Inflammation Types and Characteristics

• Lecture focuses on chronic inflammation
• Annabel Vila, MD, Associate Professor of Pathology is the presenter

Learning Objectives

• Describe the different morphologic patterns of acute inflammation including:
  • Serous
  • Fibrinous
  • Purulent or suppurative
  • Abscess
  • Ulcers
• Describe the different outcomes of acute inflammation:
  • Complete resolution
  • Healing via connective tissue replacement (scarring or fibrosis)
  • Progression to chronic inflammation
• Describe the causes and morphologic features of chronic inflammation
• Describe the roles of the different cells and mediators in chronic inflammation:
  • Macrophages
  • Giant cells
  • Lymphocytes
  • Eosinophils
  • Mast cells
  • Neutrophils
• Describe granulomatous inflammation, immune granulomas, and foreign body granulomas
• Briefly describe the main diseases with granulomatous inflammation:
  • Tuberculosis
  • Leprosy
  • Syphilis
  • Sarcoidosis
  • Cat-scratch disease
  • Crohn's disease
• Describe the systemic effects of inflammation including:
  • Fever
  • Acute-phase proteins
  • Septic shock
  • Systemic inflammatory response syndrome (SIRS)

Morphologic patterns of acute inflammation

• Morphologic patterns include:
  • Purulent or suppurative inflammation and abscesses
  • Fibrinous inflammation
  • Serous Inflammation
  • Effusion
  • Ulcers

Purulent Inflammation and Abscesses

• This is characterized by the production of pus

Pus

• Pus is an exudate consisting of neutrophils, liquefied debris of necrotic cells, and edema fluid
• Pyogenic bacteria cause liquefactive tissue necrosis

Abscesses

• These are localized collections of pus often walled off by fibrous tissue
• They are relatively inaccessible to the circulation

Gross exam of acute appendicitis

• Typically shows hyperemia, mural edema, and serosal purulent exudate

Microscopic exam of acute appendicitis

• Secondary to food impaction shows mural abscesses around partly digested food material

Location of Fibrinous Exudate

• Commonly found lining body cavities like the meninges, pericardium, and pleura

Pathogenesis of Fibrinous Exudate formation

• Increased vascular permeability where larger molecules like fibrinogen pass out of the blood and fibrin is deposited in the extracellular spaces

Microscopic exam of Fibrinous Exudate

• Fibrin appears as an eosinophilic meshwork of threads
• Fibrinous exudates may be dissolved by fibrinolysis and cleared by macrophages
• If the fibrin is not removed, it can stimulate the ingrowth of fibroblasts and blood vessels leading to scarring

Microscopic Examination of Fibrinous Exudate

• Shows an extensive deposit of fibrin on the pericardial surface and scant fibrovascular proliferation in an early phase of viral pericarditis

Gross Exam of Fibrinous Exudate

• Autopsy specimen shows that anterior heart surface is coated by fibrinous deposits, in a shaggy irregular appearance
• A characteristic finding in fibrinous pericarditis, which may be seen in viral infections

Serous Inflammation

• This presents as an exudation of cell-poor fluid into spaces created by injury to surface epithelia or into body cavities like the peritoneum, pleura, or pericardium

Effusion

• The fluid is not infected by destructive organisms and does not contain large numbers of leukocytes

Fluid in body Cavities

• Fluid may be derived from the plasma as a result of increased vascular permeability
• Secretions of mesothelial cells can also contribute as a result of local irritation to the cavity
• Accumulation of fluid in these cavities

Gross examination of Serous Inflammation

• Pericardial fluid is in the potential space between the serous parietal and visceral pericardium

Serous Pleural Effusion Gross

• Transudate or serous pleural effusion is clear yellow
• It is translucent and optically inverts
• Usually signs of cardiac or circulatory disease, not primary lung disease

Serous Inflammation Microscopic

• Low-power view of a cross-section of a skin blister

Staphylococcal Scalded Skin Syndrome

• Shows very superficial erosions that began as small blisters in the axillae and neck region
• With very gentle pressure, skin peels off

Ulcers

• Local defect, or excavation, of the surface of an organ or tissue
• Produced by the sloughing of inflamed necrotic tissue

