Inflammation. Part 1. Dr François Leclair Pr Christian Laboisse Pathology Department Nantes University Hospital JPEMS 2014

Transcription

1 Inflammation Part 1 Dr François Leclair Pr Christian Laboisse Pathology Department Nantes University Hospital JPEMS 2014

2 Introduction

3 Two important points :

4 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult.

5 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal.

6 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm.

7 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm. Because it s capable of also injuring normal tissues especially when inflammation is :

8 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm. Because it is capable of also injuring normal tissues especially when inflammation is : - very strong (e.g., when the infection is severe),

9 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm. Because it is capable of also injuring normal tissues especially when inflammation is : - very strong (e.g., when the infection is severe), - prolonged (e.g., when the aggressor resists eradication)

10 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm. Because it is capable of also injuring normal tissues especially when inflammation is : - very strong (e.g., when the infection is severe), - prolonged (e.g., when the aggressor resists eradication) - inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases.)

11

12 Two important points : 1 - Inflammation is a protective response intended to eliminate the initial cause of cell injury, necrotic cells and tissues resulting from the original insult. Without inflammation, infections would go unchecked and wounds would never heal. 2 - But the inflammatory reaction and the subsequent repair process can cause considerable harm. Because it s capable of also injuring normal tissues especially when inflammation is : - very strong (e.g., when the infection is severe), - prolonged (e.g., when the aggressor resists eradication) - inappropriate (e.g., when it is directed against self-antigens in autoimmune diseases.)

13 What original insult?

14 What original insult? -Infections (virus, bacterium, fungus)

15 What original insult? -Infections (virus, bacterium, fungus) -Mechanical trauma

16 What original insult? -Infections (virus, bacterium, fungus) -Mechanical trauma -Chemical trauma

17 What original insult? -Infections (virus, bacterium, fungus) -Mechanical trauma -Chemical trauma -Thermal, electrical injury

18 What original insult? -Infections (virus, bacterium, fungus) -Mechanical trauma -Chemical trauma -Thermal, electrical injury -Irradiation

19 What original insult? -Infections (virus, bacterium, fungus) -Mechanical trauma -Chemical trauma -Thermal, electrical injury -Irradiation - ( )

20 In medical terminology, the suffix «itis» refers to inflammation (e.g., appendicitis, peritonitis, ) Inflammation is the main phenomenon in a lot of diseases (infections, autoimmune diseases, allergic diseases ) important to know few stuff about inflammation!

21 Inflammation only occurs in vascularised tissues. No vessels no inflammation (cornea, cartilage).

22 1 Acute inflammation 2 Chronic inflammation 3 Tissue repairing (scar)

23 I Acute inflammation Acute inflammation is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation.

24 Normal

25 Physiology of tissue perfusion - microcirculation La capillary wall is a semi-permeable membrane: allows a flux of water and electrolytes and does not allow HMW protein flux. The net flux is determined by two forces acting in opposite directions Hydrostatic pressure Protein oncotic pressure

26 Inflamed

27 Inflamed 1- First step: vascular response. increased blood flow: redness and warmth

28 Small blood vessels adjacent to area of injury get dilated with increased blood flow. The tissue is congestive.

29 Explains redness (erythema) and warmth.

30 Inflamed 1- First step: vascular response. Exudation = Leakage of plasma with proteins oedema. Two components: -increased hydrostatic pressure -Increased vascular permeability

31 oedema - role of endothelial cell activation «the endothelial inflammatory phenotype» Endothelial remodeling (flat -> tall) Increased junctional permeability: opening of gaps Expression of adhesion proteins: P- selectin

32 Oedema Exudation : passage of water with a lot of proteins through blood vessels. This liquid = «exudate = inflammatory oedema». Which proteins in that liquid? A lot, such as immunoglobulins, complement, fibrinogen and fibrin (forming scab).

33 Explains swelling

34 Inflamed 2- Second step: cellular response. Cells (neutrophils +++) emigration

35 Cell emigration : 1- Margination : leukocytes accumulate along the vascular endothelial surface. 2- Leukocytes extravasation («diapedesis») out of the circulatory system (migration through inter-endothelial spaces). 3- Migration to the site of tissue damage, following a chemokines gradient. On the site of damage activated to perform their functions. Chemokines = proteins coming from the aggressor (e.g., bacterial product such as LPS) or from cells already on the site (macrophages+++).

