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"Opportunities are usually "Opportunities are usually disguised by hard work, so disguised by hard work, so most people don't recognize most people don't recognize

them."them."

- Ann Landers- Ann Landers

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Acute and chronic

inflammation

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Introduction:

““Inflame” – to set fire.Inflame” – to set fire. Inflammation is “dynamic response of Inflammation is “dynamic response of

vascularized tissue to injury.”vascularized tissue to injury.” Is a protective response.Is a protective response. Serves to bring defense & healing Serves to bring defense & healing

mechanisms to the site of injury.mechanisms to the site of injury.

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Acute inflammatory reactions are triggered by a variety of stimuli: • Infections (bacterial, viral, parasitic) and microbial toxins • Trauma (blunt and penetrating) • Physical and chemical agents (thermal injury, e.g., burns or frostbite; irradiation; some environmental chemicals) • Tissue necrosis (from any cause) • Foreign bodies (splinters, dirt, sutures)

• Immune reactions (also called hypersensitivity reactions)

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The nomenclature used to describe inflammation in different tissues employs the TISSUE NAMETISSUE NAME and the suffix “-“-ITISITIS””

e.g

pancreatITIS

meningITIS

pericardITIS

arthrITIS

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Inflammation-6 InflammationInflammation provoked response to tissue injuryprovoked response to tissue injury

chemical agentschemical agents cold, heatcold, heat trauma trauma invasion of microbesinvasion of microbes

serves to serves to destroy, dilute or wall off the injurious agentdestroy, dilute or wall off the injurious agent

induces repairinduces repair

protective responseprotective response

can becan be potentially potentially harmful harmful

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Lewis Triple Response:Lewis Triple Response:

FlushFlush:: capillary dilatation. capillary dilatation. FlareFlare:: arteriolar dilatation. arteriolar dilatation. WealWeal:: exudation, edema. exudation, edema.

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Red, Warm & SwollenRed, Warm & Swollen(Flare, Flush & Weal – Lewis)

Triple response

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Gastric Ulcer:Gastric Ulcer:

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Laryngitis:Laryngitis:

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Mouth Aphthus ulcerMouth Aphthus ulcer

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Acute Enteritis:Acute Enteritis:

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PneumoniaPneumonia

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Cardinal Signs of InflammationCardinal Signs of Inflammation

Celsus, a Roman writer of the first century AD, first listed the four cardinal signs of inflammation:

Rubor (Redness) Calor (Warmth) Tumor (Swelling) Dolor (Pain) Functio laesa (Loss of function, later

added by Virchow)

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Cardinal Signs of InflammationCardinal Signs of Inflammation

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Acute InflammationAcute Inflammation

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PATHOGENESIS:PATHOGENESIS: Three main processes occur Three main processes occur at the site of inflammation, due to the release of at the site of inflammation, due to the release of chemical mediators:chemical mediators:

Acute InflammationAcute Inflammation

1.1. Increased blood flow (redness and warmth)Increased blood flow (redness and warmth)

2.2. Increased vascular permeability (swelling, Increased vascular permeability (swelling, pain & loss of function)pain & loss of function)

3.3. Leukocytic InfiltrationLeukocytic Infiltration

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The inflammatory response consists of a vascular and a cellular reaction

Intensive Care Med. (2004) 30: 1702-1714

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Acute inflammation involves:

alteration of vascular caliber following very brief

vasoconstriction (seconds), vasodilatation leads to increased

blood flow and blood pooling creating redness and warmth (rubor

and calor)

changes of microvasculature increased permeability for plasma

proteins and cells creating swelling (tumor). Fluid loss leads to

concentration of red blood cells and slowed blood flow (stasis)

emigration of leukocytes from microcirculation

due to stasis and activation leads migration towards offending agent

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Mechanism of Inflammation:Mechanism of Inflammation:

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Inflammation-21Vascular changes and fluid leakage during acute inflammation lead to

Edema in a process called Exudation

Transudate

•result of hydrostatic

or osmotic imbalance

•ultrafiltrate of plasma

•Low protein content

•specific gravity < 1.015

Exudate

•result of inflammation

•vascular permeability

•high protein content

•specific gravity >1.020

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Neutrophil MarginationNeutrophil Margination

