Block 1 Chronic Inflammation & Repair Flashcards
Outcomes of acute inflammation
Resolution, fibrosis (scar), abscess formation/liquefaction, chronic inflammation
Non-granulomatous inflam
D/t persistent infxn, prolonged exposure to toxins, allergic/immune/AI rxns; peptic ulcer disease, atherosclerosis, bronchial asthma, RA
Granulomatous inflammation
Distinct pattern evoked by certain agents (fungal, immune-med processes, foreign bodies, unknown); 1-2 mm nodules with epithelioid cells, lymphocytes +/- necrosis (caseating)
Giant cells
Multinucleated epithelioid cells, induced by interferon-gamma; present in granulomatous chronic inflammation
SIRS
Systemic inflammatory response syndrome/acute phase response: fever, acute phase proteins, increased pulse/bp, leukocytosis
Sepsis
Large amounts LPS -> increased TNF, IL-1, IL-12 -> septic shock: DIC, hypotension, metabolic disturbances (acidosis)
Exogenous and endogenous pyrogens
Ex: bacterial LPS stimulate release
End: IL-1, TNF cause COX to convert AA to PGs
*PGE2 -> NTs to reset temp set-point in hypothalamus
Acute phase proteins
When hepatic synth unregulated by cytokines (IL-6), make you feel sick (anorexia, somnolence, malaise, rigors, chills)
CRP (opsonin), fibrinogen, serum amyloid A (may cause 2’ amyloidosis in CI)
Types of leukocytosis
Neutrophilia (bacterial), lymphocytosis (viral), eosinophilia (parasite, allergy, asthma)
Tissues that heal
High proliferative capacity, stems cells not destroyed, ECM intact (scaffold, cell polarity maintained)
Repair
Organization & fibrosis; org=replace inflam with fibrosis in parenchymal organs; fib=extensive collage deposition with CI
Factors influencing repair
Extent, type of injury (cells involved, proliferative capacity, integrity of ECM), resolution/chronicity of injury/inflam
Embryonic, multipotent, & adult stem cells
E: pluripotent -> generate all types of tissue lineages
M: become lineage-committed SCs
A: somatic stem cells, lineage-specific; have niche
Proliferative capacities of tissues
Labile: continuously proliferating, replace self; e.g. skin, cervix, vagina, GI tract, uterus, urinary tract, bone marrow, hematopoietic tissues
Stable: arrested in G0 with ability to replace necrotic tissue if normal stroma intact; e.g. liver, kidney, pancreas, SM, endoth, fibroblast, chrondrocyte
Permanent: cannot divide -> scar; e.g. neurons, skeletal mm, cardiac mm
Cyclins
Act with CDKs to induce cascade of P -> mitosis
p53
Most important regulator of cyclins; TF increasing CDKI p21; loss = uninhibited cell growth
EGF and TGF-a
Share common receptor
EGF: overexpressed/mutated in lung, brain cancers; ERB-B2 (Her-2/Neu) overex in some breast ca
Both produced by keratinocytes, WBCs in response to injury, mitogen for epith cells, hepatocytes, fibroblasts
HGF/scatter factor
From fibroblasts, endoth, liver nonparenchymal cells; promotes scatter/migration cell during dev, mitogen for epith of lung, liver, breast, skin
Receptor c-MET mut/overex in renal and thyroid papillary cancers
VEGF
Promotes vessel formation in early dev (vasculogenesis), new vessel growth (angio-, lymphangiogenesis)
Avastin (bevacizumab)
Blocks VEGF, used in metastatic disease; treatment of wet macular degeneration, retinopathy of prematurity, diabetic macular edema
PDGF
From endoth, MFs, SM; stored in platelet granules; chemotactic for fibro, MF; GF for fibro, SM; promotes collagen synth
FGF
FGF-7 (keratinocyte GF): wound repair/ reepithelialization
2: same as FGF-7 + angiogenesis; chemotactic for fibro, MF, endoth; hematopoiesis; lung, liver, cardiac, sk mm dev
TGF-b
