objectives Overview

Historical aspect

Acute inflammation

Mediators of inflammation

Morphologic Patterns of Inflammation

Outcomes of Acute Inflammation

Chronic inflammation

Systemic effects on inflammation

Consequence of Defective Inflammation

Implication of inflammation in medical practice

INFLAMMATION

Protective Mechanism

Tissue damage

Necrotic tissue

Foreign Invader

Plasma protein

leukocyte phagocytes

Types

Acute

chronic

BU

T

adly

ncontrolled

riggered

Inflammatory Response

TISSUE INJURY

In 3000 BC Egyptian Papyrus

Celsus (Roman Writer)- 1st century AD- listed four cardinal signs

Rubor (Redness)

Tumor (Swelling)

Color (Heat)

Dolor (Pain)

In 19th century Rudolf Virchow

Functio Laesa

More Prominent in ACUTE INFLAMMATION

JULIUS COHNHEIM (1839- 1884) provided

one of the first microscopic descriptions of

inflammation.

The Russian biologist ELLIE METCHNIKOFF

discovered the process of PHAGOCYTOSIS by

observing the ingestion of rose thorns by

amebocytes of starfish larvae (1882) & of bacteria by mammalian leukocytes (1884).

SIR THOMAS LEWIS : established the concept that chemical substances, locally induced by injury, mediate the vascular changes of inflammation.(1924)

The reaction so elicited is known as TRIPLE RESPONSE or REDLINE RESPONSE consisting of following:

Redline: appears within a few seconds following stroking & results from local vasodilation of capillaries & venules.

Flare: is the bright reddish appearance or flush surrounding the redline & results from vasodilation of adjacent arterioles.

Wheal: is the swelling or edema of the surrounding skin occurring due to transudation of fluid into the extravascular spaces.

‘Inflammation is a localized protective response elicited by injury or destruction of tissues which serves to destroy , dilute or wall off both the injurious agent and injured tissue .’

Medical dictionary of pathology

characteristic Rapid Host Response

Alterations in vascular calibre

Increase blood flow

Structural changes in microvasculature

Plasma protein & Leukocyte leave circulation

Emigration

Leukocyte

To accumulate in injurious foci

normal

inflamed

• Bacterial, viral, fungal, parasitic

• ischemia, trauma, chemical injury• release uric acid, ATP, DNA-binding protein• Hypoxia – HIF-1α – VEGF – permeability –inflammation

hyper sensitivity reactionAuto-immune diseaseImmune mediated inflammatory disease

INFLAMATION

Connective tissue cellsMast cells

Macrophages

Fibroblasts

Connective tissue matrix Elastic fibers

Collagen fibers

Proteoglycans

Vessels Soluble proteinsNeutrophils Complement Eosinophils CoagulationPlatelets Kinin system MonocytesLymphocytes

Changes in vascular flow and caliber

Vasodialation

Induce by – histamine, NO

Increase blood flow– heat & redness

increase RBC concentration

Vascular congestion of small vessels – localized redness

Increased vascular permeability

Hallmark of acute inflammation

Accomplished by the following steps Contraction of endothelial cells –

increase interendothelial space

Mediated by – histamine, bradykinin, substance-p

Endothelial injury – cell necrosis and detachment

Sometimes neutrophils that adhere to endotheliam – may injure endothelium – thus amplify the tissue reaction

Increased transport of fluid and protein – transcytosis

•

•

•

Lymph flow is increased

Drains edema fluid that accumulate at extra vascular space

Lymph channels proliferate to control the edema

Painfull enlargement of draining lymph node – LYMPHADENITIS

Secondarily infected lymphatics –LYMPHANGITIS

TELLTALE sign red streak near wound indicative of infection involvement of lymphatics

Reaction of LEUKOCYTES in inflammation

Inflammation causes migration of

leukocytes from vessels to site of injury.

