Inflammation and Repair (part 2)

chronic inflammation

prolonged inflammation in which active inflammation, tissue injury, and repair/fibrosis coexist

causes of chronic inflammation

persistent microbes/unresolved tissue injury, immune dysregulation (autoimmunity/hypersensitivity), toxic/metabolic/environmental exposures

macrophage plasticity (M1)

M1-skewing supports pathogen killing but can injure tissue

macrophage plasticity (M2)

M2-like repair programs can also promote fibrosis or tumor immune evasion

TNF, IL-1B, IL-6

recruit and activate leukocytes, endothelium, and systemic acute-phase responses, helpful during acute defense; damaging when persistent or in xs

ROS and proteases

kill microbes and clear debris, but can injure cells proteins, lipids, DNA, and ECM

resolution signals

efferocytosis, macrophage metabolic shifts, angiogenic cues, fibroblast regulation move tissue toward repair

cytokine function

timing and context depending, not simply good or bad

macrophage-T cell crosstalk

sustains cytokine loops such as TNF, IL-1B, IL-6, and IL-17

innate memory and metabolic rewiring can

make inflammatory responses more durable

neuts, endothelial cells, and fibroblasts amplify inflammation through

chemokines, proteases, ROS, and ECM signals

failed resolution

shifts tissue from repair toward progressive injury and fibrosis

granulomatous inflammation

persistent antigen containment, macrophage-rich response to difficult-to-eradicate antigen

pattern: epithelioid macrophages, giant cells, lymphocytes, variable necrosis

granuloma

attempted containment that may become destructive

protective acute effects

fever, acute-phase protein production, leukocytosis and mobiilization of immune cells, sickness behavior that conserves energy

pathologic persistent effects

tissue injury, metabolic dysregulation, vascular dysfunction, and chronic disease progression

acute-phase reactants (APRs)

system biomarkers or inflammation, plasma proteins that change during systemic inflammation, IL-6 is a major driver (trends and clinical context matter more than 1 value)

positive APRs

CRP, serum amyloid A, fibrinogen; procalcitonin in selected infectious/sepsis contexts

negative APRs

albumin and transferrin commonly decrease

acute inflammation (onset)

minutes to hours

acute inflammation (dominant cells)

neutrophils early; macrophages follow

acute inflammation (tissue effect)

edema, exudate; often resolves

acute inflammation (examples)

appendicitis, acute bronchitis

chronic inflammation (onset)

weeks to months or longer

chronic inflammation (dominant cells)

macrophages, lymphocytes, plasma cells

chronic inflammation (tissue effect)

ongoing injury and repair/fibrosis

chronic inflammation (examples)

arthritis, granulomatous disease

chronic inflammation is a driver of

CVD, cancer, and metabolic disease

NF-kB/NLRP3 cytokines support

atherosclerosis and tumor-permissive microenvironments

mechanisms of tissue repair

hemostasis, inflammation, proliferation, remodeling

hemostasis

clot formation stops bleeding and provides platelet-derived signals

inflammation

DAMPs/PAMPs activate macrophages, mast cells, and endothelium

proliferation

tissue helped move here through macrophage efferocytosis and resolution signals, fibroblasts deposit ECM to form granulation tissue, VEGF-driven angiogenesis restores O2 and nutrients, keratinocytes re-epithelialize the wound

remodeling

collagen reorganizes as cellularity and vascularity decline, persistent TGF-B overactivation can drive fibrosis and scarring

tissue proliferative activity (tissue groups)

labile, stable, permanent

labile

continuous division, eg. epithelium, BM

stable

quiescent but inducible proliferation, eg. liver, kidney, fibroblasts, endothelium

permanent

very limited regeneration, eg. neurons, cardiomyocytes

tissue proliferative activity (outcome)

depends on cell capacity, ECM integrity, vascularity, duration of inflammation

systemic factors influencing tissue repair

nutrition/protein status, glycemia and metabolic status, perfusion/oxygenation/circulatory status, age/comorbidities/medications/hormone or immunosuppressive state

local factors

infection/biofilm, ischemia/edema/necrosis/foreign material, wound size/location/type, mechanical tension/pressure and local microenvironment

chronic wounds examples

diabetic foot ulcers, venous leg ulcers, pressure injuries, arterial ulcers

shared mechanisms of chronic wounds

infection/biofilm, ischemia or pressure, persistent ROS/proteases, defective angiogenesis

pathophys of diabetic chronic wounds

hyperglycemia, neuropathy, vascular insufficiency, disregulation of angiogenesis/fibroblasts/keratinocytes/ECM turnover, cytokine/GF/MMP imbalance keep wound open`

hyperglycemia effect on chronic wounds (diabetes)

increases oxidative stress and inflammatory mediators

neuropathy effect on chronic wounds (diabetes)

delays injury detection and promotes repeated trauma

vascular insufficiency effect on chronic wounds (diabetes)

limits O2, nutrients, and immune trafficking

hypertrophic scar

raised scar w/in wound boundary, driven by exaggerated collagen deposition

keloid

extends beyond original wound edge, sustained fibroblast activation, TGF-B, VEGF, and mechanical signaling contribute

xs granulation/contracture

can block re-epithelialization, persistent myofibroblasts and tension can deform wound

fibrosis development

pathologic ECM accumulation from persistent injury or failed resolution

fibrosis core mechanisms

fibrosis-to-myofibroblast activation, TGF-B signaling, inflammation/oxidative stress/hypoxia/metabolic disfunction/matrix stiffness, imbalanced ECM deposition vs degradation

consequence of fibrosis

distorted architecture, stiffness, and organ disfunction

scar (scope)

focal/local

scar (trigger)

acute injury that resolves

scar (biology)

organized repair and remodeling

scar (reversibility)

mature scar usually permanent

scar (impact)

cosmetic/local mechanical effect

fibrosis (scope)

patchy to diffuse; organ level

fibrosis (trigger)

persistent injury/inflammation

fibrosis (biology)

myofibroblasts and TGF-B-driven ECM

fibrosis (course)

often progessive architecture distortion

fibrosis (reversibility)

early fibrosis sometimes partly reversible

fibrosis (impact)

organ disfunction common