Chronic inflammation is characterized by prolonged inflammation, simultaneous tissue injury and healing, and infiltration by mononuclear cells. It occurs in persistent infections, prolonged exposure to toxic agents, and autoimmune conditions. The macrophage plays a prominent role in chronic inflammation through recruitment, proliferation, differentiation, and release of inflammatory mediators and proteins. Granulomatous inflammation forms aggregations of activated macrophages that appear in response to bacteria, parasites, fungi, dusts, and foreign materials. Chronic inflammation involves ongoing tissue damage, repair through angiogenesis and fibrosis, and macrophage-driven processes.

2. Chronic inflammationChronic inflammation
 Difficult to defineDifficult to define
 Inflammation of prolonged duration in whichInflammation of prolonged duration in which
active inflammation, tissue injury and theactive inflammation, tissue injury and the
healing proceed simultaneouslyhealing proceed simultaneously
 Occurs in:Occurs in:
– Persistent infections - AFB, fungi, TreponemesPersistent infections - AFB, fungi, Treponemes
 Low toxicityLow toxicity
 Delayed hypersensitivityDelayed hypersensitivity
 Granulomatous inflammationGranulomatous inflammation
– Prolonged exposure potentially toxic agentsProlonged exposure potentially toxic agents
 SilicaSilica
 Toxic plasma lipidsToxic plasma lipids →→ atherosclerosisatherosclerosis
– Autoimmunity - RA, lupus Autoimmunity - RA, lupus

3. Chronic inflammation isChronic inflammation is
characterized by:characterized by:
 Infiltration with mononuclear cellsInfiltration with mononuclear cells
(macrophages, lymphocytes & plasma(macrophages, lymphocytes & plasma
cells)cells)
 Tissue destructionTissue destruction
 Repair involving angiogenesis and fibrosisRepair involving angiogenesis and fibrosis
 Macrophage is theMacrophage is the prima donnaprima donna of chronicof chronic
inflammationinflammation

4. Key macrophage events
1. Recruitment from circulation
2. Local Proliferation
3. Immobilization
4. Differentiation (microglia, kupffer,
alveolar macrophage, osteoclasts).
Macrophage
prominent role due the large repertoire of
products it can produce when activated Tox. O2
Proteases
Collagenases
Chemotx factors
Coag factors
AA metabolites
NO
PDGF FGF
TGF-β
Tox. O2
Proteases
Collagenases
Chemotx factors
Coag factors
AA metabolites
NO
PDGF FGF
TGF-β

5. Note that theNote that the
activatedactivated
macrophagemacrophage
releasesreleases
products thatproducts that
are similar toare similar to
those releasedthose released
by PMNsby PMNs

6. Antigen
Presentation
to T cells
Antigen
Presentation
to T cells
Lymphocyte
Activated
Lymphocyte
Macrophage
Activated
macrophage
IFN-γ
IL-1
TNF-
α
Other
inflammatory
mediators
Other
inflammatory
mediators

7. Granulomatous InflammationGranulomatous Inflammation
 Aggregations ofAggregations of
activated, modifiedactivated, modified
(epitheliod)(epitheliod)
appearanceappearance
 Granuloma – focalGranuloma – focal
collection ofcollection of
granulomatousgranulomatous
inflammationinflammation
 BacteriaBacteria
– TuberculosisTuberculosis
– LeprosyLeprosy
 ParasitesParasites
– SchistosomiasisSchistosomiasis
 FungiFungi
– HistoplasmosisHistoplasmosis
– BlastomycosisBlastomycosis
 Metal/DustMetal/Dust
– BerylliosisBerylliosis
– SilicosisSilicosis
 Foreign bodyForeign body
– SplinterSplinter
– SutureSuture
– Graft materialGraft material
 SarcoidosisSarcoidosis

8. GranulomaGranuloma

10. RepairRepair
 Regeneration of injured tissue by parenchymalRegeneration of injured tissue by parenchymal
cells of the same typecells of the same type
 Replacement by connective tissueReplacement by connective tissue
 Starts as early as 24 hoursStarts as early as 24 hours
 Granulation tissue at 3 - 5 daysGranulation tissue at 3 - 5 days
 Four Components:Four Components:
– AngiogenesisAngiogenesis
– Migration and proliferation of fibroblastsMigration and proliferation of fibroblasts
– Deposition of extracellular matrix (ECM)Deposition of extracellular matrix (ECM)
– Remodeling (Maturation & organization of fibrousRemodeling (Maturation & organization of fibrous
tissue)tissue)

11. Proliferative PotentialProliferative Potential
 Labile cells - continuously dividingLabile cells - continuously dividing
– Epidermis, mucosal epithelium, GI tractEpidermis, mucosal epithelium, GI tract
epithelium etcepithelium etc
 Stable cells - low level of replicationStable cells - low level of replication
– Hepatocytes, renal tubular epithelium,Hepatocytes, renal tubular epithelium,
pancreatic acinipancreatic acini
 Permanent cells - never dividePermanent cells - never divide
– Nerve cells, cardiac myocytes, skeletalNerve cells, cardiac myocytes, skeletal
musclemuscle

