1. Acute and chronic inflammation. Repair: cell growth and regeneration
Acute and chronic inflammation. Repair: cell growth and regeneration. Wound healing.
2011

2. Acute inflammation
is early, immediate, response of vascularized living tissue to local injury, non-specific
its purpose is
1) to destroy injurious agent
2) to reconstitute a damaged tissue (healing)
repair already begins during early phases of inflammation
injured tissue is replaced by regeneration of parenchymal cells
by connective tissue formation - scarring

3. Causes of inflammation
microbial infections: bacteria, viruses, fungi, etc.
hypersensitivity reactions
physical agents: burns, UV light, radiation, trauma
chemical agents: acids, alkalis, oxidising agents, toxins, endotoxins, even toxic catabolites derived from endogenous processes, such as in uraemia, etc.
tissue necrosis: ischemia

4. Main clinical signs and symptoms of inflammation
Acute inflammation is characterised by five major signs described by Celsus and Virchow
rubor = redness from dilatation of blood vessels
calor = increased heat and fever- redness and heat -due to an increased rate and volume of blood flow because of vasodilatation, release of pyrogens
tumor = swelling from edema
dolor = pain form oedema and histamine release, pain is said to be due to an accumulation of acid metabolites that stimulate nerve endings
functio laesa = loss of function form pain and swelling

5. Morphologic and functional changes in acute inflammation
microcirculatory response
cellular response

6. CELLS OF THE INFLAMMATORY RESPONSE
Neutrophilic leukocytes
leukocytes are the first cells to appear at the site of acute inflammation
is to degrade cell debris and to ingest and kill microbes- phagocytosis
Eosinophilic leukocytes
associated with hypersensitivity responses
Basophils and mast cells
mast cells are usually seen in tissues in type I hypersensitivity reactions mediated by IgE
binding of IgE to the receptor on mast cells and basophils leads to degranulation of granules and release of the granule contents (heparin, histamine, and enzymes, such as acid hydrolase) into the tissues

7. Monocytes and macrophages
macrophages are major scavenger cells of the body
enzymes, such as lysozyme and hydrogen peroxide- degrade particulate material including micro-organisms
they control many of the cellular, vascular and reparative responses of inflammation by releasing chemotactic factors, cytokines (tumour necrosis factor) and growth factors (PDGF) and transforming growth factor beta (TGF-beta)
Lymphocytes and plasma cells
these are principal cells of specific immune responses- produce antibodies

8. The components of acute and chronic inflammatory responses and their principal functions. The roles of these cells and molecules in inflammation will be described in this chapter.

9. Microcirculatory response
increased blood flow and permeability of blood vessels
Vasodilatation leads to hyperaemia (= increased amount of blood in infl. area )- heat and redness
increased permeability of blood vessels- associated with slowing of the circulation- called stasis
increased passage of fluid out of microcirculation because of increased permeability in acute inflammation = exudation of fluid
vascular leakage- loss of protein-rich fluid from blood vessels
reduction of osmotic pressure within blood vessels
increase in interstitium- accumulation of fluid out of blood vessels
inflammatory oedema- major feature of acute inflammation

10. Formation of transudate and exudate
Formation of transudates and exudates. A, Normal hydrostatic pressure (blue arrows) is about 32 mm Hg at the arterial end of a capillary bed and 12 mm Hg at the venous end; the mean colloid osmotic pressure of tissues is approximately 25 mm Hg (green arrows), which is equal to the mean capillary pressure. Therefore, the net flow of fluid across the vascular bed is almost nil. B, A transudate is formed when fluid leaks out because of increased hydrostatic pressure or decreased osmotic pressure. C, An exudate is formed in inflammation because vascular permeability increases as a result of increased interendothelial spaces.
Formation of transudate and exudate

11. The major local manifestations of acute inflammation, compared
to normal.
Vascular dilation
extravasation of plasma fluid and proteins (edema)
leukocyte emigration
The major local manifestations of acute inflammation, compared to normal. (1) Vascular dilation and increased blood flow (causing erythema and warmth), (2) extravasation and deposition of plasma fluid and proteins (edema), and (3) leukocyte (mainly neutrophil) emigration and accumulation in the site of injury.

