1. Acute inflammation is stimulated by injury or infection and involves vascular changes, neutrophil migration, and phagocytosis to resolve the stimulus and restore tissue structure and function. 2. Outcomes include resolution, tissue destruction via abscess or ulcer formation, or progression to chronic inflammation. 3. Chronic inflammation involves lymphocyte and macrophage infiltration and scarring, and can be caused by persistent infection, prolonged toxic exposure, or autoimmunity.

1. Inflammation Outcomes:
Healing, Sepsis

3. Summary of acute inflammation
• Stimulated by physical injury, infection, foreign body
• Resident macrophages and/or damaged endothelium, mast cells—
IL-1, TNF, endothelin, histamine
• Vascular response: vasodilation, endothelial contraction,
exudation of plasma
• Neutrophils: marginate (selectin-glycoprotein), adhere (integrin-
CAM), extravasate (CD31), migrate (IL-8, chemotactic stimuli)
• Phagocytosis: recognition, engulfment, killing
 Phagocytosis receptors bind mannose, oxidized lipids,
lipopolysaccharides, lipoteichoic acids, opsonins
 Killing is O2-dependent (respiratory burst, NADPH oxidase generated
H2O2; myeloperoxidase generated HOCl; iNOS generated NO) or
independent (lysozyme, lactoferrin, defensins)
• Responding leukocytes cause pain and loss-of-function via
prostaglandins, enzymes
• Complete resolution; fibrosis, organization or scarring; abcess
formation; progression to chronic inflammation

4. Outcomes of Acute Inflammation
• Resolution of tissue structure and function with elimination of
stimulus
• Tissue destruction and persistent inflammation
 Abscess
• pus-filled cavity (neutrophils, monocytes and liquefied cellular debris)
• walled off by fibrous tissue and inaccessible to circulation
• tissue destruction caused by lysosomal and other degradative enzymes
 Ulcer
• loss of epithelial surface
• acute inflammation in epithelial surfaces
 Fistula
• abnormal communication between organs or an organ and a surface
 Scar
• Causes distortion of structure and sometimes altered function
• Chronic inflammation
 Marked by replacement of neutrophils and monocytes with lymphocytes,
plasma cells and macrophages
 Accompanied by proliferation of fibroblasts and new vessels with
scarring

5. Causes of chronic inflammation
• Persistent infections
 Organisms usually of low toxicity that invoke delayed
hypersensitivity reaction
 M. tuberculosis and T. pallidum causes granulomatous reaction
• Prolonged exposure to potentially toxic agents
 Exogenous agents include silica which causes silicosis
 Endogenous causes include atherosclerosis caused by toxic
plasma lipid components
• Autoimmunity
 Auto-antigens provoke self-perpetuating immune responses that
cause chronic inflammatory diseases like RA, MS
 Responses against common environmental substances cause
chronic allergic diseases, such as bronchial asthma

6. Granulomatous inflammation
• Focus of chronic inflammation encountered in a limited
number of conditions
• Cellular attempt to contain a foreign body or an offending
agent that is difficult to eradicate (i.e. Tb)
• Microscopic aggregation of macrophages that are
transformed into epithelioid cells, surrounded by a collar
of lymphocytes and occasionally plasma cells
• Epithelioid cells have a pale pink granular cytoplasm with
indistinct cell boundaries, often merging as giant cells
 Foreign body epitheloids have dispersed nuclei
 Infectious body epitheloids have marginal or horse-shoe nuclei
• Enlarged granuloma with central necrosis is an abcess
• Enlarged granuloma on a surface is an ulcer

