Q No 1

A 22-year-old woman nursing her newborn develops a tender erythematous area around the nipple of her left breast. A thick, yellow fluid is observed to drain from an open fissure. Examination of this breast fluid under the light microscope will most likely reveal an abundance of which of the following inflammatory cells?

(A) B lymphocytes

(B) Eosinophils

(C) Mast cells

(D) Neutrophils

(E) Plasma cells

Acute mastitis

Q No:2/5

A 5-year-old boy punctures his thumb with a rusty nail. Four hours later, the thumb appears red and swollen. Initial swelling of the boy’s thumb is primarily due to which of the following mechanisms?

(A) Decreased intravascular hydrostatic pressure

(B) Decreased intravascular oncotic pressure

(C) Increased capillary permeability

(D) Increased intravascular oncotic pressure

(E) Vasoconstriction of arterioles

Infl edema

Q No 3/9

A 36-year-old woman with pneumococcal pneumonia develops a right pleural effusion. The pleural fl uid displays a high specific gravity and contains large numbers of polymorphonuclear(PMN) leukocytes. Which of the following best characterizes this pleural effusion?

(A) Fibrinous exudate

(B) Lymphedema

(C) Purulent exudate

(D) Serosanguineous exudate

(E) Transudate

Diagnosis: Bacterial pneumonia, pleural effusion

Q No 4/11

A 10-year-old boy with a history of recurrent bacterial infections presents with fever and a productive cough. Biochemical analysis of his neutrophils demonstrates that he has an impaired ability to generate reactive oxygen species. This patient most likely has inherited mutations in the gene that encodes which of the following proteins?

(A) Catalase

(B) Cytochrome P450

(C) Myeloperoxidase

(D) NADPH oxidase

(E) Superoxide dismutase

Ans: D

Diagnosis: Chronic granulomatous disease

Q No 5/14

A 41-year-old woman complains of excessive menstrual bleeding and pelvic pain of 4 months. She uses an intrauterine device for contraception. Endometrial biopsy reveals an excess of plasma cells and macrophages within the stroma. The presence of these cells and scattered lymphoid follicles within the endometrial stroma is evidence of which of the following conditions?

(A) Acute inflammation

(B) Chronic inflammation

(C) Granulation tissue

(D) Granulomatous inflammation

(E) Menstruation

Diagnosis: Chronic endometritis

Q No. 6

Regeneration, repair and

wound healing

Regeneration:When healing takes place by

proliferation of parenchymal cells of same type.

Repair:When healing takes place by proliferation of

connective tissue elements resulting in FIBROSIS or

SCARRING.

Regeneration

requires intact extracellular matrix framework

In mammals : compensatory growth (hypertrophy and

hyperplasia) rather than true regeneration (eg. growth

after partial hepatectomy and nephrectomy)

Continuously cycling cells ( bone marrow, epithelium of

skin and GI mucosal epithelium) regenerate if stem

cells are intact

Cell types ( based on their proliferative

capacity) 1.

Labile cells ( continuously dividing cells)

Surface epithelia: skin, oral cavity, vagina, cervix

Excretory duct epithelia: saliv.glands, pancreas, biliary tract

Columnar epithelia: GI, uterus

Transitional epith: urinary tract

Bone marrow cells and hematopoietic cells

Derived from pleuripotent stem cells….

Cell types ( based on their proliferative

capacity) 2.

Stable cells ( quiescent cells)

They don’t but can enter G1

Liver, kidney, pancreas ( acini)

Fibroblasts, smooth muscle, endothelium,

lymphocytes etc.

Cell types ( based on their proliferative

capacity) 3.

Permanent cells ( nondividing cells)

Can’t enter the cell cycle

Neurons(?) ( neural precursor cells!)

Skeletal muscle(?) ( satellite cells!)

Myocardium

Stem cells

Prolonged self-renewal capacity and asymmetric replication

Embryonic stem cells, adult stem cells (bone marrow SC, tissue SC)

REGENERATIVE MEDICINE ( therapeutic cloning !)