12. Composition of inflammatory exudate
exudate is fluid
rich in plasma proteins (albumins, immunoglobulins, fibrinogen)
converted into fibrin by tissue tromboplastin
Fibrin can be recognised microscopically-pink fibres or clumps, macroscopically- most easily seen on acute infl. of serosal surfaces-acute fibrinous pericarditis- „bread and butter„ appearance.
Transudation= increased passage of fluids (very low level of plasma proteins, and no cells) through blood vessels with normal permeability- increased hydrostatic pressure or decreased plasma osmotic pressure -composition similar to ultrafiltrate of plasma

13. Significance of the process of exudation
helps to destroy infectious agent by its diluting
by flooding the area with blood rich in immunoglobulins and other important defensive proteins
by increasing lymphatic flow -lymphatic drainage may to spread infectious agents
acute inflammation of lymphatics= lymphangitis
acute inflammation of lymph nodes= lymphadenitis

14. Cellular response NEUTROPHILIC LEUKOCYTES MACROPHAGES LYMPHOCYTES
remain predominant cell type for several days in acute inflammation.
emigration of neutrophils -leukocytes actively leave the blood vessel by moving through dilated intercellular junctions, pass through basement membrane and reach the extracellular space
MACROPHAGES
LYMPHOCYTES
movements of these cells are similar to that of neutrophils- chemotactic mediators for macrophages- complement factor C5 and lymphokines (secreted by lymphocytes)
ERYTHROCYTES enter extracellular space passively –
RBCs are pushed out from the blood vessel by hydrostatic pressure- the process is called erythrodiapedesis
when large numbers of erythrocytes enter the inflamed area = haemorrhagic inflammation

15. The complex process of leukocyte migration through blood vessels, shown here for neutrophils. The leukocytes first roll, then become activated and adhere to endothelium, then transmigrate across the endothelium, pierce the basement membrane, and migrate toward chemoattractants emanating from the source of injury. Different molecules play predominant roles in different steps of this process - selectins in rolling; chemokines (usually displayed bound to proteoglycans) in activating the neutrophils to increase avidity of integrins; integrins in firm adhesion; and CD31 (PECAM-1) in transmigration. ICAM-1, intercellular adhesion molecule 1; IL-1, interleukin 1; PECAM-1, platelet endothelial cell adhesion molecule 1; TNF, tumor necrosis factor.

16. Major events in phagocytosis
recognition and attachment of bacteria by the phagocytic cells - either directly (large inactive particles) or after opsonization (antigen is coated by opsonins)
engulfment - extensions of cytoplasm (pseudopods) flow around the particles - formation of phagocytic vacuole, this vacuole fuses with membrane of lysosomal vacuoles-degranulation of leukocytes
bacterial killing and degradation-killing of bacterial organisms is accomplished by activities of reactive oxygen species
Failure of oxidative metabolism during phagocytosis - leads to a severe disorder of immunity = in chronic granulomatous disease of childhood

17. Phagocytosis of a particle (e.g., a bacterium) involves:
Phagocytosis of a particle (e.g., a bacterium) involves (1) attachment and binding of the particle to receptors on the leukocyte surface, (2) engulfment and fusion of the phagocytic vacuole with granules (lysosomes), and (3) destruction of the ingested particle. iNOS, Inducible nitric oxide synthase; NO, nitric oxide; ROS, reactive oxygen species.
Phagocytosis of a particle (e.g., a bacterium) involves:

18. MORPHOLOGIC PATTERNS IN ACUTE INFLAMMATION
Serous inflammation
is characterised by abundant serous exudate
derived either from the blood stream or from the secretory activity of mesothelial cells
pleural or pericardial cavities, skin, mucosal surfaces
serous exudate is easily removed- complete regeneration

19. Acute inflammation
Serous

20. Serous inflammation

21. Fibrinous inflammation
Caused by more serious injuries
permeability of blood vessel is greater
and more proteins including large molecules of fibrinogen pass the vascular wall
Fibrinous exsudate can be removed-process called resolution
when fibrinous exsudate is not removed
fibrin may stimulate the ingrowth of fibroblasts into the blood vessel wall, thus leading to scarring- this process is called organization

22. Acute inflammation
Fibrinous

23. Fibrinous inflammation

24. Suppurative or purulent inflammation
is characterized by production of large amounts of purulent exsudate (pus)
Abscess localized collection of purulent exudate
Ulcer = is a local defect in the tissue, mainly in the mucosal or cutaneous surfaces

