Inflammation Jan Laco, MD, PhD

Inflammation complex protective reaction caused by various endo- and exogenous stimuli injurious agents are destroyed, diluted or walled-off without inflammation and mechanism of healing could organism not survive can be potentially harmfull

Terminology Greek root + -itis metritis, not uteritis kolpitis, not vaginitis nephritis, not renitis glossitis, not linguitis cheilitis, not labiitis

Mechanisms A) local - mild injury B) systemic – severe injury 3 major changes 1. alteration – tissue change 2. exudation - inflammatory exudate liquid + proteins (exudate) cellular (infiltrate) 3. proliferation formation of granulation and fibrous tissue usually - all 3 components - not the same intensity

Classification several points of view according to length acute × chronic (+ subacute, hyperacute) according to predominant component 1. alterative 2. exudative 3. proliferative

Classification according to histological features non-specific (not possible to trace etiology) - vast majority specific / granulomatous (e.g. TBC) according to causative agent aseptic (sterile) - chemical substances, congelation, radiation - inflammation has a reparative character septic (caused by living organisms) - inflammation has a protective character

Acute inflammation early response important role in inflammation has microcirculation! supply of white blood cells, interleukins, fibrin, etc.

Local symptomatology classical 5 symptoms (Celsus, 1st c. BC) 1. calor – heat, warmth 2. rubor – redness, erythema 3. tumor – swelling, edema 4. dolor - pain 5. functio laesa – function loss/impairment

Systemic symptoms fever (irritation of thermoregulatory centre) TNF, IL-1 IL-6 – high RBCs sedimentation rate (via fibrinogen) leukocytosis - increased WBCs number bacteria – neutrophils parasites – eosinophils viruses - lymphocytosis leukopenia - decreased WBCs number viral infections, salmonella infections, rickettsioses immunologic reactions – “acute phase reactants“ C-reactive protein, complement, SAA, fibrinogen, ...

Vascular changes 1. arteriolar vasodilation (redness + warmth) 2. increased permeability of vessels widened intercellular junctions retraction of endothelial cells (histamin, VEGF, bradykinin) protein-poor transudate (edema) protein-rich exudate 3. endothelial injury – direct x leukocyte-dependent proteolysis – protein leakage  platelets adhesion  thrombosis

Cellular events leukocytes margination  rolling  adhesion  transmigration by diapedesis (in venules) transmigration neutrophils (1-2 days) monocytes (2-3 days) chemotaxis (along chemical gradient) endogenous signaling molecules – ILs, LTs, C5a exogenous – toxins, bacterial proteins, ... phagocytosis (see below) passive migration of RBCs no active role in inflammation - hemorrhagic inflammation

Phagocytosis 1. recognition and attachment 2. engulfment facilitated by opsonins (IgG, C3b) 2. engulfment pseudopods formation  phagocytic vacuole + lysosome  phagolysosome 3. killing and degradation oxidative burst – reactive oxygen metabolits – superoxide ion, hydrogen peroxide, hypochlorous radicals lysosomal acid hydrolases in highly virulent microorganisms can die leukocyte and not the microbe in highly resistant microorganisms - persistence within macrophage - activation after many years (TBC)

Outcomes of acute inflammation 1. resolution - restoration to normal, in limited injury chemical substances neutralization normalization of vascular permeability apoptosis of inflammatory cells increased lymphatic drainage 2. healing by granulation tissue / fibrous scar tissue destruction fibrinous inflammation  adhesions, fibrosis purulent inflammation  abscess formation (pus, pyogenic membrane, resorption - pseudoxanthoma cells - weeks to months) 3. progression into chronic inflammation

Chronic inflammation reasons: persisting infection or prolonged exposure to irritants (intracell. surviving of agents - TBC) repeated acute inflammations (otitis, rhinitis) primary chronic inflammation - low virulence, sterile inflammations (silicosis) autoimmune reactions (rheumatoid arthritis, glomerulonephritides, multiple sclerosis)

Chronic inflammation chronic inflammatory cells ("round cell" infiltrate) lymphocytes (T and B), plasma cells eosinophils – parasites, allergies monocytes / macrophages activation by various mediators - fight against invaders B lymphocytes  plasma cells, Ig production NK cells monocytes-macrophages specialized cells (siderophages, gitter cells, mucophages)

Morphologic patterns of inflammation 1. alterative poliomyelitis anterior acuta, diphtherial myocarditis 2. exudative 2a. serous 2b. fibrinous 2c. suppurative 2d. necrotizing, gangrenous 2e. non-purulent 3. proliferative primary (rare) x secondary (cholecystitis)

