Acute Phase Reactants and Growth Factors

8/6/2019 Acute Phase Reactants and Growth Factors

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PRESENTOR:DR.T.NEELIMA

1styear postgraduate in the department ofPATHOLOGY.


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INTRODUCTION:

Within the spectrum of systemic reaction toinflammation 2 physiological responses in particular areregarded as being associated with acute inflammation.

yThe first involves the alteration of the temperature set-point in the hypothalamus and the generation of thefebrileresponse.

y

The second involves alterations in metabolism and generegulation in the liver.


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y Three cytokines that are released from the site oftissue injury -- IL-1, TNF- and IL-6 are considered toregulate the febrile response, possibly as a protectivemechanism. These cytokines mediate fever through

the induction of PGE.yAt the same time, IL-1 and IL-6 can act on the adrenal

pituitary axis to generate adrenocorticotropichormone (ACTH) and, subsequently, induce the

production of cortisol. This provides a negativefeedback loop, since corticosteroids inhibit cytokinegene-expression.


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y Definition:

Proteins whose concentration either increaseor decrease by atleast 25% following an infection ortissue trauma leading to a characteristic change in thelevels and composition of plasma proteins

ACUTE PHASE REACTANTS


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VARIOUS ACUTE PHASE REACTANTS contd ..

9.LPS binding protein.

10.Ceruloplasmin.

11.Hemopexin.

12.Serum amyloid A.

13.Serum amyloid P.


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yAlthough most APRs are synthesized by hepatocytes,

some are produced by other cell types, includingmonocytes, endothelial cells, fibroblasts andadipocytes.

y There are 2 types of APRs- POSITIVE and NEGATIVE.

y

Positive APRs increase in plasma concentration duringacute phase response.

yNegative APRs are decreased in plasma concentration

during the acute phase response to allow an increase inthe capacity of the liver to synthesize the induced APRs


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ACUTE PHASE RESPONSE

The varied concentrations of the acute phaseproteins combined with fever and leucocytosis is

called the acute phase response.

Liver synthesizes acute phase proteins in response tocirculatory cytokines produced during

inflammation.(IL-6 and some extent IL-1)


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FUNCTIONS OF ACUTE PHASE REACTANTS

APRs have a wide range of activities that contributeto host defense.They can directly neutralize

inflammatory agents, help to minimize the extent oflocal tissue damage, as well as participate in tissuerepair and regeneration.

There is a rapid increase in the plasma

concentration of many complement cascadecomponents ,the activation of which ultimately resultsin the local accumulation of neutrophils, macrophagesand plasma proteins.


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ALPHA-1 ANTITRYPSIN

y Major component of globulins which has thecapacity to combine with and inactivate trypsin.

yIt is able to neutralise the activity of proteases andhence is an intrinsic factor in the homeostaticmechanism modulating endogenous proteolysis

within body preventing inappropriately severe

biochemical response to inflammation.


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APPLIED PATHOLOGY

y 1.Alpha-1 antitrypsin defiency leads to-

a.EMPHYSEMA

b.CIRRHOSIS.2.Cigarette smoking is the major source of irritant thattriggers leucocytes in lung to release proteases and -

AT acts an antiproteinase inhibiting damage to the

lung.


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ALPHA-1 ACID GLYCOPROTEIN(OROSOMUCOID)

y It is a binder of progesterone and hence helps in itstransport and metabolism.

y

It binds to certain drugs and keeps them in inactivatedstate.

APPLIED PATHOLOGY:

Measurement of this protein have clinical utility in

interpreting levels of drugs (like LIDOCAINE)that mayachieve high concentration without expectedtherapeutic effect owing to be complexed in inactiveforms .


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CYSTEINE PROTEASE INHIBITOR

y It is also an antiproteinase capable of inhibitingcomplement components ,coagulation and fibrinolytic

factors.APPLIED PATHOLOGY:

Depressed levels are associated with-

1. SEVERE LIVER DISEASE

2. PROTEIN LOSING DISORDERS3. DIC


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HAPTOGLOBIN

y It combines with Hb released by lysis of RBC inorderto preserve body iron and protein stores.