Common Locations of Ulcers

• Mucosa of the mouth, stomach, intestines, or genitourinary tract
• Skin and subcutaneous tissue of the lower extremities in older people with circulatory disturbances

Aphthous Ulcers (Canker Sores)

• Clinical photograph displays aphthous ulcers
• Clusters of numerous 1-3 mm ulcers throughout the lower lip
• Lesions appear as single or multiple, shallow, hyperemic ulcerations

Acute Gastric Ulcer

• Clinical photograph showing acute gastric ulcer perforation in a patient presenting with free air under the diaphragm

Gastric Epithelial Ulcer

• Hematoxylin & eosin shows an ulcer in the gastric epithelial surface

Outcomes of Acute Inflammation

• Usual outcome is resolution, but excessive exudate and necrosis results in:
  • Suppuration or abscess formation
  • Repair and organization leading to fibrosis and scar formation
  • Persistence leading to chronic inflammation

Chronic Inflammation Definition and Morphologic Patterns

• Chronic inflammation occurs with persistent or recurrent inciting injury, or if the inflammatory reaction is insufficient
• Major morphologic patterns include:
  • Chronic nonspecific inflammation
  • Granulomatous inflammation

Cells and Mediators

• In chronic inflammation macrophages play a key role

Macrophages Origins

• Bone marrow produces hematopoietic stem cells
• These stem cells differentiate into blood monocytes
• Monocytes can then turn into activated macrophages

Macrophages

• Macrophages are found in skin, lung, brain etc
• Can be classically or alternatively activated

Classically activated macrophages (M1)

• Stimulated by microbial products and IFN-y
• Produces ROS, NO, lysosomal enzymes, IL-1, IL-12, IL-23, and chemokines
• Leads to microbicidal actions, inflammation

Alternatively activated macrophages (M2)

• Stimulated by IL-13 and IL-4
• Produces growth factors, TGF-B, IL-10
• Leads to tissue repair, fibrosis, and anti-inflammatory effects

Immune Granulomas

• Require T-cell interaction

Antigen-presenting cells

• Present antigen to T cells which secrete cytokines
• Cytokines recruit leukocytes and trigger monocyte activation and fibroblast activity
• Epithelioid and giant cells can be found

Etiology of Chronic Inflammation

• Persistent infections such as Mycobacterium tuberculosis and M. leprae
• Hypersensitivity diseases
  • Prolonged exposure to potentially toxic agents, exogenous or endogenous
• Autoimmune diseases where self (auto) antigens evoke self-perpetuating immune reaction

Allergic Diseases

• Chronic inflammation can result from excessive immune responses against common environmental substances
• May show mixed acute and chronic inflammation patterns due to repeated inflammation bouts
• Fibrosis may dominate in later stages

Other Diseases linked to Chronic Etiology

• Atherosclerosis
• Cardiovascular Diseases
• Alzheimer's Disease

Major Morphologic Patterns of Chronic Inflammation

• Chronic nonspecific inflammation:
  • Characterized by mononuclear cells (macrophages, lymphocytes, plasma cells), fibroblasts, and new vessels
  • Can also cause scarring and tissue distortion due to deranged architecture

Granulomatous inflammation

• A subtype of chronic inflammation characterized by granuloma formation
• Granulomas are a cellular attempt to contain a difficult-to-eradicate agent
• The lesion is due to activated T lymphocytes leading to macrophage activation
• They are collections of activated macrophages, often with T lymphocytes, and central necrosis (caseating)

Granulomatous Inflammation Morphologic Features

• Activated macrophages differentiating into epithelioid cells that begin to resemble epithelial cells
• Multinucleate giant cells
• Multinucleated giant cells that can be produced from fused macrophages

Granlulomas Subtypes

• Granulomas are divided into noncaseating and caseating subtypes

Noncaseating Granulomas

• Lack of central necrosis
• Common etiologies include:
• Foreign material
• Sarcoidosis
• Chron's disease
• Cat scratch disease

Caseating Granulomas

• Exhibit central necrosis
• Common etiologies include:
• Tuberculosis
• Fungal infections