36

37 Cell emigration : 1- Margination : leukocytes accumulate along the vascular endothelial surface. 2- Leukocytes extravasation («diapedesis») out of the circulatory system (migration through inter-endothelial spaces). 3- Migration to the site of tissue damage, following a chemokines gradient. On the site of damage activated to perform their functions. Chemokines = proteins coming from the aggressor (e.g., bacterial product such as LPS) or from cells already on the site (macrophages+++).

38 Cell emigration : 1- Margination : leukocytes accumulate along the vascular endothelial surface. 2- Leukocytes extravasation («diapedesis») out of the circulatory system (migration through inter-endothelial spaces). 3- Migration to the site of tissue damage, following a chemokines gradient. On the site of damage activated to perform their functions. Chemokines = proteins coming from the aggressor (e.g., bacterial product such as LPS) or from cells already on the site (macrophages+++).

39

40

41 Woman, 47 year old, abdominal pain. Fallopian tube resection :

42 Woman, 47 year old, abdominal pain. Fallopian tube resection : Vascular dilatation congestive tissue Oedema A fold filled with numerous neutrophils.

43 Woman, 47 year old, abdominal pain. Fallopian tube resection : Vascular dilation congestive tissue Oedema Acute salpingitis A fold filled with numerous neutrophils.

44 Few words about Neutrophils («PMN = PolyMorphoNuclear Neutrophils») Three-lobulated nucleus

45 Few words about Neutrophils («PMN = PolyMorphoNuclear Neutrophils») First cells to arrive on the site the cells of acute inflammation Role : bacterial killing by phagocytosis and by releasing enzymes. But : sligthly «stupid» cells that intervene even for a non-bacterial inflammation. e.g. : Chondrocalcinosis calcium pyrophosphate deposition disease.

46 PMN calcium pyrophosphate deposition

47 Let s sum up: Acute inflammation = 1 - Vascular step. Increased blood flow congestion. Exudation oedema Cellular step (neutrophils +++)

48 Variations of acute inflammation : -Vasculo-exudative - Hemorrhagic - Suppurative - Necrotising inflammation

49 Variations of acute inflammation : -Vasculo-exudative - Hemorrhagic - Suppurative - Necrotising inflammation

50 -sunburn -hives

51 -Quincke oedema

52 -pleural effusion

53 Variations of acute inflammation : -Vasculo-exudative - Hemorrhagic - Suppurative - Necrotising inflammation

54 -fulminans purpura

55 Variations of acute inflammation : -Vasculo-exudative - Hemorrhagic - Suppurative - Necrotising inflammation

56 Suppurative inflammation = numerous and quite exclusively neutrophils.

57 Suppurative inflammation = numerous and quite exclusively neutrophils. - clinically / gross examination : pus

58 Suppurative inflammation = numerous and quite exclusively neutrophils. - clinically / gross examination : pus - bacterial infection

59 Suppurative inflammation = numerous and quite exclusively neutrophils. - clinically / gross examination : pus - bacterial infection - 3 forms :

60 Suppurative inflammation = numerous and quite exclusively neutrophils. - clinically / gross examination : pus - bacterial infection - 3 forms :. Abscess (localised collection of pus)

61 Man, 54 year old, headache. Brain MRI :

62 Brain surgery : Normal brain Collection of neutrophils.

63

64 Liver abscess

65 Suppurative inflammation = numerous and quite exclusively neutrophils (dead or alive). - clinically / gross examination : pus - bacterial infection - 3 forms :. Abscess (localised collection of pus). Phlegmon (not collected amount of PMN) e.g. : complication of pharyngitis.

66

67 Suppurative inflammation = numerous and quite exclusively neutrophils. - clinically / gross examination : pus - bacterial infection - 3 forms :. Abscess (localised collection of pus). Phlegmon (not collected amount of PMN) e.g. : complication of pharyngitis.. Empyema (pus fills a hollow cavity) e.g. : subdural empyema.