APPLIED PATHOLOGY:Increased levels of haptoglobin seen in-

STRESS

INFECTION

ACUTE INFLAMMATION

TISSUE NECROSIS

LIVER DISEASE


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APPLIED PATHOLOGY contdy Decreased levels of haptoglobin are seen in-

y 1.HEMOLYSIS and also in cases of slow and

steady breakdown of RBC as in MECHANICAL HEARTVALVES,HEMOGLOBINOPATHIES,EXERCISEASSOCIATED TRAUMA.

2.THERMAL BURNS

3.AUTOIMMUNE HEMOLYTIC ANAEMIA.4.LIVER DISEASE.


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y COMPLEMENT FACTOR 3:

It acts as an opsonin and aids in microbial

resistance.

APPLIED PATHOLOGY:

Depression of C occurs in AI disorders wherecomplement system is activated and C becomesbound to immune complexes deposited in tissuesthereby removing them from plasma.


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Hence C is a convenient marker for rheumaticdisorders like-LUPUS ERYTHEMATOSIS

RHEUMATOID ARTHRITIS

and also in-

RECURRENT PYOGENIC INFECTIONSGLOMERULONEPHRITIS.


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HEMOPEXIN

y Hemopexin binds with heme released by degradationof hemoglobin.

APPLIED PATHOLOGY:Decreased levels of hemopexin are seen in

LIVER FAILURE

INTRAVASCULAR HEMOLYSIS.


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CRP levels are also elevated in

y UNSTABLE ANGINA

y POST MENOPAUSAL HORMONE THERAPY

y RHEUMATOID ARTHRITIS

yALLERGIC RHINITISyASTHMA


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FUNCTIONS OF ACUTE PHASE REACTANTSPROTEIN FUNCTION

1.Alpha-1 antitrypsin

2.Alpha-1 acid glycoprotein3.Cysteine protease inhibitor

4.Haptoglobin.

5.Fibrinogen.

6.C-Reactive protein andcomplement factor 3.

1.Inactivates proteases.

2.Transports progesterone.3.Antiproteinase.

4.Binds hemoglobin.

5.Coagulation factor.

6.Opsonic activity and directlyparticipates in microbialresistance.


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DIFFERENCE BETWEEN COMPETENCE FACTOR

AND PROGRESSIVE FACTORS

Competent factors render the cell competent torespond while the progressive factors , stimulateDNA synthesis in cells already competent torespond


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APPLIED PATHOLOGY:

Cancer cells differ fundamentally from normalcells when exposed to growth factors in passingstraight into mitotic division without an initial phaseof co-ordinated integrin mediated attachment to thematrix.


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APPLIED PATHOLOGY

y EGF levels are elevated in serum of patients associatedwith-

1.GASTRIC CARCINOMA.2.CARCINOMA OF TONGUE.

y EGF levels are also elevated in KELOID formations.


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PLATELET DERIVED GROWTH FACTOR

It is stored in -granules of platelets and releasedwhen activated.

It is also produced by activated macrophages and othercells.

It acts as a competence factor hence an additionalaction of a progression factor such as EGF or IGF is

needed for cell division.It acts on fibroblasts ,smooth muscle cells and

monocytes.

It also has a chemotactic activity.


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APPLIED PATHOLOGY

y PDGF levels are elevated in CARCINOMAS

SARCOMAS

LYMPHOMAS(but never in the normal individuals)

y Eg : In patients with BREAST CARCINOMA, there isan excellent correlation between stage of the cancer

and serum level of the growth factor.


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FIBROBLAST GROWTH FACTOR

It consists of two groups-basic FGF (b FGF)

acidic FGF(a FGF)

Basic FGF is formed in many tissues while acidic FGFis restricted to brain and neural tissue.

They bind to heparin and particularly heparansulphate.


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They are not present in body fluids and their action islocal , being restricted to immediate area of secreting

cell.

It stimulates the formation of mesoderm fromectoderm,an effect inhibited by heparin.

In response to injury their important action isstimulation of growth of fibroblasts and endothelialcells(angiogenesis)


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TGF-

It is a family of proteins involving promotion orinhibition of cell growth.

