INTRODUCTION TO CELL INJURY

 HYPERTROPHY

·         Increase in size of parenchymal cells.

·         Resulting in enlargement of effected organ or tissue.

Causes:-

·         Increase functional demand

·         Stimulation by harmone & growth factors.                                     

Mechanism:-

·         Increased production of cellular protein

·         Due to the increased activation of gene responsible for the production of there protein.

Hypertropy caused based on:- 

1. Physiologic hypertropy

2. Pathologic hypertropy

 

1.    Physiologic hypertropy:-

In case of increase endocrine stimulation

·         Breast development at  puberty

·         Utreus development in pregnancy

·         Breast development in lactation

 

Increase mechanical demand

Physiologic (straited muscles of weight lifter)

 

2.    Pathologic hypertropy:-

 

Example in disease of hypertropy

 

1)    Cardiac muscle hypertropy:-

·         Overload demand on cardiac is caused disease Cardiovascular disease

·         Pressureload- Example – Hypertension, Contraction of arota

·         Volumeload- Example- volvular disease.

 

2)    Smooth muscle hypertropy :-

Increase resistance to outflow of the bladder wall .

              Example- in case of enlarge prostate.

3)    skeletal muscles hypertropy:-

Example:- Hypertrophied muscles in athletes and manual labourers.(over inc. of muscle)

                  Muscles fibres will be abnormal in pathologic hypertropy.

      Hyperplasia:-

It’s increase in the number of parenchymal cells resultings in enlargement of the organ or tissue.

·         Both hyperplasia &hypertropy occur together

·         Hyperplasia occur when the cells population in capable of deviding or occurs due to increased recruitment of cells from go resting phase of the cells cycle to undergo mitosis .

Hyperplasia caused based on →1) Physiological

                                                →2) pathological

 

1)   Physiological hyperplasia:-

(A)Harmonal hyperplasia:-

·         Hyperplasia occuring  under the influence of hormonal stimulation.

Example-  breast development  at puberty

                                                                                  Same as hyperperplasia

               Utreus development in pregnancy

                (B)Compensatory hyperplasia:-

·         Hyperplasia occurs during removal of part of organ

Example- liver regrowth after a part of resection, kidney ,bone marrow hyperplasia

          2)pathological hyperplasia:-

         Exercise stimulation by harmone’s growth factorson target cells.

 

 

(A)Endometrial hyperplasia:-

* Endometrial harmonal stimulation due to increaseof estrogen.

* Endometrial carcinoma arises from endometrium of utreus .

 

(B) usual ductal hyperplasia:-

It’s fibrocytic changes of the breast.

 

(C)benign prostatic hyperplasia:-

It’s present in old age of the person.

 

(D)prostatic hyperplasia:-

  Testosterone   5@-reduction   Dihydrotestosterone

 

Dihydrotestosterone                    Responsible to increase of prostate size

 

    Metaplasia :-

·          Metaplasia is a reversible change of  one type of mature differentiated cell (epithelial or mesenchymal ) is replaced by another cell type usually in response to irritation or annormal stimuli.

·         Often metaplasia reverse back to normal on removal of stimuli but if abnormal stimuli persists for lomg time then epithelial metaplasia may progress to dysplasia & furthur into cancer stage reach.

 

Mechanism:-

·         The reverse cells (stem cells )of the irritated tissue

·         Differentiated into  amore protective cell type due to the influence of growth factor cytokines & matrix component.

                                                                                 squamous metaplasia

                                Epithelial metaplasia                                                               metaplasia                                                         Columnar metaplasia      

     osseous metaplasia

                              Mesenchymal metaplasia                                                                                                                                                                                          cartilagenous metaplasia

(A)Epithelial metaplasia :-

(a)squamous metaplasia:-

Exp.

(1) Respiratory tract in bronchus:-

In chronic irritation of tabacco smoking

                        ↓

Branchus stratified ciliated columnar epithilium

↓tobacco, smokimg irritants

                           Squamous epithilium

(2) In uterine endo cervix:-

Uterine cervix again divided into –

       Endocervix                                                      Ectocervix

↓                                                                ↓                                                               Columnar epithilium                       lined by squamous epithelium 

↓                                                                                                                                                                                                      

 in cases of chronic inflammation this                                                                                            endo cervical columnar epithelium is replacedby                                                                                         ↓

squamous epithelium this is b\c of chronic inflammation

(3)Gall bladder is lined by columnar epithelium:-

              In care of Gall bladder stone

↓

stone in the bile duct there stone can irritate to mucosa lining

↓                                                                                                               mucosa in gall bladder contantly irritation by stone

↓                                                                                                                     that result in metaplasia of gall bladder mucosa into squamous epithilium type.

-so the columnar epithelial of the gall bladder of mucosa in replaced by squamous epithelium.

 

(b) Columnar metaplasia:-

Example :- Barrett’s esophagus

 

·         Stratified squamous epithelium   gastric reflux   Intestinal columnar epithelium

 

·         Intestinal metaplasia in healed chronic gastric ulcer.

 

(B)Mesenchymal metaplasia:-

(a)osseous metaplasia:- 

Where the end product in ossification & calcification .

