach the particle to the ingesting leukocyte 2. engulf & subsequent formation of phagocytic vacuole 3. kill and degrade the ingested material opsonization=opsonins (an antibody or other substance that binds to foreign microorganisms or cells) coat microbes and target them for phagocytosis the most important opsonins are antibodies of the immunoglobulin G (*IgG*) that bind to microbial surface antigens, *breakdown products of C3*, and *plasma carbohydrate-binding lectins called collectins* (bind to microbial cell wall sugar groups)

29. Identify the 2 basic forms of extracellular matrix. List the 3 basic components of extracellular matrix. Describe the regular functions of the extracellular matrix and the role it plays in regeneration.

2 basic forms of extracellular matrix: 1. interstitial matrix 2. basement membrane 3 basic components of extracellular matrix 1. fibrous structural proteins like collagen and elastin for strength and recoil 2. water-hydrated gels like proteoglycans and hyaluronan, which permit resilience and lubrication 3. adhesive glyocproteins that connect matrix elements to one another and to cells functions of ECM: provide support for the cell, control cell proliferation, provide scaffolding for tissue renewal (*KEY for regeneration because you need the basement membrane for organized regeneration of tissues*), establish tissue microenvironment.

E. prostaglandins 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 fac-tor 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, where-as nitric oxide produced in macrophages aids in microbial killing.

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

A Collagen degradation exceeds synthesis 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. collagen deposition 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 corticoste-roids. 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. 1 month: 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 inflamma-tory cells. Macrophages and granulation tissue are seen 2 to 3 days postoperatively. Neovascularization is most promi-nent 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

E Release of lysosomal enzymes from neutrophils she has an infective endocarditis with septic embolization, producing a cerebral abscess. The tissue destruction that accompanies abscess formation as part of acute inflammatory processes occurs from lysosomal enzymatic destruction, aided by release of reactive oxygen species. Nitric oxide generated by macrophages aids in destruction of infectious agents.

A 29-year-old woman with a congenital ventricular septal defect has had a persistent temperature of 38.6° C and headache for the past 3 weeks. A head CT scan shows an enhancing 3-cm, ring like lesion in the right parietal lobe of her brain. Which of the following actions by inflammatory cells has most likely produced this CT finding? A Elaboration of nitric oxide by macrophages B Formation of immunoglobulin by B lymphocytes C Generation of prostaglandin by endothelium D Production of interferon-γ by T lymphocytes E Release of lysosomal enzymes from neutrophils

D Wound contraction is a characteristic feature of healing by second intention that occurs in larger wounds. Collagen synthesis helps fill the defect, but does not contract it. Adhesive glycoproteins such as fibronectin help to main-tain a cellular scaffolding for growth and repair, but they do not contract. The inhibition of metalloproteinases leads to decreased degradation of collagen and impaired connective tissue remodeling in wound repair. Edema diminishes over time, but this does not result in much contraction.

A 40-year-old man underwent laparotomy for a per-forated sigmoid colon diverticulum. A wound infection complicated the postoperative course, and surgical wound dehiscence occurred. Primary closure was no longer pos-sible, and the wound "granulated in." Six weeks later, the wound is only 10% of its original size. Which of the fol-lowing processes best accounts for the observed decrease in wound size over the past 6 weeks? A Elaboration of adhesive glycoproteins B Increase in synthesis of collagen C Inhibition of metalloproteinases D Myofibroblast contraction E Resolution of subcutaneous edema

E. TNF: Fever is produced by various inflammatory mediators, but the major cytokines that produce fever are inter-leukin-1 (IL-1) and tumor necrosis factor (TNF), which are produced by macrophages and other cell types. IL-1 and TNF can have autocrine, paracrine, and endocrine effects. They mediate the acute phase responses, such as fever, nausea, and neutrophil release from bone marrow. Brady-kinin, generated from the kinin system on surface contact of Hageman factor with collagen and basement membrane from vascular injury, promotes vascular permeability, smooth muscle contraction, and pain. Histamine released from mast cells is a potent vasodilator, increasing vascular permeability. Leukotriene B4, generated in the lipoxygenase pathway of arachidonic acid metabolism, is a potent neu-trophil chemotactic factor. Nitric oxide generated by macro-phages aids in destruction of microorganisms; nitric oxide released from endothelium mediates vasodilation and in-hibits platelet activation.