68 Variations of acute inflammation : -Vasculo-exudative - Hemorrhagic - Suppurative - Necrotising inflammation

69 Outcomes of acute inflammation :

70 amage

71 amage Acute inflammation

72 Rapid destruction of the aggressor amage Acute inflammation

73 Rapid destruction of the aggressor Resorption of exudate and PMN amage Acute inflammation

74 Rapid destruction of the aggressor Resorption of exudate and PMN Resolution and return to initial aspect (e.g : minor burn) amage Acute inflammation

75 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn)

76 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn)

77 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis)

78 Fibrin (from exudate) Pleura Scar Lung parenchyma Organized pleuritis

79 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis)

80 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Incomplete destruction of the aggressor

81 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Incomplete destruction of the aggressor Ongoing injury

82 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Incomplete destruction of the aggressor Ongoing injury Chronic inflammation

83 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

84 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Suppuration (e.g: abcsess) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

85 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Suppuration (e.g: abcsess) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

86 Chemical mediators of inflammation. Mediators are proteins produced locally by inflammatory cells at the site of inflammation, or they are synthesized by the liver and circulate in the plasma. They have a responsibility in all the events of inflammation. They allow inflammatory cells to get activated or they may have opposing effects, thus serving to control the response. There are dozens of mediators

87 Few mediators to know : Histamine, bradykinin : involved in allergic phenomenons. Prostaglandins and Leukotrienes targets of anti-inflammatory drugs. Complement Coagulation factors

88 Inflammation Part 2 Dr François Leclair Pr Christian Laboisse Pathology Department Nantes University Hospital JPEMS 2014

89 II - Chronic inflammation Chronic inflammation may be more insidious, is of longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring). Histologically, it starts when mononucleated cells (with a non-lobulated nucleus) arrive on the site.

90 Chronic inflammation : only a cellular response.

91 Chronic inflammation : only a cellular response. Wich cells?

92 Chronic inflammation : only a cellular response. Wich cells? - Macrophages

93 Chronic inflammation : only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells

94 Chronic inflammation : only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils

95 Chronic inflammation : only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils - Mast cells

96 Chronic inflammation : only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils - Mast cells

97 Macrophages Large nucleus Cytoplasm : numerous vacuoles of phagocytosis.

98 Macrophages Macrophages are normally diffusely scattered in most connective tissues, and are also found in organs (= specialized macrophages) :

99 - Kupffer cells in the liver -

100 - Kupffer cells in the liver -

101 - Osteoclasts in the bones -

102 - Osteoclasts in the bones -

103 - Alveolar macrophages in the lungs -

104 Macrophages Macrophages are normally diffusely scattered in most connective tissues, and are also found in organs (= specialized macrophages). Inflammation influx of macrophages coming from blood (margination, leukocytes extravasation, migration).

105 Macrophages Macrophages are normally diffusely scattered in most connective tissues, and are also found in organs (= specialized macrophages). Inflammation influx of macrophages coming from blood (margination, leukocytes extravasation, migration). When in the blood = «monocytes» when in tissues = «macrophages»

106 Macrophages Macrophages are normally diffusely scattered in most connective tissues, and are also found in organs (= specialized macrophages). Inflammation influx of macrophages coming from blood (margination, leukocytes extravasation, migration). When in the blood = «monocytes» when in tissues = «macrophages» Role : phagocytosis (pathogens or killed cells from the host) and releasing enzymes.

107 Enzymes Macrophages: secretory functions Protease Elastase Collagenase Plasminogen activator Acid hydrolases Phosphatases Lipase ROS Complement fractions Cytokines chemokines: Il-1, TNF inos Growth factors: PDGF TGFbeta

108 Activated macrophages: additional functions: link between innate and adaptive immunity (T cells) and repair

109 Morphological plasticity of macrophages Epithelioid cells Multinucleated giant cells

110 Chronic inflammation : a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils - Mast cells

111 Lymphocytes Round nucleus. Cytoplasm hardly seen. When B lymphocytes differenciated = plasma cells

112 Lymphocytes B and T cells.

113 Lymphocytes B and T cells. intervene when it s an adaptative response (immune response, cellular or with antibodies) but also, for unknown reason, in a non-immune response. In any chronic inflammation!