Example:-  * Arterial wall – occurs in old age in vessels wall mainly in female

                    * Myositis ossification – ossification occurs invite of injured muscles most common site in Thigh , Arm

                    * Stroma of tumour – some of the tumour are calcified and formed stroma

                   * Cartilage of laryanx in elderly

  (b)  cartilagenous metaplasia:-

End product is made up of cartilage

Healing of fracture :- it occur in during of immobility in particular area.

    Dsysplasia:-

It’s means disorder of cellular development or disorder cell growth . after proceeded or accompanied with metaplasia & hyperplasia

·         Dysplasia is not a cancer but may progress to cancer

·         Dusplasia is an abnormal growth of cell that is charactrisied by change in cell size , shape and loss of cellular organization .

·         Dysplasia mainly occur in epithelial cell epithelial dysplasia may be of varying grade (mild ,moderate , severe)

·         Two most common example of dysplasia are uterine cervix & respiratory tract.

 

     Reversible cell injury :-

If ischemia or hypoxia is for short time duration then effect on cell can be reverting back to normal condition is called RCI.

·         Normal cell

·         Some condition we are seeing in biochemical  & ultra structural in the presence of RCI

1) decrease generation of cellular ATP

2) intracellular lactic acidosis

3) Damage to plasma membrane pumps

4) Reducedprotein symthesis

(1) decreased generation of cellular ATP :-

All living cell require continuous supply of oxygen to produce oxygenated blood is also required for all cells.

Ischemia  /hypoxia /O2 ↓

     ↓

Mitrochondria affected

                ↓

Synthesis of ATP in the presence of oxidative phosphorylation

       ↓

↓energy dependent process

       ↓

Decreased function of Na+ ,k+, ATP are pump in cell membrane

 

·         But when adequate O2 supply to cell then it can be reverting back to normal condition .

 

(2)Intra cellular lactic acidosis :-

Hypoxia O↓            anaerobic glycolycis           ↓rapid deplection of glycogen

                                                                            ↑accumulation of lactic acid

 

     

Intracellular lactic acidosis

↓

Decreased intracellular pH

↓

Nuclear clumping chromatin

↓

In RCI, only nuclear charges are seeing

 

                                                                                                General swelling of cells

                                                                                                  

                                                                                                Clumping of chromatin

 

(3)damage of plasma membrane pump:-

 Cellular fatty acis which are required for continuous repair of cell membrane .

(a) failure function of Na+ k+ ATP are pump:-.

ATP  areare

                                                         

K+       K+                                Na+     Na+               K+                           H2O       H2O             H2O                                                                 K+

 

 

 

 

If ATP are pump failure

↓                                                                                                                                             Na+ inside to cell                                                                                                                                    ↓                                                                                                                                   Water inside of cell                                                                                                                                    ↓                                                                                                                               Cellular swelling (Hydropic swelling)

This changes seeing in RCI

(b)            Failure of Ca pump:-

Membrane damage cause disturbance in the calcium ion. exchange a cross the cell membrane.

Ca-           Ca-      Ca-                    Ca-

                                                                                       Exam calcium move in cell

 

 

 

 

 

Particularly in mitochondria causing swelling & deposition of phaspholipid rich amorphous densities

 

4)Reduction of protein synthesis

As the result of continuous Hypoxia ↓ O2                                                                                       ↓                                                                                                                                 Swelling of organelles(As Endoplasmic reticulum & Golgi apparatus )                                               ↓                                                                                                                          Detachment of Ribosomes from  rough ER & golgi body                                                                       ↓                                                                                                                      Decreased protein synthesis

 This changes seeing in detachment of Ribosomes are seeing in reduced protein synthesis in RCI.

                 Irreversible cell Injury :-

·         Persistence of ischemia  or hypoxia is caused the irreversible cell injury to damage structure and function of cells.

·          In this stage injured cell can not return to normal .

                           

 

                             strain

   Normal cell                      Adaptation

        

                RCI

 

      Cell injury

                   Persistence injury causing agent

 

 

                                             Necrosis

Irreversible cell injury                                    cell death

                                          apoptosis

 

 

1)    Damage to cell membrane function & plasma membrane :-

                                               ↓

Reduction in ATP , depletion of protein reduced intra cellular pH & leakage of lysosomal enzyme into the plasma                                                                                                                         ↓                                                                                                                     Continued influx of water                                                                                                                 ↓                                                                                                                                      Damage/loss of membrane phaspholipids & loss of protective amino acids (like glycine)            ↓                                                                                                                 Damage of cell membrane                                                                                                                  ↓                                                                                                                       Massive influx of Ca.

2)    Calcium Influx:-

 

Massive Ca++ influx (into mitochondria)

                      ↓                                                                                           activation of many enzymes and large flocculent mitochondrial densities formation .

 

 

Nuclear  change in IRCI:-

 

Activated  endonuclear                                                                                                                           ↓                                                                                                      nuclear damage

 

Some specific term:-

 

(A) Pyknosis:- degeneration and condensation of nuclear chromatin.

Means:-   breakdown of nuclear & stick to each other

 

(B) Karyorrhexix :-  Nuclear fragmentation

 

(C) Karyolysis:-  Dissolution of the nucleus

 

Normal cell →pyknosis

 

                                          Apoptosis               Necrosis

 

          Karyorrhexis

                  ↓

            Karyolysis

 

cell death in three conditiion .