A 41-year-old man has had a severe headache for the past 2 days. On examination, his temperature is 39.2° C. A lumbar puncture is performed, and the cerebrospinal fluid obtained has a WBC count of 910/mm3 with 94% neutrophils and 6% lymphocytes. Which of the following substances is the most likely mediator for the fever observed in this man? A Bradykinin B Histamine C Leukotriene B4 D Nitric oxide E Tumor necrosis factor (TNF)

C. interferon gamma Figure A shows diffuse reticulonodular pulmonary densities, and Figure B shows noncaseating granulomas with many epithelioid cells and two prominent large Langhans giant cells. this is likely sarcoidosis. Macrophage stimulation and transformation to epithelioid cells and giant cells are characteristic of granuloma formation. Interferon-γ promotes the formation of epi-thelioid cells and giant cells. Bradykinin is released in acute inflammatory responses and results in pain. Complement C5a is chemotactic for neutrophils. Although occasional neutro-phils are seen in granulomas, neutrophils do not form a major component of granulomatous inflammation. Macrophages can release nitric oxide to destroy other cells, but nitric oxide does not stimulate macrophages to form a granulomatous re-sponse. Prostaglandins are mainly involved in the causation of vasodilation and pain in acute inflammatory responses.

A 43-year-old man has had a cough and fever for the past 2 months. A chest CT scan shows the findings in the fig-ure (A). A transbronchial lung biopsy is performed, yielding a specimen with the microscopic appearance shown in the figure (B). Which of the following chemical mediators is most important in the pathogenesis of this lesion? A Bradykinin B Complement C5a C Interferon-γ D Nitric oxide E Prostaglandins

CRP 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 sedimenta-tion 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 macro-phages. 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 opso-nized 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)

4. Compare and contrast acute and chronic inflammation. Describe the cells involved in each type of inflammation, the morphologic patterns, and the settings each type of inflammation is seen in.

Acute inflammation has a *rapid onset* and is short in duration, lasting just a few minutes or a few days, and is characterized by fluid and plasma protein *exudation* and predominantly *neutrophil* accumulation. The damage to tissue is usually mild and self-limiting. *local and systemic signs are prominent*. Chronic inflammation may last longer (days to years) and there is an influx of *lymphocytes and macrophages/monocytes* associated with vascular proliferation and *fibrosis* (scarring). The *local and systemic signs are less prominent* than acute inflammation.

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 me-diates 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

C. injury to CT framework Hepatocytes are stable cells with an extensive abillity 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 con-trol 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 Vascular endothelial growth factor The figure shows a subacute infarction with granulation tissue formation containing numerous capillaries stimulated by vascular endothelial growth factor, repre-senting 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 ne-crosis 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

24. Describe the clinical and pathologic changes that are part of the acute-phase response. Identify the roles of IL-1, TNF, and IL-6.

acute phase response: fever, elevated plasma levels of acute phase proteins, leukocytosis *IL-1 and TNF lead to fever* because they *increase levels of cyclooxygenases that convert AA into prostaglandins*. *IL-6 stimulates production of acute phase proteins*

31. Define the term angiogenesis and identify the role that VEGF, FGF-2, Ang1, and Ang2 play in angiogenesis. Compare angiogenesis to the process of vasculogenesis.