This recruitment accomplish by the

following steps

In the lumen – margination, rolling, adhesion

Migration across endothelium

Migration toward the site of injury by

chemotaxis

Blood flow reduces at early stage of inflammation

Redistribution of leukocyte along the endothelium

Leukocyte – adhere – detach – bind = Rolling

Mediated by

Cytokines

TNF, IL-1, Chemokines

Selectin

L-selectin

E-selectin

P-selectin

Responsible for rolling

Progressively rolling action slows down

Bind firmly with endothelium

Mediated by – Integrins

TNF & IL-1 induce expression of Integrins

Chemokine activate rolling leukocyte

Cytokine induced integrin binds with leukocyte to produce firm adhesion to the endothelium

Leukocyte Migration through Endothelium

Leukocyte moves by extending a pseudopod

Network of filaments in the interior of pseudopods

Locomotion involves rapid assembly of actin monomers into linear polymers at pseudopodledging edge

Cross-linking of filaments

Disassembling of filaments away from the ledging edge

These events are controlled by Calcium ions and Phosphoionositol on actinregulating proteins -filamin, calmodulin.

These components interact with actinand myosin in pseudopod to produce contraction

Release of soluble mediators

Vasodilation

Increased blood flow

Extravasation of fluid (permeability)

Cellular influx (chemotaxis)

Elevated cellular metabolism

Heat (calor)

Redness (rubor)

Swelling (tumor)

Pain (dolor)

Physiological Symptoms Responses

Mediators of inflammationMediators Principal sources Actions

CELL DERIVED

Histamine Mast cell, basophil, platelet

Vasodilation , increased vascular permiability, endothelial activation

Serotonin Platelets Vasodilation , increased permeability

Prosta glandin Mast cell, leukocyte Vasodilation, pain, fever

Leukotrienes Mast cell, leukocyte Chemotaxis, leukocyte adhesion & activation

Platelet- activating factor Leukocyte, mast cell Degranulation, Oxidative burst

Reactive Oxygen Species Leukocyte Microbicidal, Tissue damage

Nitric Oxide Endothelium, Macrophages

Vascular smooth muscle relaxation

Cytokine ( TNF, IL-1)Chemokines

Macrophage, mast cellleukocyte

Local endothelial activationChemotaxis, leukocyte activation

Mediator Principal source Functions

PLASMA PROTEINDERIVED

Complement Products(C5a, C3a, C4a)

Plasma (produced in liver)Leukocyte chemotaxis and activation, vasodialation

Increased permeability, smooth muscle contraction

Endothelial activation, leukocyte recruitment

Kinins Plasma (produced in liver)

Protease activated during coagulation

Plasma (produced in liver)

Platelet Activating Factor

Also synthesize other mediators like Eicosonoids by leukocytes and other cells

Causes Vasoconstriction and Bronchoconstriction

Regulated by Acetyl hydrolases

PAF mediates its effects via single G-protein coupled receptor

Bioactive phospholipid derived mediator

Coagulation & Kininsystems

Complement system

Systemic effects of acute inflammation

Fever

Leucocytosis (15-20,000)Bacterial infection- NeutrophiliaViral infection -LymphocytosisParasitic infection- Eosinophilia

Hypotension

Increased ESR and C-reactive protein

Classification of Inflammation

BASED ON EXUDATE Suppurative (purulent) inflammation Serousinflammation Catarrhal inflammation (inflammation of mucous membranes) Fibrinous inflammation: fibrinogen -fibrin Pseudomembranous inflammation: surface necrosis

Necrotizing inflammation

Hemorrhagic inflammation

Ulcerative inflammation

BASED ON HISTOLOGICAL FEATURE

BASED ON CAUSATIVE AGENT

Based on EXUDATE

Suppurative (purulent) inflammation: pus

Localized proliferation of pus-forming organisms, such as Staphylococcus aureus(e.g., skin abscess).