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The sequence of events in the journey of The sequence of events in the journey of leukocytes from the vessel lumen to the interstitial leukocytes from the vessel lumen to the interstitial

tissue tissue

1. In the lumen: 1. In the lumen: margination, rollingmargination, rolling,, and and adhesionadhesion to to endothelium. Vascular endothelium normally does not endothelium. Vascular endothelium normally does not

bind circulating cells or impede their passage. In bind circulating cells or impede their passage. In inflammation, the endothelium has to be activated to inflammation, the endothelium has to be activated to permit it to bind leukocytes, as a prelude to their exit permit it to bind leukocytes, as a prelude to their exit

from the blood vessels. from the blood vessels. 2. Transmigration across the endothelium (also called 2. Transmigration across the endothelium (also called

diapedesis) diapedesis) 3. Migration in interstitial tissues toward a chemotactic 3. Migration in interstitial tissues toward a chemotactic

stimulus stimulus

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Immune cells within a blood vessel

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Immune cell traversing endotheliumImmune cell traversing endothelium

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1. Recognition & attachment1. Recognition & attachment Opsonins (IgG and C3) coat target Opsonins (IgG and C3) coat target

2. Engulfment2. Engulfment Pseudopods flow around the particle to bePseudopods flow around the particle to be

engulfed. Particle is engulfed and fuses withengulfed. Particle is engulfed and fuses with lysosome lysosome

3. Killing/degradation3. Killing/degradation OO22 dep: Reactive O dep: Reactive O22 species in lysosomes species in lysosomes OO2 2 indep: Bactericidal permeability agents, indep: Bactericidal permeability agents,

lysozyme, MBP, lactoferrinlysozyme, MBP, lactoferrin

Phagocytosis (engulf and destroy)Phagocytosis (engulf and destroy)

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Inflammation-27A, Phagocytosis of a particle (e.g., bacterium) involves attachment and binding of Fc and C3b to receptors on the leukocyte membrane, engulfment, and fusion of

lysosomes with phagocytic vacuoles, followed by destruction of ingested particles within the phagolysosomes. Note that during phagocytosis, granule contents may

be released into extracellular tissues.

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SerousSerous (high fluid, low protein and cell content)(high fluid, low protein and cell content) CatarrhalCatarrhal Fibrinous Fibrinous (exudate is high in plasma proteins especially (exudate is high in plasma proteins especially

fibrin; seen in membrane-line body cavitiesfibrin; seen in membrane-line body cavities Hemorrhagic Hemorrhagic ((Purpura)Purpura) Suppurative or purulentSuppurative or purulent (exudate is rich in neutrophils; (exudate is rich in neutrophils;

abcess, phlegmon, empyeme)abcess, phlegmon, empyeme) UlcerationUlceration ( (nnecrotic and eroded epithelial surface ecrotic and eroded epithelial surface

underlying acute and chronic inflammation; trauma, toxins, underlying acute and chronic inflammation; trauma, toxins, vascular insufficiencyvascular insufficiency

GangrenousGangrenous PseudomembranousPseudomembranous

ACUTE INFLAMMATIONCLASSIFICATION

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Catarrhal

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Exudate: - watery, relatively protein-poor fluid, with scanty fibrin - On serous membranes (pleura, pericardium, peritoneum, synovium, meninges, conjunctiva) - On respiratory/GI mucosa - In the skinOUTCOME

•May heal completely•May transform to fibrinous inflammation

Serous inflammation

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Superinfection with St. aureus: the vesicles are filled

with pus

Blisters in chickenpox

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Serous inflammationSerous inflammation::- outpouring of a thin fluid - outpouring of a thin fluid - is derived from either the- is derived from either the plasma or the secretions plasma or the secretions of mesothelial cells lining of mesothelial cells lining the peritoneal, pleural, the peritoneal, pleural,

andand pericardial cavities pericardial cavities

(called (called effusioneffusion).).