·         Necrosis

·         Apoptosis

·         

Necrosis:-

Autophagy

 

 

Definition:-

Necrosis is the series of morphological changes that follow cell death in letholy injured of living cells.

·          In which cellular membrane fall apart and cellular enzymes leak out and ultimately digest the cell.

·         Necrosis is caused by various agent such as hypoxia, chemical & physical agents ,microbial agent, immunological injury etc.

Types:-

Types of necrosis based on etiological &morphological appearance.

1) Coagulative Necrosis

2) Liquefactive Necrosis

3) Caseous Necrosis

4) Fat Necrosis

5) Fibrinoid Necrosis

1) coagulative Necrosis :-

* This is the most common type of necrosis caused by irrversible cell injury.

*it’s mainly caused by sudden stop of blood flow and less often from bacterial &chemical agents.

* The organ commonly affected area are heart,kidney &spleen.

 * Denaturation of all protein and its own lysosomal enzymes are also denatured.

* Later dineted by Leukocytes.

For exp- All infarcts expect brain.

2)Liquefactive Necrosis :-

* Tissue get converted into liquid viscous mass

*It’s due to ischemic injury and fungal or bacterial infection.

*Hydrolytic enzymes caused to tissue degradation &  material become ; semi fluid material (creamy yellow pus )

Example- Brain infarets, & abscess cavity.

 

 3)caseous Necrosis :-

* this type of Necrosis is found in the centre of foci of tuberculosis infecfection .

*It’s combine feature of both coagulative & liquefactive necrosis.

*It’s resemble like dry cheese (yellow white colour) soft & granular

Example-Tuberculosis

4) Fat Necrosis:-

* Fat necrosis mainly occurs in fat rich anatomic location in the body like breast.

*Fat become fat distruction ; calcified to produce chalky white area.

*calcium deposition around the inflammatory border

Example – Acute pancreatitis

5) Fibrinoid Necrosis :-

Deposition of fibrin like material

Commonly seen in immune complex mediated vasculitis

Apoptosis:-

Example –Auto immune disease /vasculitis, peptic ulcer.

 

 

*Apoptosis is the pathway of genetically intracellular programmed cell death (cell suicide) in which unwantedhost cells are eliminated  by activation of intrinsic enzymes that degrade cell’s own DNA,Nuclear &cytoplasmic proteins

* Apoptosis always present physiologic & pathologic condition.

*absence of survival factor /Absence of getting signal to cell;socell size is decrease and containing apoptic bodies.

*In apoptosis no inflammation is present.

Causes of apoptosis:-

Apoptosis always present in pathological & physiological situations.

Apoptosis in physiologic situation

1)    Development of embryogenesis :-

·         during embryo which includes implantation, organogenesis, metamorphosis etc.

·         during all these stage of development ;lots of cells are known unneeded, and they die via apoptosis in programmed manner.

 2)Harmone- dependent apoptosis tissue:-

Eg- When mother stopped breast feeding to her child.then lactin harmone reduces the breast size and return back to their normal previous size that occur by apoptosis.

 3)Cell population:-

Apoptosis is the very common phenomena in multicellular organism. When the number of cell is very high then apoptosis occuring and reducing the no. of cells and maintain it.

Eg- replacement proliferation such as in intestinal epithelium

4)   Elimination of blood cells after they have performed their role during their life span.

5)   loss of immature B& T cells in the bone marrow and thymus by clonal deletion & cytotoxicity

Apoptosis in pathologic situation

1)    Damage  to host cell DNA:-

Eg-  Chemotherapy in treatment of cancer irradiation by therpy performed mild thermal injury or Hypoxia.

2)    Endoplasmic stress:-

It’s due to accumulation of large excess of misfolded pattern formed by free redical injury or from mutations

3)    Certain viral Infection:-

Exp- council man bodies in viral hepatitis,

Progressive depletion of CD4 + T cells in HIV infection.

Cell death by cytotoxic T cell in transplant refection reaction

 

 

                                                                                    Normal size of cell round / oval masses

 

 

 

 

                                                                                                Chromatin condensation eosiniphilic cytoplasm become                                                                                                         more dense & organells                                                                                                                       are tightly packed                                                                                                                                                                                                                                                                                                                                          Chromatin has aggregation just                                                                                            beneath the nuclear membrane

                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        Formation  of apoptotic bodie                                                                                   &apoptotic blebs

 

 

 

                                                                                    They are completely

                                                                                                            separted ditached.

 

Content of apoptotic bodies:-

1)      Cytoplasm

2)      Densly packed organelles

3)      With or without material

Definition and brief description of Inflammation ,healing /repair :-

Inflammation:-

·        Inflammation is response of vascular connective tissue towards injury but those tissue are not vascular they will not inflammation

·       Most of the tissue of body are vascular connective tissue

·         Aim of the inflammation is to defense from increase circulation ( wbc  ,leukocytes , antibodies  etc) to the site where they are needed to eliminate of injurious agent ,followed by removal of the necrosed cells and tissue.

·        the injurious agents causing inflammation may be under .