The main action is to inhibit the cell growth.eg:It has been implicated in the cessation of mitoticactivity of liver cells following the regenaration causedby hepatectomy.


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TGF- contd.It is chemotactic to fibroblasts and stimulates the

production of connective tissue matrix proteins suchas collagen and fibronectins.

It has mesoderm inducing properties duringembryogenesis.

Both TGFs act synergistically with FGF andmagnify its effects.


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APPLIED PATHOLOGYy TGF- is an excellent marker for presence of

malignancy.Hence it is useful in screening.

y

TGF- is not that tumour specific.It shows somespecificity for BREAST CARCINOMA.

y TGF- is an effective predictor of diagnosis ofmalignancy at an early stage.It also aids in theprognosis of HEPATOCELLULAR CARCINOMA.


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APPLIED PATHOLOGY contdy One third of the patients who developed

carcinoma(ADENO/SQUAMOUS CELLCARCINOMA) of LUNG were seropositive for TGF-.

y TGF has high sensitivity and high specificity.

y TGF- is elevated in-

1.HEPATOCELLULAR CARCINOMA

2.BLADDER CARCINOMA.y TGF- has a role in bone resorption and also in

scerotic metastasis.


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NERVE GROWTH FACTOR It is involved in the development and maintenance of

the sympathetic nervous system and neural crestderived neurons.

It is not involved in nerve cell division but involvesbranching and organisation of nerve cell dendriticprocesses both in CNS and PNS.

They have a neurotropic effect and selectively prevent

cell death.


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APPLIED PATHOLOGY:

It has been suggested that lack of NGF isresponsible for the neuron loss that characterisessome degenerative diseases.

Eg : Alzheimers disease.

Amyotropic lateral sclerosis.

Parkinsons disease.

NGF plays a role in the inflammation caused by RSV

infection.


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APPLIED PATHOLOGY:

In adults ,the IGF-1 blood level is regulated by growth

hormone and is hence high in ACROMEGALY.RELAXIN , secreted by ovary ,is related to IGF family

and is involved in the maturation of the female genitaltract during pregnancy.

IGF-1 along with EGF and FGF cause NODULARHYPERPLASIA OF THYROID.


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VASCULAR ENDOTHELIAL GROWTH FACTORy It promotes blood vessel formation.

APPLIED PATHOLOGY:

y

VEGF promotes angiogenesis in CANCER,CHRONICINFLAMMATORY STATES and WOUND HEALING.

y It plays a role in RETINOPATHY OF PREMATURITYby promoting angiogenesis through the internal

limiting membrane of retina into vitreous.(lack of Oexposure)


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VON HIPPEL LINDAU DISEASEyVHL gene mutation leads to elevated levels of

VEGF,PDGF AND TGF .They inturn lead to-

ANGIOGENESIS

ENDOTHELIAL STABILIZATION

AUTOCRINE GROWTH STIMULATION


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ROLE OFVEGF,PDGF ANDTGF INVON HIPPEL

LINDAU DISEASE


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GM-CSFy It stimulates the proliferation and differentiation of

progenitor cells.

y It is a central regulator of innate immunity.

APPLIED PATHOLOGY:

GM-CSF deficiency leads to decreased degradation ofsurfactant due to dysfunctional alveolar macrophages

leading to PULMONARY ALVEOLAR PROTEINOSIS.


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GROWTH FACTOR RECEPTOR DEFECTSy There are 3 known pathologic mechanisms that can

result in causing abnormally prolonged receptordimerization that results in continuous mitogenic

signalling.1.Loss of extracellular binding domain leading to

permanent dimerisation of GF receptor

2.Mutations in transmembrane domain that promotedimerization.

3.Over expression of receptor leading to increasedconcentration of dimers.


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PLATELET DERIVED GROWTH FACTOR RECEPTOR

y Over expression of PDGFr along with EGFr is notedin CNS neoplasms like-

ASTROCYTOMA.

GLIOBLASTOMA.


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Thus growth factors and their receptors have a

wide spectrum in the pathogenesis ofvarious disorders in the human body.


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THANK YOU.

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Acute Phase Reactants and Growth Factors