S. aureus contains coagulase. which cleaves fibrinogen into fibrin and traps bacteria and neutrophils

Pyogenic bacteria, eg, staphylococci, streptococci, gram–negative bacilli, anaerobes.

Serous inflammation: (effusion)

Thin, watery exudate

Insufficient amount of fibrinogen to produce fibrin

Example -blister in second-degree burns, viral pleuritis

EXUDATE TRANSUDATE

Caused by inflammation

High protein content

Specific gravity high

Generally associated with infection

caused by disturbances

of hydrostatic or colloid osmotic pressure

Less protein content

Specific gravity less

Generally associated with thermal or chemical injury

Rivalta’s test:: is a very simple, inexpensive method that does not require special laboratory equipment and can be easily performed in private practice. This test was originally developed by the Italian researcher Rivalta around 1900 and was used to differentiate transudates and exudates in human patients.

A test tube is filled with distilled water and acetic acid is added. To this mixture one drop of the effusion to be tested is added. If the drop dissipates, the test is negative, indicating a transudate. If the drop precipitates, the test is positive, indicating an exudate

Catarrhal inflammation (inflammation of mucous membranes)

Marked secretion of mucus.

Infections, eg, common cold (rhinovirus); allergy (e.g. hay fever)

Fibrinous inflammation: fibrinogen -fibrin Due to increased vessel permeability. with deposition of

a fibrin-rich exudate Often occurs on the serosal lining o f the pericardium,

peritoneum, or pleura

Danger of adhesions

Example: fibrinous pericarditis

Pseudomembranous inflammation:

surface necrosis Bacterial toxins damage mucosal lining, producing a

membrane composed of necrotic tissue

Example ― pseudomembranes associated with Corynebacteriumdiphtheriaeproduces a toxin causing pseudomembrane formation in the pharynx

and trachea.

Necrotizing inflammation:

Marked tissue necrosis

Highly virulent organisms (bacterial, viral, fungal)

Eg, plague (Yersinia pestis), anthrax (Bacillus anthracis),

mucormycosis, maxillofacial gangrene (noma).

Hemorrhagic inflammation:

Destruction of blood vessel walls resulting in leakage of a

large number of red blood cells resulting in the red

coloration of inflammatory exudate.

Example ― Epidemic hemorrhagic fever, Leptospirosis and

Plague

Ulcerative inflammation:

Necrosis on or near the surface leads to loss of tissue and

creation of a local defect (ulcer)

Example ― Ulcerative gingivitis

Nonspecific:

Produce non-specific histologic picture

Specific:

Produce a specific histologic picture that is peculiar to that type of infection e.g. TB.

Aseptic(sterile)

chemical substances, radiation

Septic

(caused by living organisms)

Is the persistence of inflammation with attempts

of repair resulting from persistence of theinjurious agent.

Persisting infection or prolonged exposure to irritants (intracellular surviving of agents -TB)

Repeated acute inflammations (otitis, rhinitis)

Primary chronic inflammation -low virulence, sterile inflammations (silicosis)

Autoimmune reactions (rheumatoid arthritis, glomerulonephritis, multiple sclerosis)

Mechanism...... Defective acute inflammatory response

Poor blood supply Poor general nutrition Abnormal neutrophil function Anti-inflammatory drugs, especially corticosteroids

Agent is resistant to phagocytosis and/or intracellular destruction Intracellular infectious agents, e.g. tuberculosis, salmonellosis, brucellosis, viral

infections

Foreign-body reactions

The provoking agent is a body constituent as in: Auto-immune diseases, e.g. diffuse lymphocytic thyroiditis (Hashimoto’s

disease), auto-immune atrophic gastritis, adrenal atrophy, etc.

Reactions to altered self-antigens, e.g. contact dermatitis to rubber, nickel, etc

Continuing some features of acute inflammation Polymorph infiltration

Fibrinous exudation

Increased vascularity

Features of healing-repair and/or regeneration

Infiltration by chronic inflammatory cells Lymphocytes

Plasma cells

Macrophages

Eosinophils

Granulomatous inflammation

A distinct pattern of chronic inflammation characterized by formation of granulation tissue.