1)    Infective agents :-

Like bacteria,viruses and their toxins, fungi, parasites

2)    Tissue necrosis :-

Caused by various agent such as ischemia, physical agent (exp- heat cold radiation mechanical trauma ) chemical agent (exp - organic & inorganic toxins)

3)    Immunological agents :-

Like cells mediated antigen antibody reactions .

4)    Inert materials :-

Such as forgein bodies dirt matter , suture etc

Sign of inflammation :-

·         The word inflammation from the latin word inflamm are means fire/burning

Celsus ,A roman writter  in first centuary AD given the four sign of inflammation.

He said  “rubor et tumor cum colore et dolare”  

Which means redness and swelling with heat pain .

Where as

Rubor – redness          ,   colore – heat

Tumor - swelling         ,    dolare - pain

·         later  Rudolf Virchow  in 19^th centuary AD added 5^th sign”functio leara” means loss of function

Steps of inflammation response- 5R

1)      Recognition – of the injurious agents

2)      Recruitment – of inflammatory cells (leucocytes)

3)      Removal – of the injurious agent

4)      Regulation (control)  - of the inflammatory response

5)      Repair /resolution /healing

Types of inflammation :- 

·          Depending upon the defence capacity of the host and duration of response.

·         Main classification of inflammation is acute & chronic

·        Inflammation on the basis of organ.

1)      Dermitis

2)      Nephritis

3)      Glomerulo-nephritis

4)      Conjunctivitis

5)      Meningitis

6)      Myocitis

7)      Arthritis

8)      Hepatitis

      *   Inflammation on the basis of duration

1) acute inflammation`

2) chronic inflammation

1) Acute inflammation:-

Acute inflammation is a short duration  less than 2 weeks and represent the early body reaction ,resolves quickly healing.

2)Chronic inflammation :-

Longer duration & occurs after a delay

Either when the causative agent of acute inflammation persist for a long time .

 

 

Basic difference B/W acute & chronic inflammation:-

                                        Acute inflammation                          Chronic inflammation

Onset           .                           Rapid in min/hrs.                                         Slow , day ,week

Cells                                       Neutrophils                                            Lymphocytes , monocytes

Tissue  injury                         Mild self limited                                       Severe & Progressive

Sign- local & systemic                      Prominent                                       Less prominent

Acute  inflammatory Response :-

Acute inflammation mechanism divided by two process

     Vascular events                                                            Cellular events

1)      Alteration of micro -                                               1)Recruitment of leucocytes

vasculature caliber                                              at the site of infection     ( arterioles , capillaries.& venules )                                                                           and  increase blood flow

                ↓

2)      To bring cells and protein                                         2)after activation of

                 to the site of injury                                                          leukocytes which leading

                                                                                                            to the process of  

                                                                                                           destruction of invaders and

                                                      production of many chemical mediator       

  3)By vasodilation & increased  

vascular permeability

Acute Inflammation in vascular changes :-

Vascular changes again divided into two changes

1) changes in the vascular flow & caliber

2) Increased vascular permeability.

 

Fig

     

 

 

 

 

 

 

       1)Changes in Vascular flow & Caliber:-

           

                    Immediate transient vasoconstriction of arterioles

                                                ↓                                                                                              Persistent progressive vasodilation of arterioles  Elevate local hydrostatic

                        pressure &  deviate osmotic pressure .

                                                ↓

                     Endothelial cells swelling & separation

                                                ↓

                           Increase oozing of fluid (Tramudate)

                                                ↓

                                                Exudate

                                                ↓

                              Leucocytes start margination

                                                ↓

                                 Leucocytes  migration

 

 

2)increased vascular permeability :-

a) increased oozing out of fluid ,blood cells & protein from the blood vessels into interstitid tissue.

b) mechanism / causes of increased vascular permeability

1) contraction of endothelial cells and leads to intracellular gap in venules.

2) retraction of endothelial cells

3) direct damage to endothelial cells

4) endothelial injury due to leukocytes

5) leakage from new blood vessels/ increased transcytocin of protein.

1) contraction of endothelial cells and leads to intracellular gap in venules.

fig

 

 

 

 

                                                                                                                          

 

·        It is  most common among all

·        It occurs immediately and its short lived (few minutes)

·        Reversible , tramient & immediate short lived

·        Contraction performed by histamine ,bradykinin & leukotrinen.

·         2) retraction of endothelial cells

·         2) retraction of endothelial cells

 

2)    retraction of endothelial cells :-

·         it is reversible mechanism

·         retraction performed by cytokinin mediation TNF( tissue necrotic factor )&IL-1(interleukin-1)

 

3)    direct damage to endothelial cells :-

·         it’s seen in severe injuries (burn, toxins, infections etc)

·         direct injury to arterioles ,capillaries & venules

·         immediate start leakage & unstained response

·         cell necropsis and detachment occurs

·         it’s develop with 2-12  hrs & persist longer.

 

fig

 

 

 

 

 

(3) endothelial injury due to leukocytes:-

·         leucocyte may accumulate during inflammatory response

·         leucocyte adhering (adhesion) to endothelial cell

·         then leucocytes may release toxic oxygen species and proteolytic enzymes causing injury

·         its act in mostly venules ,pulmonary capillaries

·         it lived long.