angiogenesis: process of new blood vessel development from -re-existing vessels, mainly venules VEGF: increased permeability, growth factor, major inducer of angiogenesis after injury and in tumors, stimulates migration and porliferation fo endothelial cells FGF2: stimulates proliferation of endothelial cells, promotes migration of marophages and fibroblasts to the damaged area and stimulates peithelial cell migration to cover epidermal wounds Ang1: interacts with tyrosine kinase receptor on endothelial cells called Tie2. growth factor, plays role in structural maturation of new vessels Ang2: growth factor, plays role in structural maturation of new vessels vasculogenesis is the growth of blood vessels during embryonic development. these vessels are formed de novo by coalescence of endothelial precursors called angioblasts

32. Describe the role of fibroblasts in tissue repair. Identify the growth factors involved in recruitment and activation of fibroblasts.

fibroblasts go to site of injury and proliferate to lay down CT in the scar. The *recruitment and activation of fibroblasts include PDGF, FGF-2, and TGF-beta*. The major source of these is inflammatory cells like macrophages

23. Recognize the morphology of a granulomatous inflammation and identify the settings where this pattern of chronic inflammation is seen.

granulomatous inflammation morphology: *activated macrophages may have pink or granular cytoplasm* with indistinct cell boundaries=*epitheliod cells* (look like epithelia). aggregates of macrophages are *surrounded by lymphocytes*. *older granulomas may have a rim of fibroblasts and CT*. Frequently *multinucleate giant cells* are found in granulomas. associated with caseous necrosis. they are seen in *TB*, immune-mediated inflammatory diseases, and seen in a disease of unknown etiology called *sarcoidosis* forming foreign body granulomas.

34. Identify factors that can influence the tissue repair process.

infection (delays healing) nutrition (deficiencies can delay) glucocorticoids (anti-inflammatory) mechanical variables like increased pressure can break apart wounds poor perfusion impairs healing type and extent of injury location of injury and the tissue type abberrations of cell growth and ECM production

1. Define the term inflammation.

inflammation is a protective response that attempts to eliminate the cause of cell injury as well as necrotic cells and tissues resulting from original insult and initiate the process of repair

26. Review the differences between labile, stable/quiescent, and permanent tissues. Describe the ability of these tissues to regenerate after injury.

labile=continuously dividing tissues; readily regenerate after injury as long as the pool of stem cells is preserved. stable/quiescent=only have minimal replicative activity in their normal state; have a limited capacity to regenerate after injury with the exception of the liver. permanent=terminally differentiated and nonproliferative; can't regenerate and scar

16. Identify the inflammatory defect in the following disorders, and predict the consequences of the inflammatory defect: (A) leukocyte adhesion deficiency type 1 (B) chronic granulomatous disease (C) Chédiak-Higashi syndrome.

leukocyte adhesion deficiency type I: *defective synthesis of CD18beta subunit of the luekocyte integrins LFA-1 and Mac-1* leads to *impaired leukocyte adhesion to and migration through the endothelium*; leads to *defective phagocytosis* and generation of oxidative burst. likely immune deficient. chronic granulomatous disease: defect in microbicidal activity because they *can't make ROS* due to *deficiency in phagocyte oxidase enzyme*. so they engulf the bacteria, but can't kill it and the microbes *get surrounded by activated macrophages forming granulomas* chediak-higashi syndrome: defect: *defect in phagolysosome* formation leading to severe *immunodeficiency*

15. Recognize the possible complications of an inflammatory response such as injury to surrounding tissue.

leukocytes can secrete potentially harmful stuff like ROS and enzymes, so they can also cause injury to normal cells and tissues when bystander tissues get effected or when the inflammatory response is inappropriately directed against host tissues, like in autoimmune disease

13. Describe how leukocytes are activated and which functions are enhanced by their activation.

leukocytes use various receptors to sense presence of pathogens and engaging those receptors induces responses in leukocytes that are part of their normal defensive functions and are grouped under leukocyte activation. leukocyte activation *enhances phagocytosis* of particles, *intracellular destruction of phagocytosed microbes and dead cells*, liberation of substances that destroy extracellular microbes and dead tissues, and production of mediators.

