Inflammation Jan Laco MD Ph D Inflammation l

Inflammation Jan Laco, MD, Ph. D

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

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

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

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

Classification l according to histological features – non-specific (not possible to trace etiology) - vast majority – specific / granulomatous (e. g. TBC) l 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 l early response l important role in inflammation has microcirculation! l supply of white blood cells, interleukins, fibrin, etc.

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

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

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

Cellular events leukocytes margination rolling adhesion transmigration by diapedesis (in venules) l transmigration l – neutrophils (1 -2 days) – monocytes (2 -3 days) l chemotaxis (along chemical gradient) – endogenous signaling molecules – ILs, LTs, C 5 a – exogenous – toxins, bacterial proteins, . . . phagocytosis (see below) l passive migration of RBCs l – no active role in inflammation - hemorrhagic inflammation

Phagocytosis l 1. recognition and attachment – facilitated by opsonins (Ig. G, C 3 b) l 2. engulfment – pseudopods formation phagocytic vacuole + lysosome phagolysosome l 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 l in highly resistant microorganisms - persistence within macrophage - activation after many years (TBC) l

Outcomes of acute inflammation l 1. resolution - restoration to normal, in limited injury – – l 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) l 3. progression into chronic inflammation

Chronic inflammation l 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 l 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 l NK cells l monocytes-macrophages specialized cells (siderophages, gitter cells, mucophages) l

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

Morphologic patterns of inflammation l 2 a. 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 l 2 b. 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

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

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

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

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

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

Leprosy l l l 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 l 2. tuberculoid – sterile – in peripheral nerves – tuberculoid granulomas - anesthesia l death – secondary infections + amyloidosis

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

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

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

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

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