25. Acute inflammation
Purulent (suppurative)

26. Purulent-suppurative inflammation
Bronchopneumonia

27. Purulent inflammation

28. Acute inflammation
Purulent (suppurative) peritonitis

29. Ulcerative, pseudomembranous inflammation
acute ulcer- intense leukocyte infiltrate and vascular dilatation in the margins
chronic ulcer -more developed fibroblastic reaction, scarring and infiltration of lymphocytes, macrophages and plasma cells

32. Fibrinopurulent and pseudomebranous
Pseudomembranous colitis

33. SYSTEMIC CLINICAL SIGNS OF ACUTE INFLAMMATION
fever
results either of direct activity of cytokines or through local activity of prostaglandins
changes in the peripheral white blood cells
leucocytosis- the total number of neutrophils in the peripheral blood is increased
is common feature especially in bacterial infections
„ shift to the left“ means an increased number of immature neutrophils in peripheral blood
Leukocyte count-may reach levels of about 15 or 20 thousands cells per mm3- extreme levels (more than 40 thousand)- referred to as leukemoid reaction
viral infections tend to produce neutropenia (decreased number of leukocytes) with lymphocytosis (excess of lymphocytes in the blood)

34. CHRONIC INFLAMMATION
acute inflammation usually disappears after a few days and tissue returns to normal
Complete resolution -means total restoration and regeneration of injured area.
Healing by scarring -occurs after tissue destruction, in case of tissue defects, with abundant fibrin leakage, secondary infection,
Progression to chronic inflammation
chronic inflammatory response may follow acute inflammation that failed to destroy injurious agent or may be chronic from the onset (without a clinically apparent acute phase)

35. Outcomes of acute inflammation: resolution, healing by scarring, or chronic inflammation
Outcomes of acute inflammation: resolution, healing by scarring (fibrosis), or chronic inflammation (see text).

36. Causes of chronic inflammation
persistent infection - caused by distinctive infectious agents, such as mycobacterium, treponema pallidum, some fungi, by organisms of lower toxicity, by intracellular organisms
prolonged exposure to undegradable material, such as silica particles, carbon particles which, after being inhaled, set up a chronic inflammatory response in lungs
autoimmune diseases= immune reaction set up against own tissues or cells - reveal a chronic inflammatory pattern- for example rheumatoid arthritis

37. MORPHOLOGIC FEATURES AND CLINICAL SIGNS OF CHRONIC INFLAMMATION
chronic inflammation is an inflammatory response
characterized by the presence of lymphocytes, plasma cells and macrophages
it is distinguished from acute inflammation
by the absence of cardinal signs such as rubor, calor, dolor, tumor
active hyperemia, fluid exudation and neutrophilic emigration are absent
it is distinguished from acute inflammation by its long duration, which permits a manifestation of immune response
Often associated with scarring, fibroproliferation

38. chronic
acute
Chronic inflammation in the lung, showing the characteristic histologic features: collection of chronic inflammatory cells (asterisk), destruction of parenchyma (normal alveoli are replaced by spaces lined by cuboidal epithelium, arrowheads), and replacement by connective tissue (fibrosis, arrows). B, By contrast, in acute inflammation of the lung (acute bronchopneumonia), neutrophils fill the alveolar spaces and blood vessels are congested.

39. Histologic hallmarks of chronic inflammation
infiltration by macrophages, lymphocytes and plasma cells
proliferation of fibroblasts and myofibroblasts and proliferation of small blood vessels, together known as formation of granulation tissue
in most cases, the process of chronic inflammation is accompanied by a proliferation of connective tissue (deposition of collagen fibres), referred to as fibrosis
usually marked tissue destruction

40. Granulation tissue
Reparation component of inflammation is represented by granulation tissue composed of budding capillaries, fibroblasts and occasional inflammatory cells

41. CHRONIC INFLAMMATORY CELLS
MACROPHAGES
play central role in chronic inflammatory infiltrate-macrophages are the most effective phagocytic cells in acute and chronic inflammatory response
enzymatic degradation and phagocytic activity
following activation-macrophages produce biologically active products, such as:
enzymes - neutral and acid proteases
chemotactic factors for leukocytes
growth factors and promoting factors for fibroblasts and blood vessels- thus macrophages may modulate a formation of non-specific granulation tissue
cytokines, such as interleukin I , TNF,etc.