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Serous inflammationSerous inflammation is marked by the outpouring is marked by the outpouring

of a thin fluid that,of a thin fluid that, depending on the size of injury, is depending on the size of injury, is derived from either the plasma or the secretions of derived from either the plasma or the secretions of mesothelial cells lining the peritoneal, pleural, and mesothelial cells lining the peritoneal, pleural, and

pericardial cavities (called pericardial cavities (called effusioneffusion).).

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A focus of inflammation showing A focus of inflammation showing numerous eosinophilsnumerous eosinophils

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Causes on serous membranes - Viruses: pleura, pericardium, meninges - Chronic uraemia: pericardium - Immune complexes in SLE : pericardium, pleura, joints - Irritation: adjacent to pulmonary infarction (pleurisy), myocardial infarction (pericarditis); joints

Fibrinous inflammation

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Inflammation-36Different morphological patterns of acute inflammation can be found

depending on the cause and extend of injury and site of inflammation

Serous inflammation

Fibrinous inflammation

Purulent inflammation

ulcers

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Fibrinous pericarditisFibrinous pericarditisDeposits of fibrin on the pericardium.Deposits of fibrin on the pericardium.

MorphologyMacro:the serous membrane is opaque and reddish, and is covered by coagulated fibrinMicro:the fibrin appears as homogeneous masses of eosinophilic material

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Fibrinous pericarditis: A pink meshwork of fibrin exudate (F) overlies the pericardial

surface (P).

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OUTCOME

May be removed by fibrinolysisMay be converted to granulation tissue ⇒fibrous strands bridge serous surfaces (adhesions); adhesions of pleura may undergo secondary calcification: callus of pleuraBacterial superinfection purulent inflamm.⇒Diffuse peritonitis may be lethal

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LOBAR PNEUMONIA - Causative agent: Streptococcus pneumonia; The entire lobe is affected; the exudate is localized in the alveoliMacro: the affected lobe is consolidated, resembles to the liver by palpation (hepatisation)Micro: fibrin fills the alveolar spaces, days later the exudate turns into fibrinosopurulentOutcome:

Heals completelyComplications develop, such as lung abscess

Fibrinous inflammation of the lungs

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Exudate: the neutrophilic granulocytes (NGs) predominateCausative agents: pyogenic, pus-producing bacteria (Staphylococcus, Neisseria, etc.)Pus: viscous, creamy fluid composed of viable and dead NGs, bacteria, cell debris and exuded plasma proteins

Purulent/suppurative inflammation

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- Skin or deep tissuesAbscessPhlegmon

- Preformed cavitiesEmpyema

- Serosal surfaces

- Airways and urethra

Sites of purulent inflammation

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SPECIFIC TYPES

Abscess

Furuncle

Carbuncle

Cellulitis Lymphangitis

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Lung abscessLung abscess

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- Localized collection of pus; no fibroblastic rim

- In the skin, perianal region, lungs, liver, kidneys, brain

- Healing by granulation tissue fibrosis⇒

- The abscess has a tendency to break through intramuscular septa. Eventually, the pus reaches a surface, where it is discharged.

- Sinus: the channel draining the abscess

Abscess

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Variants of skin abscessVariants of skin abscess

Causative agent: StaphylococcusCausative agent: Staphylococcus Folliculitis - suppuration of a hair follicleFolliculitis - suppuration of a hair follicle Furuncle (boil) - suppuration of a hair follicle Furuncle (boil) - suppuration of a hair follicle

+ + subcutaneous tissuesubcutaneous tissue Carbuncle - suppuration of several hair Carbuncle - suppuration of several hair

follicles follicles + subcutaneous tissue+ subcutaneous tissue Patients should be examined towards diabetesPatients should be examined towards diabetes

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Folliculitis on the nose; carbuncle on the faceFolliculitis on the nose; carbuncle on the face

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Purulent (Suppurative) inflammationPurulent (Suppurative) inflammationA, A subcutaneous bacterial abscess with collections of pus.A, A subcutaneous bacterial abscess with collections of pus.

B, The abscess contains neutrophils, edema fluid, and B, The abscess contains neutrophils, edema fluid, and cellular debris.cellular debris.