From platelet, endoth, MF, lymphos
Pleiotropic - multiple, sometimes opposing effects: fibrogenic; stimulates fibro prolif, SM cells; inhibits endo and WBC growth; anti-inflam by inh lympho prolif
Some tumors lose receptor; high exp in hypertrophic scars, systemic sclerosis, Marfan’s
Functions of ECM
Mechanical support, maintenance of cell polarity; control cell prolif/diff via storage & presentation regulatory molecules; scaffolding for tissue renewal; establishment of microenvironments/ boundaries
Components of ECM
Fibrous structural proteins: collagen, elastin, fibrillin
Adhesive glycoproteins
Proteoglycans, hyaluronan (gels for resilience/lube)
Forms of ECM
Interstitial: between cells, made by mesenchymal cells, 3D amorphous gel; fibrillar and non-fib collagens, elastin, fibronectin, PGs, hyaluronan
Basement membrane: appx cell surface, non-fibrillar collagen (type IV), laminin, heparin sulfate, PGs
Structure of collagen
Triple helix of pre-procollagen -> 3 procollagen chains -> collagen; need vit C for hydroxylation of procollagen
Types of collagen
I, II, III, V = fibrillar (interstitial, wound healing)
IV = nonfibrillar (BM)
VII = nonfribrillar (epidermal/dermal jxn)
Ehlers-Danlos Syndrome
Defect in type I, III, V collagen
Osteogenesis imperfecta
Defect in type I collagen
Epidermolysis bullosa
Defect in type VII collagen
Elastic fibers
Elastin: for recoil, forms central core of elastic fibers, in large vessels, skin, ligaments, uterus
Fibrillin: form peripheral microfibrillar network of elastic fibers
Marfan syndrome
Defect in fibrillin
Scurvy
Lack of vitamin C = defective hydroxylation of procollagen
Proteoglycans
Protein core linked to GAG (heparan, chondroitin/dermatan sulfate); assembled in Golgi, RER; regulate CT structure and permeability; modulate cell growth/diff
Hyaluronan
Huge GAG of repeating disaccharides, assembled at PM, binds water -> compressible gel in heart valve, skin, cartilage, synovial fluid, vitreous of eye, umbilical cord
Hyaluronidases
Cleave HA into low molecular weight HA, which binds CD44 on WBC to recruit to site of inflammation, stimulates WBC prod of cytokines/chemokines
Hyaluronan concentration increased in what pathologies?
RA, scleroderma, psoriasis, osteoarthritis
Fibronectin
Binds fibrin, collagen, cells, etc.; exists in tissue & plasma forms; receptor is integrin; chemotactic for other cells; promotes wound contraction and epithelial migration
Tissue vs. plasma form of fibronectin
Tissue - synthesized locally in wound by fibroblasts
Plasma - binds fibrin in clot formation
Laminin
Most abundant GP in BM, binds cells to ECM
Cadherins
Ca-dependent adherence proteins, intxns bt cells of same type; play role in “contact inhibition”, dysfunction of E-cadherin in forms of breast, gastric cancer
Zonula adherens & desmosomes
ZA: spot-like jxns near apical surface epith cells
D: stronger jxns in epith and mm tissues
Catenins
Link cadherins to cytoskeleton
b-catenin links cadherin -> a-catenin, which links to actin cytoskeleton
Integrins
Bind cell-cell or cell-ECM (fibronectin, laminin); links to actin intracellularly; transmits signal from neighboring cells, ECM to nucleus for integration of cell prolif, diff, protein synth, attachment, migration
Selectins
WBC/endothelial interaction
Regeneration vs. repair vs. fibrosis
Reg: restitution of tissue identical to previous, fxn regained
Rep: replacement of tissue with CT, incomplete fxn regained
Fib: extensive CT in setting of CI
Granulation tissue & scar
GT: angiogenesis and fibroblast prolif with collagen deposition
Scar: tissue replaced by collagen after would healing in skin or replacement of parenchyma
