1. Inflammation Jan Laco, M.D., Ph.D.

2. 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

3. Terminology Greek root + -itis metritis, not uteritis kolpitis, not vaginitis nephritis, not renitis

4. Mechanisms local - in cases of mild injury systemic 3 major: 1. alteration 2. exsudation - inflammatory exsudate – liquid (exsudate) – cellular (infiltrate) 3. proliferation (formation of granulation and fibrous tissue) usualy - all 3 components - not the same intensity

5. Classification several points of view length: – acute × chronic (+ subacute, hyperacute) according to predominant component – 1. alterative (predominance of necrosis - diphtheria) – 2. exsudative (pleuritis) – 3. proliferative (cholecystitis - thickening of the wall by fibrous tissue)

6. Classification according to histological features – nonspecific (not possible to trace the etiology) - vast majority – specific (e.g. TB) 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

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

8. Local symptomatology classical 5 symptoms (Celsus 1st c. B.C., Virchow 19th c. A.D.) 1. calor - heat 2. rubor - redness 3. tumor - swelling 4. dolor - pain 5. functio laesa - loss (or impairment) of function

9. Systemic symptomatology fever (irritation of centre of thermoregulation) – TNF, IL-1 – IL-6 – high erythrocyte sedimentation rate leucocytosis - increased number of WBC – bacteria – neutrophils – parasites – eosinophils – viruses - lymphocytosis leucopenia - decreased " " – viral infections, salmonella infections, rickettsiosis immunologic reactions - increased level of some substances (C-reactive protein)

10. Vascular changes vasodilation – increased permeability of vessels due to widened intercell. junctions and contraction of endothelial cells (histamin, VEGF, bradykinin) protein poor transudate (edema) protein rich exsudate leukocyte-dependent endothelial injury – proteolysis – protein leakage  platelet adhesion  thrombosis

11. Cellular events leukocytes margination  rolling  adhesion  transmigration emigration of: – neutrophils (1-2 days) – monocytes (2-3 days) chemotaxis – endogenous signaling molecules - lymphokines – exogenous - toxins phagocytosis - lysosomal enzymes, free radicals, oxidative burst passive emigration of RBC - no active role in inflamm. - hemorrhagic inflammation

12. Phagocytosis adhesion and invagination into cytoplasm engulfment lysosomes - destruction in highly virulent microorganisms can die leucocyte and not the microbe in highly resistant microorganisms - persistence within macrophage - activation after many years

13. Outcomes of acute inflammation 1. resolution - restoration to normal, limited injury – chemical substances neutralization – normalization of vasc. permeability – apoptosis of inflammatory cells – lymphatic drainage 2. healing by scar – tissue destruction – fibrinous inflammtion – purulent infl.  abscess formation (pus, pyogenic membrane, resorption - pseudoxanthoma cells - weeks to months) 3. progression into chronic inflammation

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

15. Chronic inflammation chronic inflammatory cells ("round cell" infiltrate) – lymphocytes – plasma cells – monocytes/macrophages activation of macrophages by various mediators - fight against invaders lymphocytes  plasma cells, cytotoxic (NK) cells, coordination with other parts of immune system plasma cells - production of Ig monocytes-macrophages-specialized cells (siderophages, gitter cells, mucophages)

16. Morphologic patterns of inflammation 1. alterative 2. exsudative – 2a. serous – 2b. fibrinous – 2c. suppurative – 2d. pseudomembranous – 2e. necrotizing, gangrenous 3. proliferative – primary (rare) x secondary (cholecystitis)

17. Morphologic patterns of inflammation 2a. serous - excessive accumulation of fluid, few proteins - skin blister, serous membranes - initial phases of inflamm. modification - catarrhal - accumulation of mucus 2b. fibrinous - higher vascular permeability - exsudation of fibrinogen -> fibrin - e.g. pericarditis (cor villosum, cor hirsutum - "hairy" heart fibrinolysis  resolution; organization  fibrosis  scar

18. 2c. suppurative (purulent) - accumulation of neutrophillic leucocytes - formation of pus (pyogenic bacteria) interstitial – phlegmone – diffuse soft tissue – abscess - localized collection acute – border – surrounding tissue chronic – border - pyogenic membrane Pseudoabscess – pus in lumen of hollow organ formation of suppurative fistule accumulation of pus in preformed cavities - empyema (gallbladder, thoracic)

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

20. 2d. pseudomembranous - fibrinous pseudomembrane (diphtheria - Corynebacterium, dysentery - Shigella) - fibrin, necrotic mucosa, etiologic agens, leucocytes 2e. necrotizing - inflammatory necrosis of the surface - ulcer (skin, gastric) – gangrenous - secondary modification by bacteria - wet gangrene - apendicitis, cholecystitis - risk of perforation - peritonitis

21. 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) NO agent elimination but walling off intracellulary agents (TBC)

22. Granulomatous inflammation 1. Bacteria – TBC – leprosy – syphilis (3rd stage) 2. Parasites + Fungi 3. Inorganic metals or dust – silicosis – berylliosis 4. Foreign body – suture (Schloffer „tumor“), breast prosthesis 5. Unknown - sarcoidosis

23. 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 exsudate – sero-fibrinous exsudate (macrophages)

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

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

26. 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

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

28. Syphilis 3. tertiary syphilis after long time (5 years) 1) cardiovascular - syphilitic aortitis (proximal a.) – endarteritis of vasa vasorum  scaring of media  dilation  aneurysm 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

29. Congenital syphilis 1) abortus – 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