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tissues by neutrophils

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- Empyema of gallbladder, thorax,paranasal sinuses (maxillary, sphenoidal, ethmoidal, frontal) complication: ⇒ purulent meningitis - Acute purulent otitis media (empyema of middle ear) spontaneous perforation of ⇒the tympanic membrane; mainly in children

Empyema: pus fills a preformed cavity

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Empyema of thorax

Healing: granulation tissue

secondary ⇒calcification:callus of pleura

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Purulent inflammation of serous membranes

Acute diffuse purulent peritonitis

After perforation of an abdominal organ; the peritoneal surface is hyperaemic and red, and is covered by creamy exudate

Acute purulent meningitis

Exudation into the subarachnoid space,the meningeal vessels are engorged and stand out prominently

BOTH ARE FREQUENTLY LETHAL BOTH ARE FREQUENTLY LETHAL IN SURVIVORS, HEALING WITH FIBROSIS IN SURVIVORS, HEALING WITH FIBROSIS

ADHESIONS⇒ADHESIONS⇒

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Acute purulent meningitis

The exudate localizes in the subarachnoid space,the meningeal vessels are engorged and stand out prominently

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Hemorrhagic inflammation

Sufficient vascular damage hemorrhages⇒In the bladder: hemorrhagic cystitis, caused by Gram-negative bacteria;

hematuria⇒In the lungs: hemorrhagic pneumonia in fatal cases of influenza virus infection

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Acute hemorrhagiccystitis

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Inflammation-56Acute pseudomembranous enterocolitis: plaques of yellow fibrin and inflammatory debris adherent to a reddened

mucosa

Clostridium difficile infection after antibiotic therapy eradicating normal bacterium flora of the gut diarrhea⇒Outcome: may be lethal, may heal completely, or may heal with granulation tissue.

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Gangrenous inflammation

1) Infection with putrefactive bacteria: severe and extent necrosis of the involved tissues; grayish-black, odorousAcute gangrenous cholecystitis/appendicitis - high risk of perforation within hours peritonitis⇒2) Infection of deep wounds with gas producing Clostridia: digestion of tissues. Rapid spread, severe toxaemia frequently lethal⇒

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Gangrenous inflammation

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Inflammation OutcomeInflammation Outcome

Acute Inflammation

Resolution

Chronic Inflammation

Abscess

SinusFistula

Fibrosis/Scar

Ulcer

Injury

FungusVirusCancersT.B. etc.

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Outcomes of acute inflammation: resolution,Outcomes of acute inflammation: resolution,healing by fibrosis, or chronic inflammationhealing by fibrosis, or chronic inflammation

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“Never let the competition define you. Instead, you have to define yourself based on a point of view you care deeply about.”

– Tom Chappel

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Chronic Inflammation:

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Chronic InflammationChronic InflammationAlthough difficult to define precisely, Although difficult to define precisely, chronic chronic

inflammationinflammation is considered to be is considered to be inflammation of inflammation of prolonged durationprolonged duration (weeks or months) (weeks or months) in which active in which active inflammationinflammation, , tissue destructiontissue destruction, , and attempts at repair and attempts at repair are proceeding simultaneouslyare proceeding simultaneously. Although it may follow . Although it may follow acute inflammation, chronic inflammation frequently acute inflammation, chronic inflammation frequently

begins insidiously, as a low-grade, begins insidiously, as a low-grade, smoldering, often asymptomatic response. This latter smoldering, often asymptomatic response. This latter

type of chronic inflammation is the cause of tissue type of chronic inflammation is the cause of tissue damage in some of the most common and disabling damage in some of the most common and disabling

human diseases, such as human diseases, such as rheumatoid arthritis, rheumatoid arthritis, atherosclerosis, tuberculosis, and chronic lung diseases.atherosclerosis, tuberculosis, and chronic lung diseases.