42. PLASMA CELLS
produce antibodies directed against persistent antigens or against altered tissue components
LYMPHOCYTES
when activated by the contact with antigen, lymphocytes release lymphokines- many of them stimulate macrophages
on the other hand, lymphocytes may be stimulated by cytokines released by activated macrophages
EOSINOPHILS
are characteristic of immunologic reaction mediated by IgE and of parasitic infections

43. NEUTROPHILIC LEUKOCYTES
in chronic inflammation of bone marrow (osteomyelitis)- large numbers of neutrophils may persists for months
also chronic inflammation of fallopian tube may have the pattern of chronic suppuration with large numbers of neutrophils
FIBROBLASTS
fibroproduction and accumulation of extracellular proteins- characteristic features of chronic inflammatory response

44. MORPHOLOGIC TYPES OF CHRONIC INFLAMMATORY RESPONSE
GRANULOMATOUS CHRONIC INFLAMMATION
is characterized by formation of epithelioid granulomas
granuloma- is defined as an aggregate of macrophages, two types of granulomas are recognised
epithelioid granuloma- represents immune response
macrophages are activated by T-lymphocytes
„ epithelioid cell“ are activated macrophages - large cells with abundant pale foamy cytoplasm - superficial resemblance to epithelial cells
typical feature of epithelioid granulomas is formation of Langhans-type giant cells- are derived from macrophages

45. Chronic granulomatous inflammation
Langhans cell
Epithelioid histiocytes
Granuloma (also called „specific granulation tissue“) is composed of modified macrophages)

46. tbc

47. Epithelioid granulomas occur in
infection due to intracellular organisms
Tuberculosis (Mycobacterium Tuberculosis)
Leprosy (Mycobacterium leprae)
Syphilis (Treponema pallidum)
Cat-scratch disease (Gram negative bacillus)-rounded or stellate granulomas usually within lymph nodes containing the central granular debris and leukocytes
Several parasitic and fungal infections (schistosomiasis, cryptococcus)
Sarcoidosis (Mycobacterium)
disorders due to chemical agents such as beryllium (berylliosis)
Crohn disease

48. Tuberculosis Tuberculosis
is characterized by specific granulomas, caseous necrosis and finding of Mycobacterium tuberculosis (Ziehl-Nielsen stain)

49. Chronic granulomatous inflammation
Sarcoidosis
?allergic reaction to the presence of non-virulent mycobacteria?

50. Chronic granulomatous inflammation
Sarcoidosis
Asteroid inclusions
Schaumann´s inclusions
Granuloma without caseous necrosis
Hamazaki – Wesenberg inclusions

51. NONGRANULOMATOUS CHRONIC INFLAMMATION
accumulation of sensitised lymphocytes, plasma cells and macrophages
chronic viral infections
persistent infection of parenchymal cells by viruses evokes an immune response- the affected tissue shows presence of lymphocytes and plasmacytes, cytotoxic effect is mediated either by killer- T-lymphocytes or by cytotoxic antibodies
in chronic autoimmune diseases
immune response is also mediated by killer- T-lymphocytes or by cytotoxic antibodies
the antigen is a host cell molecule which is recognised as foreign by immune system
pathologic result is cell necrosis, resulting in fibrosis and lymphocytic and plasmacytic infiltration
in chronic inflammation due to chemical toxic substances
alcohol produces chronic inflammation – liver, pancreas
cell necrosis - alteration in host molecule - becomes antigenic and evoke immune response

52. REPAIR. CELL GROWTH AND REGENERATION. WOUND HEALING
resolution -removal of debris associated with a complete restoration of the tissue to preinjury state
regeneration - complete replacement of necrotic parenchymal cells by new parenchymal cells of the same quality
resolution and regeneration- ideal outcome of healing- is possible only in the tissues with prevailing labile cells (cells capable of mitotic division- complete regeneration)
if complete resolution and regeneration is not possible, necrotic foci may be replaced by collagen
this process is termed organisation repair by scar formation

54. REGENERATION replacement of lost parenchymal cells is dependent on
regenerative capacity of the cells
number of surviving cells
maintenance of basement membranes or presence of stem cell layer
The cells of the body can be divided into 3 groups on the basis of their regenerative capacity and their relation to the cell cycle:
Labile cell (intermitotic)
Stable cell (reversible postmitotic )
Permanent cell (irreversible postmitotic)