Vasculogenesis
Embryonic formation vessels from endoth precursors (angioblasts) derived from hematopoietic/endoth cell precursors (hemangioblasts)
Angiogenesis
Vessel formation in adults; occurs in physiologic and pathologic states by 2 methods: branching/extension adjacent vessels or recruit endoth progenitor cells from bone marrow
Physiologic and pathologic causes of angiogenesis
Phy: wound healing, regeneration, menstruation, vascularization of ischemic tissue
Path: tumor dev/metastasis, diabetic retinopathy, chronic inflam
1st intention healing
Primary union, clean wound repaired by epithelial regeneration, small, thin scar results
2nd intention healing
Gap filled with granulation tissue, fills in from sides; scab, wound contracts (myofibroblasts), may be complicated by infection, heals more slowly, larger scar
Steps of repair
Blood clot, neutro/MF invasion, epithelial cells from edge of wound migrate and deposit BM to close wound, capillaries/fibroblasts enter = granulation tissue; MF clean debris, fibrin, promote angiogenesis & ECM deposition; fibro make collagen, vessels regress -> scar
Blood clotting mechanism (1st step of repair)
Vasc injury -> release P-selectin from endoth cells onto ECM -> platelet adhesion & degranulation -> integrins -> recruit neutro/MF -> fibrin clot fills gap & stabilizes platelet plug
Factors involved in epithelial cells depositing BM in wound
FGF-7, IL-6: enhance keratinocyte migration/proliferation
HGF, HB-EGF (heparin-binding)
Components of granulation tissue matrix
Initially: fibrin, fibronectin, type III collagen
Later: type I collagen mostly
What happens in week two of repair
Fibroblasts make collagens and deposit other ECM elements (elastin, PGs, hyaluronan), vessels regress (“blanching”) = scar
Fibroblast recruitment in scar formation
TGF-b (from MF, platelet, endoth), PDGF, EDGF, FGF, IL-1, TNF
Maturation of healed area
Increase matrix secretion with decrease in degradation -> remodeling (MMPs) & wound contraction (myofibroblasts)
Wound strength following healing
10% normal by 1 week, 70-80% max by 3 months
MMPs
Contain zinc, degrade ECM; produced by fibro, MF, neutro, synovial cells, epith; secretion induced by PDGF, FGF, IL-1, TNF; inhibited by TGF-b, steroids, TIMPs (tissue inh of MMP, from mesenchymal cells)
Stromelysins
MMP-3,10,11 degrade PGs, laminin, fibronectin, amorphous collagen
Gelatinases
MMP-2,9 degrade amorphous collagen, fibronectin
Interstitial collagenases
MMP-1,2,3 degrade collagen 1,2,3
Wound contraction
Occurs 1’ in large wounds (2’ intention) by myofibroblasts (from fibro via PDGF, TGF-b, FGF-2), can come from bone marrow or epith, contain smooth muscle actin
Influences on wound healing
Systemic: nutrition (protein, vit C), metabolic status (diabetes), circulation/perfusion (atheriosclerosis), hormones (steroids)
Local: infection, mechanical factor (motion), foreign bodies, size/location/type of wound
Dehiscence & ulceration
Deficient granulation tissue or scar formation
D: rupture
U: inadequate vascularization
Excessive scar formation
Hypertrophic scar: excessive collagen
Keloid: scarring beyond original wound
Exuberant granulation: projects above surrounding skin & blocks re-epithelialization
Desmoids: excessive fibro prolif, CT = may be low grade malignancy
Contractures
Excessive contraction of a wound
Fibrosis
Excessive collagen & other ECM components
Causes: repeated acute inflam, persistence of stimuli for acute inflam -> CI (continued release of GFs, cytokines, decreased MMP activity), dev immune/AI response, radiation