114 Lymphocytes B and T cells. intervene when it s an adaptative response (immune response, cellular or with antibodies) but also, for unknown reason, in a non-immune response. In any chronic inflammation! Coming from blood flow like the other leukocytes (margination, leukocytes extravasation, migration).

115 Lymphocytes B and T cells. intervene when it s an adaptative response (immune response, cellular or with antibodies) but also, for unknown reason, in a non-immune response. In any chronic inflammation! Coming from blood flow like the other leukocytes (margination, leukocytes extravasation, migration). B cells become plasma cells when totally differenciated.

116 To fight against pathogen organisms, our body has 3 lines of defense : 1. First Line of Defense: Non-specific epithelial barriers which restrict entry of pathogen. Skin and mucosal surfaces (respiratory, gastrointestinal, urinary and reproductive tract) = physical, chemical and biological barriers 2. Second Line of Defense: Innate non-specific local immune response against pathogens that cross the epithelial barrier. PMN, macrophages, lymphocytes, they defend the host from infection by other organisms in a non-specific manner and does not confer long-lasting or protective immunity to the host. 3. Third line of defense: Antigen-specific immune responses, specifically target and attack invaders that get pass first two lines of defense = adaptive immune response (antibodies, lymphocytes) that recognize and remember specific pathogens.

117 To fight against pathogen organisms, our body has 3 lines of defense : 1. First Line of Defense: Non-specific epithelial barriers which restrict entry of pathogen. Skin and mucosal surfaces (respiratory, gastrointestinal, urinary and reproductive tract) = physical, chemical and biological barriers 2. Second Line of Defense: Innate non-specific local immune response against pathogens that cross the epithelial barrier. PMN, macrophages, lymphocytes, they defend the host from infection by other organisms in a non-specific manner and does not confer long-lasting or protective immunity to the host. 3. Third line of defense: Antigen-specific immune responses, specifically target and attack invaders that get pass first two lines of defense = adaptive immune response (antibodies, lymphocytes) that recognize and remember specific pathogens.

118 Woman, 32 year old, abdominal pain.

119 Woman, 32 year old, abdominal pain. Fallopian tube :

120

121

122 lymphocytes plasma cells macrophages

123 lymphocytes plasma cells Chronic salpingitis. macrophages

124 Chronic inflammation : no vascular step, only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils - Mast cells

125 Eosinophils (PolyMorphoNuclear Eosinophils) important role in parasitic response.

126 Chronic inflammation : no vascular step, only a cellular response. Wich cells? - Macrophages - Lymphocytes / Plasma cells - Eosinophils - Mast cells

127 Mast cells important role in allergic response, by releasing histamine (among other molecules)

128 All these inflammatory cells come from bone marrow.

129 So far, we are able to say : «inflammation («itis») or not and acute and/or chronic».

130 So far, we are able to say : «inflammation («itis») or not and acute and/or chronic». But we can t determine the origin of this inflammation.

131 So far, we are able to say : «inflammation («itis») or not and acute and/or chronic». But we can t determine the origin of this inflammation. = «Non-specific inflammation».

132 lymphocytes plasma cells Non-specific chronic salpingitis. macrophages

133 So far, we are able to say : «inflammation («itis») or not and acute and/or chronic». But we can t determine the origin of this inflammation. = «Non-specific inflammation». On the contrary, when we observe inflammatory cells but also some characteristics that can allow us to come close the cause or even to make a precise diagnosis.

134 So far, we are able to say : «inflammation («itis») or not and acute and/or chronic». But we can t determine the origin of this inflammation. = «Non-specific inflammation». On the contrary, when we observe inflammatory cells but also some characteristics that can allow us to come close the cause or even to make a precise diagnosis. = «Specific inflammation».

135 The cause can be determined : either because the inflammation is «particular». or because we can see the pathogen. or both

136 the inflammation is particular

137 the inflammation is particular Most typical example : granulomatous inflammation.