7. Patterns of Inflammation
• Serous Inflammation
 Marked by outpouring of thin fluid
 From blood serum, e.g. burn blisters
 Effusion from mesothelial cells lining the pleural, peritoneal and pericardial cavity
• Fibrinous Inflammation
 A feature of pericardial and peritoneal inflammation
 Vascular permeability allows larger molecules like fibrin to pass or procoagulant
stimulus exists in the interstitium (e.g. cancer cells)
• Suppurative Inflammation
 Characterized by production of large amount of pus composed of neutrophils,
necrotic cells and edema fluid
 Involves pyogenic bacteria e.g. Streptococci and Staphylococcus aureus
 Abscesses are focal localized collections of purulent inflammatory tissue caused
by suppuration.
• Ulcers
 Local defect or excavation of the surface of an organ or tissue by sloughing of
inflammatory necrotic tissue
 Acute stage - intense polymorphonuclear infiltration and vascular dilation in
margin
 Chronic stage - margin and base develop fibroblastic proliferation, scarring and
accumulation of lymphocytes, plasma cells and macrophages

8. Systemic inflammatory response
• Acute Phase Response
 Fever
 Acute-phase protein secretion from liver
 Leukocytosis
 Tachycardia, increased blood pressure
 Shivering, chills
 Anorexia, somnolence, malaise
• Septic shock

9. Acute Phase Proteins
• Secretion of Acute Phase proteins by the liver
• C-reactive Protein (CRP)
• Serum Amyloid A (SAA)
• Serum Amyloid P (SAP)
• Complement
• Fibrinogen
• Prothrombin
• Ferritin
• Ceruloplasmin
• α1-antitrypsin
• α2-macroglobulin
• Acute phase proteins bind:
 Microbial constituents, acting as opsonins to fix
complement
 Chromatin, aiding early clearing of necrotic cells

10. • Autonomic
 redirection of blood flow from cutaneous to
vascular bed
 increased pulse and blood pressure
 decreased sweating
• Behavioral
 Rigors (Shivering)
 Chills
 Anorexia
 Somnolence
 Malaise
Autonomic and Behavioral Responses

11. Sepsis
• Systemic Inflammatory Response Syndrome involves
two or more of the following
• temperature >38.3ºC or <36ºC
• heart rate >90 beats/min; <32 mm Hg
• respiratory rate >20 breaths/min, PaCO2 or need for mechanical
ventilation
• WBC count >12,000/uL or <4,000/uL or >10% immature forms
(bands)
• Sepsis is defined as SIRS associated with suspected or
confirmed infection--positive blood cultures are not
necessary
• Severe sepsis is sepsis complicated by a predefined
organ dysfunction
• Septic shock is cardiovascular collapse (hypotension)
related to severe sepsis despite adequate fluid
resuscitation

12. Septic stimuli
• Gram-negative bacteria
 LPS, endotoxin
 Binds to LPS binding protein (LBP)
 Binds to CD14 opsonin receptor
 TLR-4 binds LPS and LPS-LBP
 Stimulates release of TNF, IL-1, IL-6
• Gram-positive bacteria
 Exotoxins, superantigens
 Bind Vb regions of TCRs and/or to MHC-II
 TLR-2 binds cell wall components
 Stimulates release of IFN-g, TNF, IL-1, IL-6

13. Progression of sepsis
• Cytokine release and amplification
 Vasular response and neutrophil migration
• Coagulation cascade
 Short arm, extrinsic pathway, activated by expression of Tissue
Factor VIIa Xa thrombin fibrin
 high plasma levels of plasminogen-activator inhibitor type-1
(PAI-1) suppress plasmin and fibrinolysis
 disseminated intravascular coagulation in 30-50% cases
• Counter-inflammatory response
 Apoptosis of Th and B-cells
• Systemic acute phase response
 increased cortisol production and release of catecholamines
 upregulation of adhesion molecules
 release of prostanoids and platelet-activating factor (PAF)
• Organ failure

14. Multiple organ failure
• Neutrophils damage tissue directly by
releasing lysosomal enzymes and
superoxide-derived free radicals
• TNF-α induces nitric oxide synthase
 nitric oxide causes further vascular instability
 contributes to direct myocardial depression
• Widespread vasodilation
• Decreased production of vasopressin
(ADH) and glucocorticoids
• Circulatory collapse and tissue hypoxia

15. Findings of shock at autopsy
• Congestion of lung
 may also have fibrinous casts lining alveolar
spaces
• Petechial or ecchymotic hemorrhages on
serosal and endothelial surfaces
• Necrosis
 proximal tubular epithelium in kidneys
 entrilobular hepatocytes