10. Describe the role that lymphatic vessels play in the inflammatory response and recognize potential complications of this role.

lymph flow is increased during inflammation to help drain edema fluid, leukocytes, and cell debris from the extravascular space. lymphatics can become secondarily inflamed and so can the draining lymph node

22. Summarize the different roles that macrophages have in chronic inflammation.

macrophages ingest and eliminate microbes and dead tissue, initiate the process of tissue repair, secrete mediators of inflammation, and display antigens to T lymphocytes and respond to signals from T cells

17. State the general properties of the chemical mediators of inflammation and recognize the role of the principal cell-derived and plasma protein-derived ones listed in lecture and Table 2-5 of the textbook.

mediators may be produced locally by cells at site of inflammation or may be derived from circulating inactive precursors (typically synthesized by the liver) that are activated at the site of inflammation most mediators act by binding to specific receptors on different target cells. the actions of most mediators are tightly regulated and short lived see class notes

***8. Recognize the vascular changes seen in acute inflammation and explain the mechanism behind each change. Describe the role these changes play in the inflammatory response.

primary vascular changes are increased *vascular permeability and vasodilation* leading to increased blood flow. mechanism that contribute to increased vascular permeability are *endothelial cell contraction leading to intercellular gaps in postcapillary venules*, *endothelial injury resulting in vascular leaking* causing endothelial cell necrosis and detachment, increased transcytosis of proteins by way of intracellular vesicular pathways, and leakage from new blood vessels.

14. Tell how cells kill and degrade microbes once they have been phagocytosed. Describe the role of reactive oxygen species and neutrophil azurophilic granules in this process.

production of microbicidal substances (ROS and lysosomal enzymes) within the lysosomse and the fusion of the lysosomes with phagosomes, exposing the ingested particles to the destructive mechanisms of the leukocytes. ROS are microbicidal but often require azurophilic granules in order to kill the bacteria

25. List the 2 reactions of repair. Identify the factors involved in determining with repair reaction will occur.

regeneration and scar formation regeneration can occur by proliferation of residual (uninjured) cells that retain the capacity to divide or by replacement from tissue stem cells. it happens typically with *epithelial of the skin and intestines* and some of the parenchymal organs like the *liver*. scar formation happens if the injured tissues can't regenerate or if the supporting structures of the tissues are severely damaged. repair occurs by the laying down of CT (fibrous) tissue resulting in a scar.

20. Recognize the role of both the coagulation and kinin systems in inflammation.

some of the molecules activated during blood clotting can trigger parts of the inflammatory response. *Hageman factor/factor XII of the coagulation cascade initiates 4 systems that can contribute to inflammatory response: the kinin system, the clotting system, the fibrinolytic system, and the complement system*. the kinin system leads to the formation of *bradykinin* which causes *increased vascular permeability, arteriolar dilation, and bronchial smooth muscle contraction* (like histamine) the coagulation system activates Factor Xa, which increases vascular permaability and leukocyte emigration. thrombin participates in inflammation by binding to protease-activated receptors expressed on platelets and endothelial cells, leading to activation and enhanced leukocyte adhesion. Thrombin also generates fibrinopeptides that increase vascular permeability and are chemotactic for leukocytes. Thrombin also cleaves C5 to generate C5a, linking coagulation with complement activation.

***11. List the steps in leukocyte recruitment from the vascular space. Define margination and list 2 causes. Explain the role of selectins, integrins, chemokines, and collagenases in this process. Define the terms diapedeis and chemotaxis.

