Ch 03: Tissue Renewal and Repair: Regeneration, Healing, and Fibrosis
A cesarean section is performed on a 20-year-old woman 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) Granulation tissue is still present (B) Collagen degradation exceeds synthesis (C) Wound strength is 80% of normal tissue (D) Type IV collagen predominates (E) No more wound strength will be gained
(A) 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. BP7 75-76 BP8 74-77 PBD7 111-112 PBD8 103, 106
A 50-year-old woman tests positive for hepatitis A antibody. The serum AST level is 275 U/L, and ALT is 310 U/L. One month later, these enzyme levels have returned to normal. Which phase of the cell cycle best describes the hepatocytes 1 month after infection? (A) G0 (B) G1 (C) S (D) G2 (E) M
(A) Hepatocytes are quiescent (stable) cells that can reenter the cell cycle and proliferate in response to hepatic injury, enabling the liver to regenerate partially. Acute hepatitis results in hepatocyte necrosis, marked by elevations in AST and ALT. After the acute process has ended, cells return to the G0 phase, and the liver becomes quiescent again. BP7 64 BP8 70 PBD7 101-103 PBD8 93
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) Hepatic oval cells (D) Hematopoietic stem cells (E) Regenerating hepatocytes
(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. BP7 59-61 BP8 61-63 PBD8 83
An experiment analyzes factors involved in the cell cycle during growth factor-induced cellular regeneration in a tissue culture. Cyclin B synthesis is induced; the cyclin B binds and activates cyclin-dependent kinase 1 (CDK1). The active kinase produced by this process is most likely to control progression in which of the following phases of the cell cycle? (A) G0 to G1 (B) G1 to S (C) S to G2 (D) G2 to M (E) M to G1
(D) CDK1 controls an extremely important transition point, the G2 to M transition during the cell cycle, which can be regulated by CDK inhibitors. The other checkpoints are regulated by a distinct set of proteins. BP7 62-63 BP8 63 PBD7 100-101 PBD8 86-87
In an experiment, release of epidermal growth factor into an area of denuded skin causes mitogenic stimulation of the skin epithelial cells. Which of the following proteins is most likely to be involved in transducing the mitogenic signal from the epidermal cell membrane to the nucleus? (A) G proteins (B) RAS proteins (C) Cyclin D (D) Cyclic AMP (E) Cyclin-dependent kinase
(B) RAS proteins transduce signals from growth factor receptors, such as epidermal growth factor, that have intrinsic tyrosine kinase activity. G proteins perform a similar function for G protein-linked, seven-spanning receptors. Cyclic AMP is an effector in the G protein signaling pathway. Cyclins and cyclin-dependent kinases regulate the cell cycle in the nucleus. BP7 65-66 BP8 64, 66 PBD7 98-99 PBD8 90-92
A 40-year-old man underwent laparotomy for a perforated sigmoid colon diverticulum. A wound infection complicated the postoperative course, and surgical wound dehiscence occurred. Primary closure was no longer possible, and the wound "granulated in." Six weeks later, the wound is only 10% of its original size. Which of the following processes best accounts for the observed decrease in wound size over the past 6 weeks? (A) Increase in synthesis of collagen (B) Myofibroblast contraction (C) Inhibition of metalloproteinases (D) Resolution of subcutaneous edema (E) Elaboration of adhesive glycoproteins
(B) 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. 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. Adhesive glycoproteins such as fibronectin help to maintain a cellular scaffolding for growth and repair, but they do not contract. BP7 75-76 BP8 74-75 PBD7 113 PBD8 104-105
An experiment involves factors controlling wound healing. Skin ulcerations are observed, and the factors involved in the healing process are analyzed. Which of the following factors is most likely to be effective in promoting angiogenesis? (A) Platelet-derived growth factor (B) Epidermal growth factor (C) Basic fibroblast growth factor (D) Endostatin (E) Interleukin-1
(C) Basic fibroblast growth factor is a potent inducer of angiogenesis. It can participate in all steps of angiogenesis. Epidermal growth factor and interleukin-1 have no angiogenic activity. Platelet-derived growth factor plays a role in vascular remodeling. Endostatin is an inhibitor of angiogenesis. BP7 72 BP8 64, 72 PBD7 95-96 PBD8 88