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In contrast to acute inflammation, which is In contrast to acute inflammation, which is manifested by vascular changes, edema, and manifested by vascular changes, edema, and

predominantly neutrophilic infiltration, predominantly neutrophilic infiltration, chronic chronic inflammation is characterized by:inflammation is characterized by:

• • Infiltration with mononuclear cellsInfiltration with mononuclear cells, which include , which include macrophages, lymphocytes, and plasma cells. macrophages, lymphocytes, and plasma cells. • • Tissue destructionTissue destruction, induced by the persistent , induced by the persistent offending agent or by the inflammatory cells. offending agent or by the inflammatory cells.

• Attempts at • Attempts at healing by connective tissue healing by connective tissue replacement of damaged tissuereplacement of damaged tissue, accomplished by , accomplished by

proliferation of small blood vessels (proliferation of small blood vessels (angiogenesisangiogenesis) ) and, in particular, and, in particular, fibrosisfibrosis

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Inflammation-65Table 5–1. Differences between Acute and Chronic Inflammation.Table 5–1. Differences between Acute and Chronic Inflammation.

   AcuteAcute ChronicChronic

DurationDuration Short (days)Short (days) Long (weeks to months)Long (weeks to months)

OnsetOnset AcuteAcute InsidiousInsidious

SpecificitySpecificity NonspecificNonspecific Specific (where immune response is activated)Specific (where immune response is activated)

Inflammatory cellsInflammatory cells Neutrophils, macrophagesNeutrophils, macrophages Lymphocytes, plasma cells, macrophages, fibroblastsLymphocytes, plasma cells, macrophages, fibroblasts

Vascular changesVascular changes Active vasodilation, increased permeabilityActive vasodilation, increased permeability New vessel formation (granulation tissue)New vessel formation (granulation tissue)

Fluid exudation and edemaFluid exudation and edema ++ ––

Cardinal clinical signs (redness, Cardinal clinical signs (redness, heat, swelling, pain)heat, swelling, pain)

++ ––

Tissue necrosisTissue necrosis– – (Usually) (Usually) + (Suppurative and necrotizing inflammation)+ (Suppurative and necrotizing inflammation)

+ (ongoing)+ (ongoing)

Fibrosis (collagen deposition)Fibrosis (collagen deposition) –– ++

Operative host responsesOperative host responses Plasma factors: complement, immunoglobulins, properdin, etc; Plasma factors: complement, immunoglobulins, properdin, etc; neutrophils, nonimmune phagocytosisneutrophils, nonimmune phagocytosis

Immune response, phagocytosis, repairImmune response, phagocytosis, repair

Systemic manifestationsSystemic manifestations Fever, often highFever, often high Low–grade fever, weight loss, anemiaLow–grade fever, weight loss, anemia

Changes in peripheral bloodChanges in peripheral blood Neutrophil leukocytosis; lymphocytosis (in viral infections)Neutrophil leukocytosis; lymphocytosis (in viral infections) Frequently none; variable leukocyte changes, increased Frequently none; variable leukocyte changes, increased plasma immunoglobulinplasma immunoglobulin

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Fish Tank GranulomaFish Tank GranulomaMycobacterium marinumMycobacterium marinum

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Chronic Chronic Inflammation:Inflammation:

Lung Abscess Lung Abscess

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AA, Chronic inflammation in the lung, showing all three characteristic histologic , Chronic inflammation in the lung, showing all three characteristic histologic features: (1) collection of chronic inflammatory cells, (2) destruction of features: (1) collection of chronic inflammatory cells, (2) destruction of

parenchyma (alveoli are replaced by spaces lined by cuboidal epithelium, parenchyma (alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and (3) replacement by connective tissue (fibrosis, arrows).arrowheads), and (3) replacement by connective tissue (fibrosis, arrows).

BB, By contrast, in acute inflammation of the lung (acute bronchopneumonia), , By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.neutrophils fill the alveolar spaces and blood vessels are congested.

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Granuloma: Granuloma:

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Giant cell (Langhans cells)Giant cell (Langhans cells)

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"People who soar, are those who refuse to sit back and wish things would change."Charles R. SwindollAuthor and Pastor

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Heat Redness Swelling Pain Loss Of Func.

The 5 Cardinal Signs of The 5 Cardinal Signs of

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