Morphologic patterns of inflammation 2a. serous excessive accumulation of fluid, few proteins e.g. skin blister, serous membranes - initial phases of inflammation, effusions modification - catarrhal - accumulation of mucus on mucosas - larynx 2b. fibrinous higher vascular permeability - exudation of fibrinogen -> fibrin formation of pseudomembranes - fibrin, necrotic mucosa, etiologic agens, leukocytes e.g. diphtheria - Corynebacterium, dysentery – Shigella spp., Cl. difficile e.g. pericarditis (cor villosum, cor hirsutum - "hairy" heart) e.g. lobar pneumonia – Str. pneumoniae fibrinolysis  resolution organization  fibrosis  scar, adhesions

pyogenic bacteria - Staphylococci interstitial 2c. suppurative (purulent) - accumulation of neutrophillic leukocytes - formation of pus pyogenic bacteria - Staphylococci interstitial phlegmone – diffuse abscess - localized collection acute – border – surrounding tissue chronic – border - pyogenic membrane pseudoabscess – pus in lumen of hollow organ (epithelium) formation of suppurative fistule accumulation of pus in preformed cavities - empyema (gallbladder, thoracic cavity)

complications of suppurative inflammation bacteremia no clinical symptoms! formation of secondary foci of inflamm. (endocarditis, meningitis) sepsis = massive bacteremia septic fever, activation of spleen, septic shock thrombophlebitis secondary inflammation of vein wall followed by thrombosis - embolization pyemia - hematogenous abscesses (infected infarctions) lymphangiitis, lymphadenitis

inflammatory necrosis of the surface - ulcer (skin, stomach) 2d. necrotizing inflammatory necrosis of the surface - ulcer (skin, stomach) gangrenous - secondary modification by bacteria - apendicitis, cholecystitis - risk of perforation – peritonitis 2e. non-purulent round cell inflammatory infiltrate

Granulomatous inflammation distinctive chronic inflammation type cell mediated immune reaction (delayed) aggregates of activated macrophages  epithelioid cell  multinucleated giant cells (of Langhans type x of foreign body type) lymphocytic rim NO agent elimination but walling off intracellulary agents (TBC) x inert foreign bodies

Granulomatous inflammation 1. Bacteria TBC leprosy syphilis (3rd stage - gumma) 2. Parasites + Fungi 3. Inorganic metals or dust silicosis berylliosis 4. Foreign body suture (Schloffer “tumor“), breast prosthesis, vascular graft 5. Unknown – sarcoidosis, Wegener´s granulomatosis, Crohn disease

Tuberculosis – general pathology 1. TBC nodule – proliferative Gross: grayish, firm, 1-2 mm (milium)  central soft yellow necrosis (cheese-like – caseous)  calcification Mi: central caseous necrosis (amorphous homogenous + karyorrhectic powder) + macrophages  epithelioid cells  multinucleated giant cells of Langhans type + lymphocytic rim 2. TBC exudate – sero-fibrinous exudate (macrophages)

Leprosy M. leprae, Asia, Africa in dermal macrophages and Schwann cells air droplets + long contact rhinitis, eyelid destruction, facies leontina 1. lepromatous – contagious skin lesion – foamy macrophages (Virchow cells) + viscera 2. tuberculoid – sterile in peripheral nerves – tuberculoid granulomas - anesthesia death – secondary infections + amyloidosis

Syphilis Treponema pallidum (spirochete) STD + transplacental fetus infection acquired (3 stages) x congenital basic microscopic appearance: 1. proliferative endarteritis (endothelial hypertrophy  intimal fibrosis  local ischemia) + inflammation (plasma cells) 2. gumma – central coagulative necrosis + specific granulation tissue + fibrous tissue

Syphilis 1. primary syphilis - contagious chancre (ulcus durum, hard chancre) M: penis x F: vagina, cervix painless, firm ulceration + regional painless lymphadenopathy spontaneous resolve (weeks)  scar

Syphilis 2. secondary syphilis - contagious after 2 months generalized lymphadenopathy + various mucocutaneous lesions condylomata lata - anogenital region, inner thighs, oral cavity

Syphilis 3. tertiary syphilis after long time (5 years) 1) cardiovascular - syphilitic aortitis (proximal a.) endarteritis of vasa vasorum  scaring of media  dilation  aneurysm (thoracic aorta) 2) neurosyphilis – tabes dorsalis + general paresis degeneration of posterior columns of spinal cord  sensory + gait abnormality cortical atrophy  psychic deterioration 3) gumma – ulcerative lesions of bone, skin, mucosa – oral cavity

Congenital syphilis 1) abortus 2) infantile syphilis hepatomegaly + pancreatitis + pneumonia alba 2) infantile syphilis chronic rhinitis (snuffles) + mucocutaneous lesions 3) late (tardive, congenital) syphilis > 2 years duration Hutchinson triad – notched central incisors + keratitis (blindness) + deafness (injury of n. VIII) mulberry molars + saddle nose