(4) leakage from new blood vessels/ increased transcytocin of protein:-

Fig

 

 

 

 

 

 

 

·         leakage performed by VEGF( vascular endothelial growth factor)

·         here leakage can see at the site of new vessels formation and increase of vascular permeability either it natural or unnatural

·         at this site increase transport of fluid & proteins

 

cellular events :-

·         cellular phase of the acute inflammation

·         leucocytes are recruited to the site of infection.

·         Then leucocytes ingent and destroy the injurious agents (microbes/ necrotic tissue/ foreign bodies)

·         Leucocytes also secrete growth factor for the repair of injured cells

·         Here two thing we should be know of

1)      Leucocytes recruitment

2)      Leucocytes activation

1)Leucocytes recruitment:-   

* Journey of leukocytes from vessels lumen to site of infection.

* Leucocytes in the lumen of blood vessels

·         Margination

·         Rolling

·         Adhesion

*Migration across the endotheliam.

1) Margination:-

In the early stage of inflammation the rate of flow of blood is increased due to vasodilation.

·         RBCs move faster and leukocytes pushed out of the central cellular column.

·         As a result ,leucocytes accumulate at the  periphery of the vessels and the process is called margination.

2)Rolling :-

There leukocytes move on the endothelial surface by stickying transiently along the way is called as rolling .

3)Adhesion :-

This weak transient adhesion is mediated via molecules

·         Here two molicules are present

1)selection

2)integrins

1)selection:-

Selection molecules present in both leucocytes &ECs.

Selection also K/a Adhesion receptors

P- selection –present on ECs& platelets

E-selection –present on ECs

L- selection – present on leucocytes.

2)Integrins :-Integrins used in adhesion.

·         Integrins are WBC; means they are present on the surface of WBC

·         Integrins role are molecule k/a inter cellular adhesion molecules (ICAM)

·         There molecule sticking on the surface of wbc ECs, and it not move forword.

·         More gapping present on the surface of endothelial wall for this its perform  transmigration.

Transmigration ( migration across the endothelial wall)

·         After adhesion, means – leucocytes- endothelium adhesion

·         Leucocytes mights into interstitium, bymoving in between the endothelial cells called transmigration or diapedsis

Chemotoxis:-

·         Chemotaxis is movement of leucocytes towards the site of infection or injury along with chemical molecules

·         Thin process in k/a chemotoxin

·         Transmigration of leucocytes after crossing several barriers (endothelium ,basement membrane, perivascular myofibroblast &matrix.)

·         Main chemotactic agents are:-

·         Soluble bacterial products (formylated peptide )

·         Leukotriene B4(LT-B4) product of lipooxygen are (LOX), pathwayof arachidonic acid metabolites

·         Components of complement system (C5a in particular)

·         Chemokines/ cytokines (1L-B,MCP-1,M1P-α, eotoxin etc.

·         Kallikerin (end product of the kinin system)

·         Mediated through G-protein coupled receptors

·         Leukocytes move by extending pseudopods.

After the recruitment of leukocytes:-

1)      To recognize the microbes / necrotic cells/foreign bodies

2)      Once if recognize the leucocytes killing & phagocytosis

1)To recognize the microbes / necrotic cells/foreign bodies:-

All there stimuli are recognize by receptors on the phagocytes they are known as phagocytic receptors

There are different kinds of receptors on phagocytes:-

1) mannore receptors

2)Scavenger receptors-present on WBC

3)opsonin receptors- bacterial surface

Phagocytosis:-

·       Phagocytosis is the killing & degradation of the foreign particles

·       Phagocytosis is the process of cellular engulfment of a solid particulates material (eg. Microbes, foreign particular material

·       Phagocytosis is k/a cell eating

·       Pinocytosis is k/a cell drinking

·       Processes of phagocytosis is performed by the three steps

1)      Recognition & Attachment

2)      Engulfment

3)      Killing & degradation

1)   Recognition & attachment :-

·         Cell surface express the receptors those who are recognize micro organism.

·         Wbc cell receptors are mannore & scavenger receptors.

·         Process of the micro organism are coated with specific protein is k/a opsonins.

 

IgG protein

                                                                                                                      Receptor for C3b

           receptoer for IgG

   Opsonisation:-      

Some molecules are joint with the surface of bacteria .there molecules are antibody; IgG antibody, C3b compliments & collection particles.

2)   Engulfment :-

·         The opsonised particle bound to the surface of phagocytes is ready to be engulfed

·         Then after ,pseudopods are formed around the attached particles due to activation of action filaments beneath cell wall

·         Pseudopods enveloping in a phagocytic vacuole.

·         Then the phagosomal & lysosomal membrane fuses to from phagolysosome.

Fig.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Killing & degradation:- 

Neutrophils → oxygen independent →bacteria kill by lysozyme                                                    +                                                                                                                                  monocytes                    oxygen dependent – mast cell→produce by ROS & its more effective

 

a)      by ROS & lysosomes enzymes

b)      the ROS is produced by oxidative burst in leukocytes.

Fig.

 

 

 

 

 

 

 

 

   2O2+ NADPH  →  NADP +  H+       

Superoxide is then coverted by spontaneous dismutation to hydrogen peroxide.