steps in leukocyte recruitment: (1) margination and rolling along the vessel wall (2) firm adhesion to the endothelium (3) transmigration between endothelial cells (4) migration in interstitial tissues toward a chemotactic stimulus *margination*: leukocytes pushed toward edge of vessel (have more potential to interact with endothelial cells). it happens because as blood flows in against the vessel wall, smaller *RBCs tend to move faster than large white cells*, pushing the *white cells toward the edge*. Endothelial cells also can have cytokines and other mediators that express adhesion molecules that the leukocytes can *loosely attach* to (rolling) *selectins* are adhesion molecules that *mediate rolling* (process of leukocytes transiently and loosely attached to the endothelial cells). they are *expressed on leukocyte cell surface* *integrins* are also expressed *on leukocyte cells surface* and *mediate firm adhesion* of leukocytes to the endothelial surfaces after rolling leukocytes sense changes in the endothelium. they're normally expressed but aren't active until *activated by chemokines* chemokines are chemoattractant cytokines secreted by cells at sites of inflammation and displayed on endothelial cell surface. when *adherent leukocytes* encounter chemokines, the *cells are activated and integrins undergo conformational changes* and cluster together and leads to *strong adherence* of leukocytes to the endothelial cells at the site of inflammation. ***collagenases are *diapedesis* is the process by which *leukocytes adhered to endothelial cells* can *migrate* through the vessel wall; they *squeeze between cells at intercellular junctions*, leading to an extravasation of leukocytes. (driven by chemokines) chemotaxis is how luekocytes move toward sites of infection (after diapedesis) along a chemical gradient

30. List the steps of scar formation and indicate the approximate timing for each step. Identify the components of granulation tissue and the microscopic appearance.

steps of scar formation: 1. formation of *new blood vessels* (angiogenesis); within 24 hours 2. migration and proliferation of fibroblasts and deposition of CT with abundant vessels and interspersed leukocytes has a pink granular appearance and is called granulation tissue; 3-5 days 3. maturation and reorganization of the fibrous tissue to produce stable fibrous scar the granulation tissue is characterized by proliferation of fibroblasts and new delicate capillaries in a loose ECM often with inflammatory cells like macrophages.

**6. Describe the stimuli, morphologic patterns, and possible outcomes for acute inflammation.

stimuli for acute inflammation are: infections, trauma, tissue necrosis, foreign bodies, and immune reactions morphological patterns of inflammation: mainly *increased blood flow* from vasodilation and *increased vascular permeability* (bring blood cells and proteins to sites of infection/injury). increased permeability causes *RBCs to be more concentrated* and that slows down blood flow; you can see this microscopically as *lots of dilated small vessels packed with RBCs=stasis*. *leukocytes accumulate along the vascular endothelial surface*=marginalization. increased vascular permeability also leads to *exudate and edema*. possible outcomes for acute inflammation: resolution (regeneration and repair), chronic inflammation, or scarring

3. Identify the main components of inflammation

the main components of inflammation are a vascular reaction and a cellular response; both are activated by mediators derived from plasma proteins and various cells

21. Describe the anti-inflammatory mechanisms within the human body and the specific roles of IL-10 and TGF-β.

the mediators of inflammation are short-lived and destroyed by enzymes. activated macrophages and other cells secreted *IL-10*, which functions to down-regulate the response of activated macrophages (negative feedback). TGF-beta is an anti-inflammatory cytokine that helps with tissue repair. Also have tyrosine phosphatases that inhibit pro-inflammatory signals.

36. Describe the morphologic appearance of scar tissue and predict its strength at certain time periods following the injury.

within 24 hours: *neutrophils* are seen at the incision margin, migrating toward fibrin clot. basal cells at cut edge of epidermis show increased mitotic activity. 24-47 hours: *epithelail cells* from both edges *migrate* and proliferate laong the dermis, *depositing basement membrane*. day 3: neutrophils have been largely replaced by *macrophages and granulation tissue* progressively invades the incision space. *collagen fibers are evident at incision*, but vertically oriented and don't bridge incision. eptiehial cell proliferation continues, giving *thick epidermal* covering layer. day 5: *neovascularization reaches peak* and *granulation tissue fills incisional space*. collagen fibrils become more abundant and begin to bridge incision. epidermis recovers *normal thickness* as differentiation of surface cells yields mature epidermal architecture with *surface keratinization* 2nd week: continued collagen accumulation, fibroblast proliferation. blanching 1st month: largely cellular CT, *no inflammatory cells*. basically normal epidermis but dermal appendages are destroyed in the line of the incision and permanently lost.