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) Re-epithelialization (B) Fibroblast growth factor elaboration (C) Collagen deposition (D) Serine proteinase production (E) Neutrophil infiltration
(C) 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. Re-epithelialization, in part driven by epidermal growth factor, is not affected by corticosteroid therapy. Angiogenesis driven by fibroblast growth factor is not significantly affected by corticosteroids. Serine proteinases are important in wound remodeling. Neutrophil infiltration is not prevented by glucocorticoids. BP7 76 BP8 77 PBD7 114 PBD8 106
An experiment infects one group of test animals with viral hepatitis. Two months later, complete recovery of the normal liver architecture is observed when the livers from these animals are examined microscopically. A second test group is infected with bacterial organisms, and after the same period of time, fibrous scars from resolving abscesses are seen microscopically in the livers. Which of the following factors best explains the different outcomes for the two test groups? (A) Nature of the etiologic agent (B) Extent of liver cell injury (C) Injury to the connective tissue framework (D) Location of the lesion (E) Extent of damage to the bile ducts
(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 is associated with liquefactive necrosis of hepatocytes and the supporting connective tissue. It heals by scarring. The other options listed may explain the amount of liver injury, but not the nature of the response. BP7 63-64 BP8 70 PBD7 90-91 PBD8 81
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) Integrins interact with the extracellular matrix proteins (e.g., fibronectin). Engagement of integrins by extracellular matrix proteins leads to the formation of focal adhesions at which 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. BP7 67-69 BP8 67-68 PBD7 104-106 PBD8 96-97
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) Leukocyte extravasation (B) Increase in vascular permeability (C) Production of collagen (D) Chemotaxis of lymphocytes (E) Migration of epithelial cells
(C) 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. BP7 73-74 BP8 64, 73 PBD7 96-97 PBD8 87-89
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) Heparin (B) Dermatan sulfate (C) Procollagen (D) Fibronectin (E) Hyaluronic acid
(D) 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. Heparin that is infused has an anticoagulant function. Dermatan sulfate, a glycosaminoglycan, acts to form a gel that provides resilience and lubrication. Procollagen produced by fibroblasts is formed into ropelike strands of collagen, which provide tensile strength. Hyaluronic acid binds water to form a gelatinous extracellular matrix. BP7 69 BP8 68 PBD7 103-104 PBD8 96-97
An experiment is conducted in which the time sequence of events in wound healing is analyzed. Histologic sections are produced from samples of the tissue at the site of a small superficial skin incision in laboratory animals. During the first week, the number of macrophages that are activated to phagocytize tissue debris increases. Which of the following signaling molecules is most likely to play a significant role in producing this finding? (A) Acetylcholine (B) Cyclic AMP (C) Heparan sulfate (D) Interferon-γ (E) Transforming growth factor β
(D) Interferon-γ is a cytokine secreted by lymphocytes at the site of inflammation; it has a paracrine effect that causes transformation of monocytes to activated macrophages. Acetylcholine is a neurotransmitter that does not act on inflammatory cells. Cyclic AMP acts as a "second messenger" within a cell. Heparan sulfate is a component of the extracellular matrix that does not have a signaling function. Transforming growth factor β has an inhibitory function on leukocytes. BP7 65-66 BP8 65 PBD8 90
An 18-year-old man lacerated his left hand and required sutures. The sutures were removed 1 week later. Wound healing continued, but the site became disfigured by a prominent raised, nodular scar that developed over the next 2 months. Which of the following terms best describes the process that occurred during this 2-month period? (A) Organization (B) Dehiscence (C) Resolution (D) Keloid formation (E) Secondary union