+                                                                                                                                                                                        HOCl +  

HOCL                                    OCl (hypochloroun free radical )

CHEMICAL MEDIATORS IN INFLAMMATION :-

·         Chemical mediators are special chemical molecules that mediate the process of acute &chronic inflammation.

·         The action of there mediators are tightly regulated.

·         Two main groups of substance acting as chemical mediators of inflammations.

(1)    Release from cells

(2)   Release from plasma ptn.

Chemical mediators substance devided based on structure →

(1)   Vasoactive amines

(2)   Lipid product → (A) prostaglandin

                              (B ) leukotrienes

(3)   cytokines →      (A) chemokines

(4)   product of complement activation .

(5)   coagulation products.

Plasma mediated:-

(A)  factor xii (Hageman factor activation)→kinin system (bradykinin coagulation /fibrin olysin  system)

(B)   complement system activation →(C3a, C5a)→Anaphylotoxins

                                                             C3b

                            ( C5b, C6b ,C7b ,C8b ,C9b)→membrane attack complex

 

Chemical mediators:-

(1)   cell derived (local mediators)

(2)   plasma ptn derived (systemic mediators)

 

(1)            cell derived (local mediators):-

 

(a) preformed mediators in secretory granules

mediators:-

·         Histamin   →  mast cell, basophils ,platelets

·         serotonin  → platelets 

·         lysosomal enzymes → netrophils ,macrophages

 

                    (b ) Newly synthesized

·         prostaglandin →  source →  all lecocytes endothelial cells platelets

·         leuckotrienes  →  source  →  all leukocytes

·         platelets activating factor →  all leukocytes & ECs

·         nitric oxide  →  macrophages

·         cytokines  →  lymphocytes, ECs, macrophages

 

 

 

 

 

 

chronic inflammation:-

chronic inflammation defined as long lasting( weak or month )inflammatory response in which tissue destruction/ injury inflammation , & attempts the healing process simultaneously.

Causes of chronic inflammation:-

(1)   persistant infections

(2)   hypersensitivity disease/ immune mediated inflammatory disease

(3)   prolonged exposer to toxic agent

(4)   chronic inflammation following acute inflammation

(5)   recurrent attack pf acute inflammation

(6)   chronic inflammation starting de nova

general characterstics feature of chronic inflammation :-

(1)   mononuclear cell infiltration.

(2)   Tissue destruction or necrosis.

(3)   Proliferative changes.

 

(1) Mononuclear cell infiltration:-

Chronic inflammatory lesions are infiltrated by mono nuclear inflammatory cell like .

(A)  Phagocytes

(B)   Lymphoids cells

 

(A)Phagocytes:-

its represented by circulating monocytes tissue macrophages ,epithelial cells and some time multinucleated gaint cells macrophages are most imp. Cells in chronic inflammation .

(B) Lymphoid cell:-

It is represented by circulating lymphocytes , plasma cells eosinophils & most cells.

 

 

(2) Tissue destruction:-

·         Tissue destruction is the most imp. Feature of the chronic inflammation .

·         Tissue destruction is performed by activated in macrophages which release a variety of biological active substance

Exp.- protease free radicals & cytokines.

 

        (3)proliferative changes :-

Proliferative changes and attempts to healing by angiogensis & fibrosis.

Cells and mediators in chronic inflammation:-

(1)   Macrophages

(2)   Lymphocytes

(3)   Plasma cells

(4)   Eosinophils

(5)   Mast cells

(6)   Neutrophils

Mechanism of Granuloma / chronic inflammation :-

     cell injury

          ↓                                                                                                     Failure to digest agent

          ↓

Weak acute inflammatory response

          ↓

                                         Engulfment by macrophages

         ↓

                        Persistence of injurious agent

                                             ↓

T cells mediated immune response                           poorly digestible agent

 

                             Activcation of CD4     +   T  cells

(release of lymphokines IL-1,IL-2 growth factor IFN-ϒ (interferon)& TNF- α monocytes chemotactic factors)

↓

Activated macrophages by IFN –ϒ(interferon)

 

Transformation to epithelioid cells gaint cells                secretion of fibroblastic proliferating

Cytokines

Granuloma

 

 

                 

 

Granuloma:-

·         It is the form of chronic inflammation that is characterized by collection of activated macrophages ,T-lymphocytes, &sometime associated with central necrosis.

·         Activated macrophages are called epithelioid cells.

Epithelioid cells :-

·         Epithelioid cells are called because its looks like epithelial cells .

·         Epithelioid cells activated by macrophages with abundant cytoplasm.

·         It may fure with one & other they form multinucleated gaint cells.

Types of granuloma :-

(1)   Foreign body granuloma  eg.- Talc fibers

(2)   Immune granuloma .

Morphology of granuloma:-

·         Activated macrophages with pink granular cytoplasm and indistinct boundaries in H & E stain. Surrounded by lymphocytes .

·         Older granuloma may show rim of fibroblast as well multinucleated gaint cells.

 

 

                                               

                                                                       

 

 

 

 

 

 

  

Disease caused by granulomatus inflammation:-

 Disease                      Caused

Tuberculosis                             →         Mycobacterium tuberculosis

Leprosy                                    →          Mycobacteriumleprai

Cat-scratch disease                →         gram negative bacillus

Syphilles                                   →         Traponema pallidom

Sarcoidosis                                →         unknown causes

Crohn disease                          →          immune reaction

Tissue repair ,Regeneration & shealing :-

·         Tissue repair is also called tissue healing

·         Our body response against injury and its attempt to restore structure & function by living tissue.