138 the inflammation is particular Most typical example : granulomatous inflammation. Woman, 41 year old, coughing. Bronchus biopsy :

139 the inflammation is particular Most typical example : granulomatous inflammation. Woman, 41 year old, coughing. Bronchus biopsy :

140

141 Lymphocytes lymphocytes Epithelioid macrophages macrophages Multinucleate giant cell GRANULOMATOUS INFLAMMATION

142 Interesting because finite quantity of etiologies!

143 Interesting because finite quantity of etiologies! - Certain bacterium : Typical Mycobacteria (tuberculosis), atypical mycobacteria, cat scratch disease, donovanosis, leprosy, importance of microbiology analysis

144 Interesting because finite quantity of etiologies! - Certain bacterium : Typical Mycobacteria (tuberculosis), atypical mycobacteria, cat scratch disease, donovanosis, leprosy, importance of microbiology analysis - Foreign body (suture, metal particule, )

145 Interesting because finite quantity of etiologies! - Certain bacterium : Typical Mycobacteria (tuberculosis), atypical mycobacteria, cat scratch disease, donovanosis, leprosy, importance of microbiology analysis - Foreign body (suture, metal particule, ) - Diseases of unknown origin : crohn disease, sarcoidosis, some autoimmune diseases (Wegener, Churg and Strauss, )

146 we can see the pathogen.

147 we can see the pathogen. Examples

148 Man, 79 year old, diarrhea. Large bowel biopsy :

149 lymphocytes plasmocytes viral nuclear inclusion Specific inflammation caused by Cytomegalovirus (CMV) infection

150 Young boy, 6 year old, abdominal pain. Appendicectomy :

151 lymphocytes, macrophages, PMN pinworm Specific inflammation caused by pinworm

152 Women, 41 year old, from Martinique. Abdominal pain. Gastric biopsy :

153 Few lymphocytes strongyloïdosis Specific inflammation caused by strongyloïdosis

154 Man, 50 year old. Abdominal pain. Gastric biopsy :

155 Normal gastric antrum

156

157

158 May-Grunwald-Giemsa stain. (Magnification x 400).

159 Helicobacter pylori May-Grunwald-Giemsa stain. (Magnification x 400).

160 Helicobacter pylori Chronic gastritis due to Helicobacter pylori May-Grunwald-Giemsa stain. (Magnification x 400).

161 Helicobacter pylori Gram negative bacterium. Adapted to live in association with surface epithelium beneath mucus barrier. Causes cell damage and inflammatory cell infiltration. In most countries the majority of adults are infected.

162 Inflammation Part 3 Dr François Leclair Pr Christian Laboisse Pathology Department Nantes University Hospital JPEMS 2014

163 III - Tissue repairing - Fibrosis - Scaring

164 III - Tissue repairing - Fibrosis - Scaring Follows a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction.

165 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Suppuration (e.g: abcsess) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

166 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Suppuration (e.g: abcsess) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

167 III - Tissue repairing - Fibrosis - Scaring Follow a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction. Repairing cannot be made only with the original cells.

168 III - Tissue repairing - Fibrosis - Scaring Follow a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction. Repairing cannot be made only with the original cells. 2 phenomenons involved :

169 III - Tissue repairing - Fibrosis - Scaring Follow a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction. Repairing cannot be made only with the original cells. 2 phenomenons involved : cells. 1- Regeneration = replacement of damaged cells by same

170 III - Tissue repairing - Fibrosis - Scaring Follow a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction. Repairing cannot be made only with the original cells. 2 phenomenons involved : cells. 1- Regeneration = replacement of damaged cells by same 2- Fibrogenesis = replacement of loss of substance by fibrosis

171 III - Tissue repairing - Fibrosis - Scaring Follow a chronic inflammation (sometimes acute inflammation!) that has caused tissue destruction. Repairing cannot be made only with the original cells. 2 phenomenons involved : cells. 1- Regeneration = replacement of damaged cells by same 2- Fibrogenesis = replacement of loss of substance by fibrosis leaves an indelible scar with a possibly loss of function.

172 Repair starts with vascular proliferation and fibroblasts proliferation (they synthesize collagen) = granulation tissue that fill the loss of tissue.