It is a protective response to chronic infection or foreign material, preventing dissemination and restricting inflammation.

Some autoimmune diseases such as rheumatoid arthritis and Crohn’s disease are also associated with granulomas

? Granuloma.......

A granuloma is a localized mass of granulation tissue with aggregationsof chronic inflammatory cells

The granuloma consists of a kernel of infected macrophagessurrounded by foamy macrophages and a ring of lymphocytes and afibrous cuff.

Causes of granuloma...... Bacteria:

Tuberculosis, Leprosy, Syphilis, Actinomycosis

Parasites: Schistosomiasis

Fungi: Histoplasmosis, Blastomycosis

Foreign bodyGranulomas Endogenous

keratin, necrotic bone or adipose tissue uric acid crystals

Exogenous wood, silica, asbestos, silicone

Unknown cause such as sarcoidosis

Ascitis / Hydroperitonium Accumulation of fluid in peritoneal cavity Classification

G-I – mild G-II – detectable with flank bulging & shifting dullness G-III – directly vbissible

Cause Transudative

Cirrhosis Heart failure kwashiokor

Exudative Cancer ( primary / Metastatic) Tuberculosis Pancreatitis serositis

Treatment Pharmacological

Diuretics – aldosteron / spironolactone / furosemide

Non-pharmacological Fluid tapping

Inflammation of pleural layer Inflamed layer rub together to

cause pain Symptom

Dry cough, fever, shortness of breath, rapid pulse

Collection of fluid in pleural space

Cause Auto-immune disease – SLE/ RA Pneumonia, Tuberculosis Pulmonary Embolism

Management Putting Chest Drain

Inflammatory reaction is greater in diabetic status

Conversely local inflammation causes intensification of diabetes

According to Russel in 1966 Cellular dehydration

Loss of alkali reserve

Vessels lumen get obliterated

Thickening of capillaries - Role in inflammation acts as a barrier to leukocytic emigration into site (Brayton et al 1970)

Role of surgical drain After surgery, have to put one or two drains, called a Jackson-Pratt

(JP) drain, placed near the incision.

This device collects fluid, under suction, from your surgical area.

The drain promotes healing and recovery, and reduces the chance of infection.

The drain will be in place until the drainage slows enough for your body to reabsorb fluid on its own.

The tube may be removed once a single tube output is less than 30cc (1 oz.) in 24 hours.

NSAIDs: Drug Effects Analgesic (mild to moderate)

Anti-gout

Anti-inflammatory

Antipyretic

Relief of vascular headaches

Platelet inhibition (ASA)

Role in inflammation

NSAIDs Adverse Effects Platelet Dysfunction

Gastritis and peptic ulceration with bleeding (inhibition of PG + other effects)

Acute Renal Failure in susceptible

Sodium+ water retention and edema

Analgesic nephropathy

Prolongation of gestation and inhibition of labor.

Hypersenstivity (not immunologic but due to PG inhibition)

GIT bleeding and perforation

Role of seratiopeptidase Serratiopeptidase is an enzyme isolated from a non-pathogenic bacteria called

enterobacteria Serratia E15

Serratiopeptidase has powerful anti-inflammatory properties and is particularly useful for post-traumatic swelling, fibrocystic breast disease and bronchitis. It is able to digest dead tissue, blood clots, cysts, and arterial plaques. Clinical studies have shown it to be effective at reducing swelling and edema and metabolizing scar tissue in the body.

A 2003 study found that 30mg of serratiopeptidase was effective at loosening and reducing mucous build-up in respiratory pathways. This was credited to its ability to reduce the neutrophil white blood cell numbers and to improve the viscoelasticity of the sputum in patients with chronic airway disease.