55. Labile cells
continuously dividing cells- they continue to proliferate, remain all the time in cell cycle
Healing in tissues with many labile cells:
injury is followed by rapid and complete regeneration
surgical removal of endometrium by curettage is followed by complete regeneration from the basal germinative layer within short time
or destruction of erythrocytes stimulates rapid erythroid hyperplasia in bone marrow which results in complete regeneration of erythropoesis

56. Stable cells-quiescent
they are considered to be in G0 phase, may undergo rapid proliferation after appropriate stimuli, they may be recruited back to the cell cycle
Healing in tissues with prevailing stable cells:
regeneration in tissues with most stable cell is possible but the following conditions must be fulfilled:
sufficient amount of viable tissue must remain
intact fibrous interstitial network and original basement membranes preserved
if complete necrosis involves both parenchyma and interstitium- no regeneration is possible and necrosis heals by scar formation

57. Permanent cells- non-dividing
cells have no regenerative capacity
Healing in tissues with permanent cells:
injury to tissue with permanent cells is always followed by scar formation, no regeneration is possible

58. REPAIR BY SCAR FORMATION
scar=mass of collagen that is the final result of the process of organization
repair by scar occurs:
if resolution fails
if the injurious agent continuously causes injury in chronic inflammation
if parenchymal necrosis cannot be repaired by regeneration because of prevalence of permanent cells

59. Process of repair by scar formation
Preparation
removal of the inflammatory exudate
Debris is liquefied by lysosomal enzymes derived of neutrophil leukocytes
is removed by lymphatics, residual particle are phagocytosed by macrophages
Ingrowth of granulation tissue
granulation tissue is highly vascularized connective tissue composed of newly formed capillaries, proliferating fibroblasts and myofibroblasts, cell debris and residual inflammatory cells
major role of the granulation tissue is to occupy the tissue defects lost by injury
Grossly granulation tissue is deeply red (because of numerous capillaries) and soft, with granularity of the surface
Collagenization
collagens are the major fibrillary extracellular proteins

60. Contraction and strengthening
Maturation of the scar
collagen content of granulation tissue progressively increases with the time, particularly the amount of type I collagen increases
the scar becomes less cellular and less vascular
the mature scar is composed of hypovascular poorly cellular collagenous mass- composed mostly of collagen type I
Contraction and strengthening
contraction decreases the size of scar- allows optimal function of the remaining tissue

62. HEALING OF SKIN WOUNDS Healing by first intention (primary union)
healing of clean uninfected surgical incision joined by surgical sutures
limited number of dead cells, minor discontinuity of basement membrane
the incisional space immediately fills with clotted blood containing fibrin

64. Healing by second intention (secondary union)
differs from primary healing in several aspects:
large tissue defects, such as large infarctions, ulcerations, abscesses
large wounds- have always more fibrin in exudate, thus more intense inflammatory reaction
much greater amount of granulation tissue is formed
final scar is much smaller than original wound due to wound contraction (mostly results of activities of myofibroblasts) - tissue retraction

65. PATHOLOGIC ASPECTS OF REPAIR
The factors that modify the quality of tissue repair include:
nutrition deficiency, particularly vitamin C deficiency decreases the ability to heal wounds
glucocorticoids have anti-inflammatory effect
persistent infection is the most important cause of delayed healing
mechanical factors, as wound dehiscence
low blood supply, presence of foreign bodies
disorders of lymphatic flow may slow down the removal of necrotic cells and cause delayed healing

66. adequate levels of circulating white blood cells
the presence or absence of diabetes mellitus and other underlying diseases
adequate levels of circulating white blood cells
type of injured tissue
perfect repair may occur only in tissues built up of labile and stable cells,
while injuries to permanent cells results in scarring, such case is myocardial infarction (no regeneration of specialised heart muscle elements)

67. large amounts of exudate slows down a healing -
healing of exudate include:
digestion of the exudate initiated by proteolytic enzymes of leukocytes-resorption of dissolved exudate= process called „ resolution“
the presence of extensive necrosis or large amounts of fibrin in the exudate or low blood and lymphatic rate
the process of resolution cannot occur and the exudate is replaced by granulation tissue and transformed into fibrous tissue -organization of exudate
for example lung carnification in pathologic healing of pneumonia

68. aberration of growth -hyperplastic scarring- if excessive amounts of collagen accumulate within the scar= keloid
-keloid formation appears to an individual predisposition of unknown reasons or excessive formation of granulation tissue= exuberant granulation - granulation tissue protrudes over the surface of the wound and in fact blocks the reepithelization- granulation tissue must be removed surgically