173 Repairement starts with vascular proliferation and fibroblasts proliferation (they synthesize collagen) = granulation tissue that fill the loss of tissue. # granulomatous inflammation

174 Surface : covered by debris and exudate (remains of an ulceration) Granulation tissue : very cellular and highly vascular area containing fibroblasts and inflammatory cells. Granulation tissue

175 Numerous capillaries Fibroblasts, PMN, lymphocytes, macrophages Granulation tissue (high power view)

176 Then, this granulation tissue endergoes reshaping to become a scar.

177 Epidermis Dermis Sebaceous and pilar appendages - Normal skin -

178 Scar in the dermis

179 -Normal heart -

180

181 Scar Loss of function

182 Pathology :

183 Pathology : Delay in / absence of scarring. Cause: persistence of pathogen, bad vasculature, persistence of foreign body, mechanical factor (mobilisation of the wound),

184 Pathology : Delay in / absence of scarring. Cause: persistence of pathogen, bad vasculature, persistence of foreign body, mechanical factor (mobilisation of the wound), Excessive scar formation :

185 Pathology : Delay in / absence of scarring. Cause: persistence of pathogen, bad vasculature, persistence of foreign body, mechanical factor (mobilisation of the wound), Excessive scar formation : - hypertrophic scar (does not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution).

186 Pathology : Delay in / absence of scarring. Cause: persistence of pathogen, bad vasculature, persistence of foreign body, mechanical factor (mobilisation of the wound), Excessive scar formation : - hypertrophic scar (does not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution). -keloid(overgrowth of dense fibrous tissue extends beyond the borders of the original wound, does not usually regress spontaneously and tends to recur after excision).

187

188 Keloid formation is a result of excessive collagen deposition during wound healing. Epidermis and underlying dermis are displaced upward by a fibrous nodule.

189 Epidermis Interlacing broad bands of collagen

190 Pathology : Delay in / absence of scarring. Cause: persistence of pathogen, bad vasculature, persistence of foreign body, mechanical factor (mobilisation of the wound), Excessive scar formation : - hypertrophic scar (does not expand beyond the boundaries of the initial injury and may undergo partial spontaneous resolution). -keloid(overgrowth of dense fibrous tissue extends beyond the borders of the original wound, does not usually regress spontaneously and tends to recur after excision). Excessive retraction (after burn +++).

191 amage Rapid destruction of the aggressor Acute inflammation Resorption of exudate and PMN Organisation of exudate to fill loss of tissue Resolution and return to initial aspect (e.g : minor burn) Scar (e.g : organised pleuritis) Suppuration (e.g: abcsess) Incomplete destruction of the aggressor? Ongoing injury Chronic inflammation

192 Chronic inflammation

193 mild Chronic inflammation

194 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation

195 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Severe with tissue destruction

196 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Severe with tissue destruction Granulation tissue

197 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction)

198 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction) Pathologic scar (delay, absence, hypertrophy, keloid, retraction)

199 So chronic inflammation can follow acute inflammation

200 So chronic inflammation can follow acute inflammation But can these 2 types of inflammation occur at the same time?

201 But how?

202 1- Because of an overlap : Vasculo-exsudative step Cellular step Neutrophils Mononucleate cells Acute inflammation Chronic inflammation

203 1- Because of an overlap : Vasculo-exsudative step Cellular step Neutrophils Mononucleate cells Acute inflammation Chronic inflammation

204 1- Because acute inflammation can aggravate a chronic inflammation :

205 1- Because acute inflammation can aggravate a chronic inflammation : Macrophages infiltrate Congestion Oedema

206 1- Because acute inflammation can aggravate a chronic inflammation : Macrophages infiltrate Congestion Oedema Multiple acute inflammation episodes have led to chronic cholecystitis. Here it s a new acute inflammation episode.