A 2006 study looked at the role serratiopeptidase has on improving immunity

studies have shown similar anti-inflammatory effects after oral surgery was performed

Trypsin –chymotrypsin --- proteolytic enzyme

When an injury occurs, the body responds with an inflammatory cascade. Excessive inflammation can retard the healing process.

Proteolytic enzyme supplementation reduces inflammation by neutralizing bradykinins and pro-inflammatory eicosanoids to levels where the synthesis, repair and regeneration of injured tissues can begin.

Proteolytic enzymes do not completely inhibit all phases of the inflammatory cascade to a point where the body is unable to trigger the normal healing process.

Low-dose chymotrypsin treatment inhibits neutrophil migration into sites of inflammation in vivo: Effects on Mac-1 and MEL-14 adhesion protein expression and function

Chemical Make-Up Hydrocortisone or cortisol is the primary agent

Glucocorticoid, which is naturally secreted by body is derivative

Currently, many AI steroids are available more powerful than cortisol, but have the same chemical structure as glucocorticoid

Long term use will inhibit body’s glucocorticoid activity and the body’s ability to produce this substance naturally

How it Works

Time Action Profile

Drug Onset Peak Duration Half Life

Cortisone PO rapid 2 hrs 1.25-1.5

dys

8-12 hrs

Cortisone IM slow 20-48

hrs

1.25-1.5

dys

Prednisolone

PO

UK 1-2 hrs 1.25-1.5

dys

18-36

hrs

Adverse effect of corticosteroids Receive long-term, high-dose steroid

Hypertension, heart failure

Osteoporosis, DM, impaired wound healing, metal depression and psychosis

Peptic ulcer, Cataract, glaucoma, growth suppression, hypocalcemia, PTH increased

Cushing syndrome

Secondary adrenal insufficiency

interferon-γ (IFN-γ) constitutes a positive factor triggering or promoting the inflammatory response

Systemic interferons, fulfil a down-regulating role, as evidenced by the observation that

exogenously administered IFN-α, -β, and -γ inhibit local inflammation.

type I interferons (IFNs), IFN-α and IFN-β, are cytokines that have antiviral, antiproliferative, and

immunomodulatory activities

Type I IFNs, through their ability to induce the immunosuppressive cytokine interleukin-10 (IL-10),

mediate the inhibition of pro-inflammatory gene products.

In addition, type I IFNs induce other immunosuppressive mediators such as suppressor of cytokine

signaling–1 (SOCS-1) and tristetrapolin (TTP), which act by divergent mechanisms to restore

homeostasis to the immune system.

Furthermore, type I IFNs mediate anti-inflammatory and protective effects in a variety of autoimmune

disease

Dimethyl Sulfoxide (DMSO)Drug of question - used with

animals and to clean floors

Highly effective in the reduction of edema

Clinical trials inconclusive or were stopped (changes in eyes)

DMSO FDA approved 50% solution for TX of cystitis

Canada approved 70% solution for TX of Scleroderma

Vets approved 90% solution for TX of edema

Public gets 99% industrial solution approved for degreasing

conclusion Humans owe to inflammation & repair their ability to

contain injuries & heal defects. Without inflammation, infections would go unnoticed, would never heal, & injured organs might remain permanent festering sores. However inflammation & repair may be potentially harmful

refferences Basics of Pathology, Robins & Cotrans

Pharmacological basis of theraputic, Goodman-Gillman

Essentials of medical pharmacology, KD Tripathi

Oxford hand book of clinical medicine, 8th edition

Reducing Inflammation with Proteolytic Enzymes, Part One: Absorption and Sources ;By G. Douglas Andersen, DC, DACBSP, CCN

Dynamic Chiropractic – July 12, 1999, Vol. 17, Issue 15 Reducing Inflammation with Proteolytic Enzymes, Part One: Absorption and Sources;By G. Douglas Andersen, DC, DACBSP, CCN

Cellular Immunology, vol.132 issue 1, jan.1991

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