Necrotizing Caseating Granuloma

• Typical histologic appearance of pulmonary tuberculosis is characterized by this specific granuloma
• Shows peripheral palisading of histiocytes surrounding a necrotic center

Pulmonary Tuberculosis

• Gross appearance in active disease shows subpleural areas of consolidation with cavitary lesions containing caseous material in the lumen

Granulomatous Inflammation noncaseating

• Such immune granulomas are present in pulmonary sarcoidosis

Immune Granulomas

• Inciting agent can not be readily eliminated
• The inciting agent can be classified as an "Unknown agent"

Sarcoidosis

• Clinical example
• Unknown etiology
• Exaggerated helper T-Lymphocyte response
• Noncaseating Granulomas

Diseases and Reactions with Granulomatous Inflammation

Tuberculosis

• Cause: Mycobacterium tuberculosis
• Tissue Reaction: Caseating granuloma (tubercle):
  • Focus of activated macrophages (epithelioid cells)
  • Rimmed by fibroblasts, lymphocytes, histiocytes, and occasional Langhans giant cells
  • Central necrosis with amorphous granular debris
  • Acid-fast bacilli

Leprosy

• Cause: Mycobacterium leprae
• Tissue Reaction: Acid-fast bacilli in macrophages; noncaseating granulomas

Syphilis

• Cause: Treponema pallidum
• Tissue Reaction: Gumma
  • Microscopic to grossly visible lesion
  • Enclosing wall of histiocytes
  • Plasma cell infiltrate
  • Central cells are necrotic without loss of cellular outline

Cat-scratch disease

• Cause: Gram-negative bacillus
• Tissue Reaction: Rounded or stellate granuloma
  • Contains central granular debris and recognizable neutrophils
  • Giant cells uncommon

Sarcoidosis

• Cause: Unknown etiology
• Tissue Reaction: Noncaseating granulomas with abundant activated macrophages

Crohn disease

• Cause: Immune reaction against intestinal bacteria, possibly self-antigens
• Tissue Reaction: Occasional noncaseating granulomas in the wall of the intestine, with dense chronic inflammatory infiltrate

Leprosy Clinical

• Nodules involving the ear lobules and face

Cat-scratch disease Clinical

• Ulcerated papule at the site of inoculation with regional submandibular lymphadenopathy

Crohn Disease: Clinical

• Resection specimen contains an ileal stricture with effaced/nodular mucosa
• Often described as cobblestone appearance and the mesenteric fat is often affected

Crohn Disease Microscopy

• High-power magnification of colon section:
• Large, well-formed granuloma in the muscularis propria
• Can contain mulitnucleated giant cells

Foreign Body Granuloma

• Caused by granulomatous inflammation as a response to traumatically introduced substances
• Occurs in the dermis, subcutaneous or soft tissue

Causes or types of Foreign Body Granulomas

• Lipids
• Wood
• Paraffin
• Lead
• Ink (tattoos)
• Silica
• Insect fragments (e.g., from tick bites)
• Virtually any non-dissolvable material too large for macrophages

Foreign body granuloma: Clinical Features

• Foreign body granuloma of several months' duration is shown between the toes of a tennis player.
• A sliver of wood is the site of entry with surrounding erythema and swelling where granulation tissue is building up

High-power view of granuloma

• Granuloma reaction to a wood splinter is shown
• Skin is walling off the splinter to be extruded

Systemic Effects of Inflammation

• Fever: Cytokines (TNF, IL-1) trigger prostaglandin production in the hypothalamus

Acute-phase proteins

• such as C-reactive protein, are synthesized due to cytokine (IL-6) action on liver cells
• Leukocytosis: Cytokines (CSFs) drive leukocyte production in the bone marrow

Septic shock

• Results in fall of blood pressure, disseminated intravascular coagulation, and metabolic abnormalities
• Induced by TNF and other cytokines

Test your knowledge of inflammation! This quiz covers purulent, serous, and fibrinous inflammation, as well as outcomes of acute inflammation and specific conditions like Staphylococcal Scalded Skin Syndrome. Questions address fluid accumulation, tissue repair and causes of ulcers.