207 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction) Pathologic scar (delay, absence, hypertrophy, keloid, retraction)

208 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Cancer (e.g : gastric cancer after long history of chronic gastritis) Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction) Pathologic scar (delay, absence, hypertrophy, keloid, retraction)

209 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Metaplasia Cancer (e.g : gastric cancer after long history of chronic gastritis) Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction) Pathologic scar (delay, absence, hypertrophy, keloid, retraction)

210 mild Resolution and return to initial aspect (e.g : cut) Chronic inflammation Metaplasia Dysplasia Cancer (e.g : gastric cancer after long history of chronic gastritis) Severe with tissue destruction Granulation tissue Scar (loss of function) (e.g : myocardial infarction) Pathologic scar (delay, absence, hypertrophy, keloid, retraction)

211 Consequence of chronic inflammation on epithelia : Metaplasia

212 Definition Metaplasia: replacement of a differentiated cell type by another mature normal differentiated cell type. Usually of the same class : - epithelial cell to epithelial cell, - connective tissue cell to another connective tissue cell An example of chronic cellular adaptation to chronic or repeated low-level injury (chronic infection or noninfectious injury). Different from dysplasia : - Metaplasia : no atypical cells - Dysplasia : atypical cells.

213 Some examples

214 Conversion of the normal ciliated bronchial epithelium to stratified squamous epithelium following tobacco smoking :

215 Conversion of the normal ciliated bronchial epithelium to stratified squamous epithelium following tobacco smoking : More resistant to cigarette smoke.

216 Metaplasia of oesophageal stratified squamous epithelium to glandular cells due to chronic gastric reflux : «Barrett metaplasia»

217 Metaplasia of oesophageal stratified squamous epithelium to glandular cells due to chronic gastric reflux : «Barrett metaplasia» Gastric metaplasia Normal squamous epithelium

218 What is the significance of metaplasia? A potentially reversible change if the cause is withdrawn. Connective tissue metaplasia is of little to no clinical consequence (an incidental finding) The significance of Epithelial metaplasia depends on the organ. Squamous metaplasia of the uterine cervix is per se an adaptive mechanism and is a physiological process. In other organs, it may lead to Dysplasia and then malignant neoplasia.

219 Chronic inflammation

220 Chronic inflammation Metaplasia

221 Chronic inflammation Metaplasia Dysplasia

222 Chronic inflammation Metaplasia Dysplasia Cancer

223 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in chronic inflammatory mucosa.

224 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in gastric chronic inflammatory mucosa.

225 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in chronic inflammatory mucosa.

226 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in chronic inflammatory mucosa.

227 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in chronic inflammatory mucosa.

228 Chronic inflammation Metaplasia Dysplasia Cancer Sequence of cancer development in chronic inflammatory mucosa.

229 Remember this chronic gastritis due to Helicobacter pylori.

230 Intestinal metaplasia in chronic gastritis Goblet cells intestinal metaplasia

231 Gastric adenocarcinoma Arise on background of chronic gastritis, intestinal metaplasia, dysplasia

232 Test yourself (understanding the pathological diagnosis)

233 Biopsy of a rapidly growing breast «lump» in a 39y old patient

234 The question is: tumor of inflammation?

235 Biopsy of a breast «lump»

236 Morphological interpretation Giant cells Optically empty vacuoles

237 Background information for the interpretation Optically «transparent» vacuoles (arrow) are present in a variety of breast carcinomas, the so-called «signet ring cell carcinomas».

238 Background information Optically «transparent» vacuoles (arrow) are present in a variety of breast carcinomas, the so-called «signet ring cell carcinomas». - Histochemistry using alcian blue: the vacuoles stain blue - Immunohistochemistry : the vacuolar cells are immunostained with an anti-cytokeratin antibody.

239 Bakground information: Cytokeratins form a variety of «intermediate filaments» specific of epithelial cells

240 In our case: Alcian blue staining: negative Cytokeratin immunohistochemistry: negative. What do you propose?

241 Giant cells The vacuolar cells have a phagocytic function: they are macrophages Inflammatory lesion: granuloma (localized accumulation of macrophages)

242 Is it a «specific granuloma»? the presence of «giant cells» in addition to macrophages favors the diagnosis of «specific granuloma», variety «foreign body granuloma» the determination of the nature of the «transparent material» ingested by the macrophages is the key to the «specificity»

243 The patient s story History of bilateral silicone implants

244 Final diagnosis Giant cells Round transparent vacuoles (phagocytized silicone) Dg: foreign body granuloma to silicone (leaking silicone implant)