·         By the two process injured tissue are replacing there are –

(1)   Regeneration

(2)   Repair

 

 

 

 

 

 

 

 

 

 

(1)Regeneration:-

* Some tissue are able to replace the damaged components and essentially return to normal state this process is called Regeneration .

*  regeneration occurs by proliferation of cells that survive the injury& retain the capacity to proliferation.

* Depending upon their capacity to divide the cells of the body can be devided into three groups.

(1) Labile cells

(2) stable cells

(3) permanent cells

 

(2)Repair:-

.

.

Cell cycle.                                                                       growth

.

 

                      Parent cell                                              reproduction

 

 

Cell repair:-

·         Repair is the replacement of injured tissue by fibous tissue.

·         Process of repair perform by two ways.

(1)   Granulation tissue formation

(2)   Wound contraction & strength.

 

(1) Granulation tissue formation:-

·         Granulation tissue are the hallmark of tissue repair

·         Granulation name is because of granules apperence on the surface of wound.

·         It appearance in pink soft granular in form

·         Granulation tissue is not a granuloma both are very different.

·         Granulation tissue is the focai of granulomatous inflammation.

·         Process of the granulation tissue formation can be devided into four phases.

(1)   Bleeding phase

(2)   Inflammation phase

(3)   Proliferation phase

(4)   Remodelling phase

 

(1) Bleeding phase :-

Bleeding may stop after few hours(4-6 hrs.) but it may vary ,following by clotting of blood at the site of injury.

(2) Inflammation phase:-

·         Inflammation is the essential component of healing process.

·         The enzymes release from neutrophils as well as autolytic enzymes release from the dyeing cells.

·         In the inflammatory phase neutrophils and monocytes are the predominant cells then there is the phase is clearance phase .

·         After the clotting ,fibrin & fibronectin remain in the tissue which form the substance3 for adhesion of various inflammatory cells.

 

(3) Proliferation phase:-

It consist of two main process-

(1)   Angiogenesis

(2)   Fibrogenesis

 

(1)Angiogenesis:-

* formation of new blood vessels at the site of injury taken place by proliferation of endothelial cells from the margin of several blood vessels.

* initially ,the proliferated endothelial cells are solids buds but with in afew hours develop a lumen & start carrying blood.

* The newly formed blood vessels are more leaky accounting for the oedematous appearance of new granulation tissue soon ;there blood vessels differentiate into muscular arterioler thin walled venules & tree capillaries.

* The process of angiogenesis is stimulated with proteolytic destruction of basement membrane

*Angiogenesis taken place under the influence of following factors.

 

(a)   VEGF(vascular endothelial growth factor) elaborated by mesenchymal cells while its receptors are present in endothelial cell only.

(b)   POGF – platelets derived growth factors,

(c)    PGF – polypeptide growth factor,

(d)   EGF – epidermal growth factors

(e)   ECM  (extracellular or matrix ) – collegen glycol ptn., proteoglycon .

 

(2)Fibrogenesis:-

* The newly formed blood vessels are present in an amorphous ground substance or matrix.

* The new fibroblast have feature intermediate b/w there of fibroblast & smooth muscles cells (myofibroblast).

* Collagen fibrils begin to appear by about 6thday .

*The myofibroblast have surface receptors for fibronectin molecules which forms bridge between collagen fibrils .

* As maturation proceeds , more and vmore collagen is formed while the member of active fibroblasts and new blood vessels decrease .

* this results in formation of inactive  looking scar this process is called cicatrisation.

 

Remodeling:-

·         The connective tissue that has been deposited by fibroblast is reorganized to produce the stable fibrous scar.

·         This process begin 2-3 weeks after injury and may continue for month or years.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Wound contraction & strength:-

·         Wound start contracting after 2-3 days and process is completed by the 14 th day.

·         During this period ,the wound is reduced by approximately 80% of its original size.

·         The wound is strengthened by proliferation of fibroblast and myofibroblast which get structural support from the extra cellular matrix.(ECM)

 

 

 

 

 

 

 

 

                           

Definition of brief description  of Edema ,Shock ,Haemorrage Embolism ,Ischemia & Infarction:-

Oedema :-

Excess fluid in the body tissue (extra vascularly ) means (excess fluid in the body either inside the cells which is intracellular edema either or in the interstitium in the body cavity which is called extra cellular edema .

                                                Or

Edema is defined as abnormal & excessive accumulation of “free fluid” in interstitial tissue space and serous cavities.

Free fluid in interstitial fluid-

·         It is also called tissue space

·         Its surrounded by tissue cells

·         Interstitial space filled with interstitial fluid provide the immediate micro environment that allow for movement of ions proteins and nutrients across the cell barriers.

·         This fluid lies free in the interstitial space b/w the cells and can be displaced from one place to another place.

·         Free fluids in interstitial space is commonly called oedema.

·         Here two term of edema are used.

Pitting edema :-

Pitting edema is known as momentary pressure of finger produces adepression .

Non pitting edema:-

No pitting depression produced by finger .