18. Restoration of Structure and Function
• Occurs if connective tissue structure relatively intact
• Surviving parenchymal cells must have the capacity to
regenerate
• Labile Cells
 Actively divide throughout life
• cells of the epidermis and gastrointestinal mucosa
• cells lining surface of the genitourinary tract
• hematopoietic cells of the bone marrow
• Stable Cells
 Undergo few divisions normally, but can be activated from G0
cells when needed
• hepatocytes
• renal tubular cells
• parenchymal cells of glands
• mesenchymal cells (smooth muscle, cartilage, connective tissue,
endothelium, osteoblasts)

19. Regeneration
• Proliferation of cells and tissues to replace
lost structures
• Whole organs and complex tissues rarely
regenerate after injury
• Compensatory growth rather than true
regeneration
 Liver hypoplasia and kidney hypertrophy
• Continuously renewing tissues regenerate
after injury if tissue stem cells are not
destroyed

20. Stem Cells
• Characterized by self-renewal properties and
capacity to generate differentiated cell lineages
 obligatory asymmetric replication
• one daughter cell retains its self-renewing capacity
• the other enters a differentiation pathway
 stochastic differentiation
• stem cell divisions generate either two self-renewing stem cells
or two cells that differentiate
• Stimulation for either outcome is conjecture—seemingly random
• embryonic stem cells (ES cells) are pluripotent
• adult (somatic) stem cells are restricted by niche
 skin, gut lining, cornea, hematopoietic tissue

21. ES cells and KO/transgenic mice
• KO mice have specific gene deletion or
inactivation
 Transform cultured ES cells
 Transformants injected into blastocysts
 Blastocyst transplanted to surrogate dam
 Mouse develops in utero
• Transgenic mice have specific human
gene insertion or replacement
 Transformed ES cells injected into blastocysts
 Continued development in surrogate dam

22. Somatic cell cloning
• Reproductive
 Transfer of adult nucleus into enucleated
oocyte restores pluripotency
 Transfer of resulting embryo to surrogate dam
 Production of cloned individual
• Therapeutic
 Transfer of adult nucleus into enucleated
oocyte restores pluripotency
 Induced to differentiate into various cell types
in vitro
 Injected into damaged organ

23. Induced Pluripotent Stem Cells
• Mouse ES cell pluripotency depends on
the expression of Oct3/4, Sox2, c-myc,
Klf4, Nanog
• Human fibroblasts from adults and
newborns have been reprogrammed
 Oct3/4, Sox2, c-myc and Kfl4
 Oct3/4, Sox2, Nanog, and Lin28
• Generated cells from endodermal,
mesodermal, and ectodermal origin
• c-myc and Kfl4 are oncogenes

24. Stem Cells in Homeostasis and Healing
• Bone marrow
 Hematopoietic Stem Cells generate all of the blood cell lineages
 Marrow Stromal Cells generate precursors of tissue to which migrated
• Liver
 Oval cells are bipotential progenitors of hepatocytes and biliary cells
• Brain
 Neural precursor cells generate neurons, astrocytes, and
oligodendrocytes in the subventricular zone and the dentate gyrus of the
hippocampus
• Skin
 Hair follicle bulge, interfollicular areas of the surface epidermis, and
sebaceous glands
• Intestinal epithelium
 crypts are monoclonal structures derived from single stem cells
 villus contains cells from multiple crypts
• Skeletal and cardiac muscle
 satellite cells beneath the myocyte basal lamina generate differentiated
myocytes after injury
• Cornea
 limbal stem cells maintain corneal transparency

27. Proliferative capacity of tissues
• Labile tissues
 Continuously dividing tissues containing stem
cells
• Stable tissues
 Parenchymal cells of solid organs in G0
 Endothelial cells, fibroblasts, smooth muscle
 Limited regeneration after wounding
• Permanent tissues
 Absolutely nonproliferative
 Cardiac muscle, neurons