(D) The healing process sometimes results in an exuberant production of collagen, giving rise to a keloid. This tendency may run in families. Organization occurs as granulation tissue is replaced by fibrous tissue. Dehiscence occurs when a wound pulls apart. If normal tissue architecture is restored, resolution of inflammation has occurred. Secondary union describes the process by which large wounds fill in and contract. BP7 76 BP8 77 PBD7 115 PBD8 106
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 c-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
(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 cells derived from manipulation of human embryos, which has 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 endodermal or ectodermal cells. BP8 62 PBD7 91-94 PBD8 82-84
A 60-year-old woman developed chest pain that persisted for 4 hours. A radiographic imaging procedure showed an apparent myocardial infarction involving a 3 × 4 cm area of the posterior left ventricular free wall. Laboratory findings showed serum creatine kinase of 600 U/L. The patient received anti-arrhythmic and pressor agents to treat the decreased cardiac output while in the hospital. Which of the following pathologic findings would most likely be seen in the left ventricle 1 month later? (A) Abscess (B) Complete resolution (C) Coagulative necrosis (D) Nodular regeneration (E) Fibrous scar
(E) The elevated creatine kinase level indicates that myocardial necrosis has occurred. The destruction of myocardial fibers precludes complete resolution. The area of myocardial necrosis is gradually replaced by a fibrous scar. Liquefactive necrosis with abscess formation is not a feature of ischemic myocardial injury. Coagulative necrosis is typical of myocardial infarction, but after 1 month, a scar would be present. Nodular regeneration is typical of hepatocyte injury because hepatocytes are stable cells. BP7 72 BP8 70-74 PBD7 110-111 PBD8 107-108
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 (C) Leukotriene B4 (D) Thromboxane A2 (E) Vascular endothelial growth factor (F) Tumor necrosis factor
(E) 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 re-epithelialization of a surface wound. Interleukin-2 mediates lymphocyte activation. Leukotriene B4 mediates vasoconstriction and bronchoconstriction. Thromboxane A2 aids vasoconstriction and platelet aggregation. Tumor necrosis factor induces endothelial activation and many responses that occur secondary to inflammation, including fever, loss of appetite, sleep disturbances, hypotension, and increased corticosteroid production. BP7 71-72 BP8 70-71 PBD7 96, 107-108 PBD8 102-103
A 24-year-old man with acute appendicitis undergoes surgical removal of the inflamed appendix. The incision site is sutured. A trichrome-stained section of the site 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) 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. BP7 75 BP8 75-76 PBD7 112-113 PBD8 104-105
In an experiment, various soluble mediators are added to a cell culture containing epidermal cells to determine which of the mediators might be useful for promoting epidermal cell growth. When epidermal growth factor (EGF) is added, it binds to epidermal cell surface receptors, inducing RAS protein activation, with subsequent transcription factor translocation and DNA transcription activation. This effect in the epidermal cells is most likely to be mediated through which of the following intracellular pathways? (A) Calcium ion channel (B) Cyclic AMP (C) Cyclin-dependent kinase (D) JAK/STAT system (E) Mitogen-activated protein kinase
(E) The mitogen-activated protein (MAP) kinase cascade is involved in signaling from activation via cell surface receptors for growth factors. This pathway is particularly important for signaling of epidermal growth factor and fibroblast growth factor. Ligand binding, such as occurs with acetylcholine at a nerve-muscle junction, alters the conformation of ion channel receptors to allow flow of specific ions such as calcium into the cell, changing the electric potential across the cell membrane. Cyclic AMP is a "second messenger" that is typically activated via ligand binding to receptors with seven transmembrane segments that associate with GTP-hydrolyzing proteins; chemokine receptors function in this fashion. Cyclin-dependent kinases act within the nucleus. JAK/STAT pathways typically are recruited by cytokine receptors. BP7 65-66 BP8 64-66 PBD7 98-99 PBD8 90-92