Eg.:-  Myoedema  , elephantiasis

Oedema :- two main type of edema

(1) Localized edema

(2)Generalized edema

(1)Localized edema :-

When ever edema is present in limited to an organ or limb.

Eg.:- lymphatic edema , inflammatory edema , allergic edema, pulmonary edema , cerebral edema ,

(2)Generalized edema :-

When it is systemic in distribution ,particularly noticeable in the subcutaneous tissue.

Eg. :- renal edema , cardiac edema , nutritional edema .

Pathogenesis of oedema /causes of edema :-

·         Oedema is caused by mechanism that interfere with normal fluid balance of plasma ,interstitial fluid & lymph flow

·         But here the main causes of edema is due to increased capillary hydrostatic pressure or diminished (decrease ) plasma osmotic pressure resulting increased interstitial fluid

·        Here some factors are effected:-

(1)   Increased capillary hydrostatic pressure

Impaired venous return

Arteriolar dilation.

(2)   Decreased colloid plasma osmotic pressure

(3)   Lymphatic obstruction

(4)   Sodium and water retention

(5)   Inflammation.

(1)Increased capillary hydrostatic pressure:-

·         The hydrostatic pressure of the capillary is the force that normally tends to drive fluid through the capillary wall into the interstitial space by counteracting the force of plasma oncotic pressure

·         Increased hydrostatic pressure are mainly caused by disorder that impaired venous  return.

·         Example of increased capillary hydrostatic pressure seen in some disorders.

(1)   Odeam of cardiac diseases:- eg.:- congestive cardiac failure ,. Constrictive pericarditis

(2)   Ascites of liver disease:- eg.:- ascites , liver cirrhosis.

 

(3)   Passive congestion:- eg. :- mechanical obstruction due to thrombosis of vein of lower legs, vercositien ,pressure by pregnant uterus , tumours etc.

(4)   Pastural edema:-eg. :- transient edema of feet and ankles due to increased venous pressure.

(5)   Arteriolar dilation :- (a) heat           (b)neurohormonal dysregulation.

 

 

 

 

 

 

 

 

 

 

(2)Decreased colloid plasma osomotic pressure:-

·         Plasma osmotic pressure maximum used by total amount of plasma protein .

·         Plasma protein tends to draw fluid into the vessels normally.

·         Reduced total plasma protein level> 5g/dl (less then 5g/dl) hypoproteinemia , means hypoalbuminemia.

·         Reduced plasma ptn caused decreased colloid plasma osmotic pressure.

·         Plasma ptn.:- plasma protein are responsible for creating the osmotic pressure inside the plasma that tense to drowfluid , from outside of the blood vessels towards the blood vessels and when ever reduced production of plasma ptn. That will there imbalance b/w the osmotic pressure & capillary hydrostatic pressure and caused result edema.

·          Reduced plasma osmotic pressure have caused.

(1)   decreased production of plasma protein.

Glomerulopathies → Nephrotic syndrome

Gastroentropathies

(2) Liver cirrhosis

(3) Mal nutrition.

(3)Lymphatic obstruction:-

* normally the interstitial fluid in the tissue space escapes by way of lymphatics.

* main function of lymphatic vessels

(a)Fluid balance:-Lymphatic system helps to maintain fluid balance . it return excess fluid and protein from the interstitial tissue space that can not be returned through blood vessels.

(b) Absorption:- most of the fat absorbed from the gastrointestinaltract are taken up in a part of the gut membrane in the small intestine that in specially adopted by the lymphatic system.

(c)Immune system:-   lymphatic system is defence the body against unwanted organism. So when ever impaired /dysfunction of lymphatic vessels then they will cause impaired removal of interstitial fluid by the lymphatic system . so if there in excess interstitial fluid leads to developmentof edema . this type of edema is called lymphoedema.

Some example of lymphoedema  :-

(1)   Removal of axillary lymph nodes-

·         Suppose with the pt diagnose with breast carcinoma then that patient under gone radical martectomy and axillary lymph nodes are affected site are also removed.

·         After removal of axillary lymph nodes patient have high chance of develop lymph odema in the superior extrimities of effected site.

(2)pressure from outside:-

* when the malignant cells are obstructs the lymph channels .

* Lymphatic obstruction can be also caused by compression from out site particularly on thoracic duct.

·         If tumour /mass cavity is present then mass compress to thoracic duct then that cause of obstruction of lymphnodes and results in edema.

·         Some time thoracic duct may rupture and that they release the content of lymph to various body cavity if lymph is release in pleural cavity that is called chylothorax and lymph is release in paritonial cavity is called chylousascites.

(3)Inflammation of the lymphatics:-

This type of inflammation seen in filoriasis (infection with wuchereria bancrofti) result in chronic lymphoedema of scrotum and legs is known as elephantiasis. This is non pitting edema.

(4)Milray’s disease or herediatory lymphoedema :-

*   It is due to abnormal development of lymphatic channels.

* thoracic duct is the largest lymphatic vessel of the lymphatic system.

Milray disease :- it is the condition that affects the normal function of the lymphatic system.

·         Lymphatic system produce & transport fluids & immune cells through out the body.

·         When impaired transport with accumulation of lymph fluid can cause swelling ( lymphoedema)