28. Growth factors
• Polypeptides that promote survival and
proliferation by signal transduction
 Increase in cell size
• true growth factors
 Increase in cell number
• mitogens
 Protection from apoptosis
• survival factors

29. Signaling mechanisms
• Receptors with intrinsic tyrosine kinase activity
 Dimeric transmembrane molecules
 Ligand binding induces stable dimerization and
phosphorylation
• 7tm GPCRs
 Seven transmembrane proteins
 Ligand binding induces association with GTP-binding
protein, which swaps GDP for GTP
 Gi or Gs protein inactivates or stimulates another
effector
• Gs activates membrane adenylyl cyclase; GTPGDP
• cAMP activates PKA, etc.
• Receptors without intrinsic enzymatic activity
 Monomeric transmembrane molecules
 Ligand binding stimulates interaction with JAKs

32. Growth Factor-mediated Proliferation
• Platelet Derived Growth Factor (PDGF)
 promotes the chemotactic migration of fibroblasts and smooth muscles
 chemotactic for monocytes
 competence factor that promotes the proliferative response of fibroblasts and
smooth muscles upon concurrent stimulation with progression factors
• Epidermal Growth Factor (EGF)
 promotes growth for fibroblasts, endothelial and epithelial cells
 is a progession factor - promotes cell-cycle progression.
• Fibroblast Growth Factor (FGF)
 promote synthesis of fibronectin and other extracellular matrix proteins
 chemotactic for fibroblast and endothelial cells
 promotes angiogenesis
 links extracellular matrix components (collagen, proteoglycans) and
macromulocules (fibrin, heparin) to cell-surface integrins.
• Transforming Growth Factors (TGFs)
 TGF-α - similar to EGF
 TGF-β - mitosis inhibitor that aids in modulating the repair process. May be
responsible for hypertrophy by preventing cell division. Chemotactic for
macropahges and fibroblasts
• Macrophage-derived cytokines (IL-1 and TNF)
 promote proliferation of fibroblasts, smooth muscle and endothelial cells

33. Repair Process
• Removal of Debris
 begins early and initiated by liquefaction and
removal of dead cells and other debris
• Formation of Granulation Tissues
 connective tissue consisting of capillaries and
fibroblasts that fills the tissue defect created
by removal of debris
• Scarring
 fibroblasts produce collagen until granulation
tissue becomes less vascular and less cellular
 progessive contraction of the wound occurs,
resulting in deformity of original structure

34. Factors that Impede Repair
• Retention of debris or foreign body
• Impaired circulation
• Persistent infection
• Metabolic disorders
 diabetes
• Dietary deficiency
 ascorbic acid
 protein

36. Healing and granulation
• Fibroplasia is a response to
 Damaged connective tissue
 Parenchymal damage exceeds regenerative capacity
• Hyperplasia of connective tissue
• Neovascularization
• Granulation
 coordinated proliferation of fibroblasts with a rich bed
of capillaries
 intensely hyperemic with a roughened or granular,
glistening surface
 healthy granulation tissue resists secondary infections

37. Healing by First Intention
• Clean, surgical incision or other clean narrow cut
• Focal disruption of epithelial basement
membrane with little cell damage
• Regeneration dominates fibrosis
• Scabbing with fibrin-clotted blood
• Neutrophils migrate to edges
• Epidermis becomes mitotic and deposits ECM
• Macrophages replace neutrophils
• Vascularization and collagen deposition fills gap
• Contraction of collagen minimizes epidermal
regeneration

38. Healing by Second Intention
• Larger area of tissue injury such as abcess,
ulcer, infarction that destroys ECM
• Large clot or scab with fibrin and fibronectin fills
gap
• Larger volume of necrotic debris must be
removed by more neutrophils and macrophages
 Opportunity for collateral damage by phagocytes
• Scar tissue formed from vascular cells,
fibroblasts, and myofibroblasts
• Contraction of myofibroblasts distorts tissue
• More prone to infection

42. Keloid—excessive cutaneous fibrosis

44. Granulation at tracheotomy