12. Components of the processComponents of the process
of fibrosisof fibrosis
 Angiogenesis - New vessels budding fromAngiogenesis - New vessels budding from
oldold
 Fibrosis, consisting of emigration andFibrosis, consisting of emigration and
proliferation of fibroblasts and depositionproliferation of fibroblasts and deposition
of ECMof ECM
 Scar remodeling, tightly regulated byScar remodeling, tightly regulated by
proteases and protease inhibitorsproteases and protease inhibitors

13. Tissue RemodelingTissue Remodeling
 Balance of deposition vs. degradationBalance of deposition vs. degradation
 Zn-dependent matrix metalloproteinasesZn-dependent matrix metalloproteinases
– Interstitial collagenasesInterstitial collagenases  type I, II, III collagentype I, II, III collagen
– GelatinaseGelatinase  type IV collagen & fibronectintype IV collagen & fibronectin
– StromelysinsStromelysins  variety of ECMvariety of ECM
– Membrane-bound matrix metalloproteinasesMembrane-bound matrix metalloproteinases
(MBMM)(MBMM)
– Tissue inhibitors of metalloproteinase (TIMP)Tissue inhibitors of metalloproteinase (TIMP)

14. Scar remodeling isScar remodeling is
regulated byregulated by
metalloproteinasesmetalloproteinases
and their inhibitorsand their inhibitors
Tissue inhibitors of
metalloproteinase

15. Wound healingWound healing
 Complex but orderly phenomenon number ofComplex but orderly phenomenon number of
processesprocesses
 Induction of acute inflammatory response byInduction of acute inflammatory response by
an initial injuryan initial injury
 Regeneration of parenchymal cellsRegeneration of parenchymal cells
 Migration and proliferation of bothMigration and proliferation of both
parenchymal and connective tissue cellsparenchymal and connective tissue cells
 Synthesis of ECM proteinsSynthesis of ECM proteins
 Remodeling of connective tissue andRemodeling of connective tissue and
parenchymal components to restore tissueparenchymal components to restore tissue
functionfunction
 Remodeling of connective tissue to achieveRemodeling of connective tissue to achieve
wound strengthwound strength

16. Healing by first intentionHealing by first intention
(primary union)(primary union)
Clean, uninfected, surgical incision with sutures:Clean, uninfected, surgical incision with sutures:
1.1. Blood clot formsBlood clot forms
2.2. < 24 hours – PMNs appear< 24 hours – PMNs appear
3.3. 24-48 hrs cut edges of epidermis thicken24-48 hrs cut edges of epidermis thicken
fromfrom
basal cell hyperplasia, and epitheliumbasal cell hyperplasia, and epithelium
migratesmigrates
for unionfor union
4. By day 3 – PMN’s replaced by4. By day 3 – PMN’s replaced by
macrophages.macrophages.
Granulation tissue invades & collagen atGranulation tissue invades & collagen at

17. Healing by first intentionHealing by first intention
(primary union)(primary union)
5.5. Incision filled with granulation tissue.Incision filled with granulation tissue.
Maximal neovascularization & collagenMaximal neovascularization & collagen
bridges gap. Epidermis covers & is mature.bridges gap. Epidermis covers & is mature.
6.6. One weekOne week – After suture removal wound– After suture removal wound
strength onlystrength only 10%10% (compared with(compared with
unwounded skin)unwounded skin)
7.7. Second week – Continued collagen depositionSecond week – Continued collagen deposition
and fibroblast proliferation. PMNs gone.and fibroblast proliferation. PMNs gone.
8.8. First month – Scar with cellular connectiveFirst month – Scar with cellular connective
tissue and no inflammatory cells. Regressedtissue and no inflammatory cells. Regressed
vascular channels.vascular channels.
9.9. Third monthThird month –– 70-80%70-80% of maximum strength.of maximum strength.

18. Healing by firstHealing by first
intentionintention

19. Healing by second intentionHealing by second intention
(separated)(separated) Large tissue defect to fill commonLarge tissue defect to fill common
denominatordenominator
 Differs from primary union in several ways:Differs from primary union in several ways:
– More fibrin, more debrisMore fibrin, more debris  more intensemore intense
inflammationinflammation
– More granulation tissue is formedMore granulation tissue is formed
– Wound contraction aided by myofibroblastsWound contraction aided by myofibroblasts

20. Healing by secondHealing by second
intention:intention:
Larger injury, abscess,Larger injury, abscess,
infarction.infarction.
Process is similar butProcess is similar but
results in much largerresults in much larger
scar and then primaryscar and then primary
unionunion

21. Factors that influence healingFactors that influence healing
 Nutrition - vitamin CNutrition - vitamin C
 Metabolic status – diabetes hindersMetabolic status – diabetes hinders
 Circulatory statusCirculatory status
 Hormones – steroids/glucocorticoids inhibitHormones – steroids/glucocorticoids inhibit
 InfectionInfection
 Mechanical stressMechanical stress
 Foreign bodiesForeign bodies
 Size, locations and type of the woundSize, locations and type of the wound
Whether a wound heals by primary orWhether a wound heals by primary or
secondary union is determined by the naturesecondary union is determined by the nature
of the wound, rather than by the healingof the wound, rather than by the healing
process itselfprocess itself