New observations: Stem cells in the brain

Bone marrow stem cells – multiple developmental option (developmental plasticity)

Some tissue stem cells – similar to embryonic stem cells

Niches Eg. Base of colon crypts, hair follicle bulges, oval cells (liver

stem cells) in canals of Hering

Stem cells

self-renewal properties

capacity to generate differentiated cell lineages.

stem cells need to be maintained during the life of

the organism.

achieved by two mechanisms:

(a) obligatory asymmetric replication: one of the

daughter cells retains its self-renewing capacity…

(b) stochastic differentiation: 50- 50.. Depending on

luck factor…

Embryonic Stem Cells: uses

• To study the specific signals and differentiation

steps required for the development of many

tissues.

• To study various disease models with help of

knockout mice or “knock-in” mice.

• ES cells may in the future be used to repopulate

damaged organs.

Reprogramming of Differentiated Cells: iPS Cells

Differentiated cells of adult tissues can be reprogrammed

to become pluripotent by transferring their nucleus to an

enucleated oocyte.

oocytes implanted into a surrogate mother

Develop embryo and ultimately cloned animal

This technique is K/A reproductive cloning(dolly).

Similar is therepeutic cloning… but ethical issues…

Bone marrow stem cells

Hematopoietic stem cells

Stromal cells: have potentially important therapeutic

applications.

Multipotent adult progenitor cells

( adult counterpart of embryonic stem cells)

Tissue stem cells 1.

Liver - Oval cells

Niche: canals of Hering

Bipotential progenitors (→ hepatocytes and biliary cells)

Activated when hepatocyte proliferation is blocked (eg.

carcinogenesis, cirrhosis, fulminant hepatic failure)

Brain- Neural stem ( precursor) cells

Niche: the subventricular zone (SVZ) & dentate gyrus of

hyppocampus

Neurogenesis ?

Being studied for degenerative neural disorder…

Tissue stem cells

Skin:

located in the hair follicle bulge, interfollicular areas of the

surface epidermis, and sebaceous glands.

Skeletal muscle- satellite cells

Niche: beneath basal lamina

Diff. toward myocytes, adipocytes, osteocytes

Intestinal epithelium:

located immediately above Paneth cells in the small intestine,

or at the base of the crypt, as is the case in the colon\

Cornea: limbal scleral cells…

Growth factors

Bind to specific receptors

Initiate cell proliferation

Act on contractility, differentiation, locomotion,

angiogenesis etc.

Growth factors

EGF, TGFα

Mitogenic for epithelial cells, fibroblasts, hepatocytes

Bind EGFR→therapeutic target ( ERB B1 and ERB B2 or HER-2/neu)

Hepatocyte Growth Factor (HGF)

Vascular Endothelial Growth Factor (VEGF)

Vasculogenesis, angiogenesis

Platelet-Derived Growth Factor (PDGF)

Migration and proliferation of fibroblasts, smooth muscle cells

Activation of oval cells

Growth factors 3.

Fibroblast Growth Factor (FGF)

Angiogenesis, wound healing, hematopoiesis, development of

skeletal muscle etc.

TGF-β

Growth inhibitor for epithelial cells and leukocytes ( blocks the

cell cycle)

Stimulates the proliferation of fibroblasts and smooth muscle

cells, fibroblast chemotaxis, production of collagen, fibronectin

etc.→ FIBROSIS

Anti-inflammatory effect

SIGNALING MECHANISMS IN CELL GROWTH

Signal Transduction Pathways

Signaling from tyrosine kinase receptors

ECM

Networks of macromolecules outside the cell

Networks: Interstitial matrix and BM

Macromolecules:

1. Fibrous structural proteins ( collagens, elastin, fibrillin,

elastic fibres)

2. Proteoglycans and hyaluronic acid

3. Cell adhesion molecules ( integrins, selectins, cadherins,

osteonectin, tenascin etc.)

Extracellular matrix

Mechanisms by which ECM components and growth factors interact and activate

signaling pathways.

REPAIR

Replacemnt of injured tissue by fibrous tissue

includes the following basic features:

• inflammation

• angiogenesis,

• migration and proliferation of fibroblasts,

• scar formation

• connective tissue remodeling.

TWO PROCESS:

(A) GRANULATION TISSUE FORMATION

(B) CONTRACTION OF WOUND

The relative contributions of repair

and regeneration are influenced by:

(1) the proliferative capacity of the cells of

the tissue;

(2) the integrity of the extracellular matrix;

and

(3) the resolution or chronicity of the injury

and inflammation.

Granulation tissue

Hallmark of healing

~ term from macroscopy ( granular, pinkish)

Microscopy: angiogenesis ( new vessels leaky→ edema),

fibroblasts, macrophages, (ly, mast cells, eosinophils)

GRANULATION TISSUE

FORMATION

THREE PHASES

(A) phase of inflammation

(B) phase of clearance

(C) phase of ingrowth of granulation

PHASE OF INFLAMMATION

FOLLOWING TRAUMA BLOOD CLOT AT SITE OF

INJURY

ACUTE INFLAMMATORY RESPONSE WITH

EXUDATION OF PLASMA

INFILTRATION OF NEUTROPHIL AND SOME

MONOCYTE WITH 24 HOURS

PHASE OF CLEARANCE

PROTEOLYTIC ENZYME FROM NEUTROPHIL

AUTOLYTIC ENZYMES FROM DEAD TISSUE CELLS

PHAGOCYTIC ACTIVITY OF MACROPHASE

CLEAR OFF NECROTIC TISSUE DEBRIS & RBC.

PHASE OF INGROWTH OF

GRANULATION

TWO PROCESSES

(1.) Neovascularisation

(2.) Fibrogenesis

GRANULATION

TISSUE

Granulation tissue

GRANULATION TISSUE

FIBROBLAST

NUCLEI

BLOOD

VESSELS

NEOVASCULARISATION

Formation Of New Blood Vesseles

Proliferaton Of Endothelial Cells From Margins Of Severed Blood Vesseles

Under Influences Of

VEGF

PDGF

TGF – β

B FGF

Angiogenesis from Preexisting Vessels

• Vasodilation: in response to nitric oxide, and VEGF

• Proteolytic degradation of the basement membrane:by MMPs

• Migration of endothelial cells toward the angiogenic stimulus

• Proliferation of endothelial cells, just behind the leading front of migrating cells

• Maturation of endothelial cells,

• Recruitment of periendothelial cells (pericytes and vascular smooth muscle cells) to form the mature vessel

ANGIOGENESIS

FIBROGENESIS

COLLGEN FIBRILS BEGINS TO APEAR BY 6TH DAYS

AS MATURATION PROCEEDS MORE AND MORE COLLAGEN FORMED WHILE THE NO. OF FIBROBLAST & NEW BLOOD VESSELES DECREASE.

THIS RESULT FORMATION OF INACTIVE LOOKING SCAR CALLED AS CICATRISATION.

SCAR

FIBROBLAST NUCLEI

CONTRACTION OF WOUND

START AFTER -2-3 DAY

COMPLETED UP TO 14TH DAY

MECHANISM INVOLVES

(1.) DEHYDRATION – REMOVAL OF FLUID BY DRYING OF WOUND

(2.) CONTRACTION OF COLLAGEN

(3.) DISCOVERY OF MYOFIBROBLAST

CONTRACTION

W

O

U

N

D

H

E

A

L

I

N

G

Healing by first intention

Healing by second intention

FACTORS INFLUENCING WOUND HEALING

•LOCAL Type, size, location surgical, blunt trauma

Blood supply face, leg

Infection delay, deforming scars

Irradiation inhibition of cell division

FACTORS INFLUENCING WOUND HEALING

SYSTEMIC

Age cardiovascular status

Metabolic diabetes infections, blood supply

status scurvy inhibition of collagen synthesis

Hormones cortisons, steroid, inhibition of collagen synthesis thyroid estrogens indirect actions androgens

Complications of wound healing

1. Deficient scar formation ( wound dehiscence,

ulceration)

2. Excessive formation of repair components (

hypertrophic scar, keloid, exuberant granulation,

desmoid or aggressive fibromatosis)

3. Contracture

Keloid

Healing of bone fractures