CPAT3201 - Lectures 3-4

What are the four major outcomes of acute inflammation?

resolution, organisation (fibrosis), suppuration (pus formation), chronic inflammation

What factors influence the progression of acute inflammation?

nature/duration of stimulus, degree of tissue destruction, tissue type

What are the key features of inflammation resolution?

mild stimulus, no tissue damage, little/no fibrin, fluid drains via lymphatics, normal structure restored

Give an example of inflammation that resolves completely.

friction blister.

What is organisation in inflammation?

healing by fibrosis with granulation tissue formation

What is granulation tissue composed of?

macrophages, newly formed microvessels, fibroblasts

What are the roles of each cell in granulation tissue?

macrophages remove debris, vessels supply nutrients, fibroblasts deposit collagen

Where does granulation tissue originate?

migrates from the wound margin into the damaged area

What is suppuration?

inflammation outcome involving pus formation due to persistent neutrophil recruitment

What is pus composed of?

living/dead neutrophils, plasma proteins, fluid, microbes, debris, nucleic acids, myeloperoxidase

What are the two main forms of pus accumulation?

abscesses (deep) and ulcers (superficial)

What typically causes suppuration?

pyogenic bacterial infection

Define chronic inflammation.

long-lasting inflammation with ongoing damage, inflammation, and repair

What are the four histological features of chronic inflammation?

persistence, cellular infiltration, tissue destruction, fibrosis

Name three types of chronic inflammation.

suppurative, granulomatous, mixed-type

What characterises chronic suppurative inflammation?

persistent pus and neutrophil presence

What is an abscess?

localised pus collection within solid tissue

What is a granuloma?

nodular lesion with macrophages, lymphocytes, and fibroblasts, formed in response to persistent irritants

What are the three types of granulomatous inflammation?

foreign body, idiopathic (e.g. sarcoidosis), immune-type (e.g. TB)

What cells are found in granulomas?

epithelioid cells, giant cells (Langhans or foreign body type), lymphocytes, fibroblasts

What is the purpose of granuloma formation?

to contain irritants/microorganisms and focus the immune response

What causes immune-type granulomatous inflammation?

microorganisms that survive in macrophages, e.g. TB or leprosy

What cytokines are involved in immune-type granulomas?

interferon-gamma (activates macrophages) and TNF (regulates lesion activity)

What are key features of TB granulomas?

central caseous necrosis, epithelioid cells, Langhans giant cells, lymphocytes, peripheral fibrosis

What is the role of tumour necrosis factor (TNF) in granuloma formation?

essential for granuloma formation and bacterial control; overproduction may be harmful

What happened to mice treated with anti-TNF antibodies during BCG infection?

they failed to form granulomas in liver, lungs, or other organs

What is mixed-type chronic inflammation?

inflammation with both neutrophils and lymphocytes/macrophages over time

Give an example of mixed-type chronic inflammation.

rheumatoid arthritis

Why is inflammation considered beneficial?

clears pathogens, activates adaptive immunity, and starts healing

What are the harmful effects of inflammation?

causes tissue damage, chronic inflammation, and systemic diseases (e.g. atherosclerosis, cancer)

What is fibrinogen and what is its role in inflammation?

liver-made glycoprotein that forms fibrin in clotting and part of inflammatory exudate.

What is fibrosis?

formation of fibrous connective tissue (scar) during healing

What are Toll-like receptors (TLRs)?

receptors that recognise microbial or damaged host signals to trigger inflammation

What is regeneration?

replacement of injured tissue by parenchymal cells of the same type

What is repair?

replacement of injured tissue by fibrous tissue (scarring)

What is healing?

tissue response to injury involving regeneration or repair (or a combination of both)

What is required for regeneration to occur?

intact tissue scaffold and cells with high proliferative capacity or stem cells

Give examples of regeneration in mammals.

liver after partial hepatectomy, skin and GI epithelia, haematopoietic cells

What type of tissue is involved in repair by fibrosis?

granulation tissue

When does macrophage debris digestion begin?

within 24-48 hours after injury

What happens around 48 hours post-injury in tissue repair?

fibroblasts proliferate and new vessels grow in

What is the main component of fibrous tissue produced by fibroblasts?

collagen

What kind of healing occurs in superficial epidermal wounds?

regeneration only

What kind of healing occurs in dermis?

regeneration + scar formation

What is the most important mechanism of cell proliferation during healing?

recruitment of quiescent (non-dividing) cells into the cell cycle

What are the 3 categories of proliferative capacity?

labile (e.g., gut epithelium), stable (e.g., hepatocytes), and permanent (e.g., neurons)

How quickly is epithelium of the small intestine replaced?

every 3-5 days

How long does skin cell turnover take on average?

every 3-4 weeks

Which cells are involved in healing?

vascular cells (endothelial, circulating), connective tissue cells, ECM elements

What are three important cytokines in healing?

TNF (pro-inflammatory), TGF-β (modulates healing), PDGF (growth factor).

What is the sequence of cell arrival during wound healing?

platelets → neutrophils → monocytes + lymphocytes → basophils + eosinophils → mast cells

What is PDGF?

platelet-derived growth factor; stimulates cell proliferation

What is TGF-β?

a cytokine and growth factor that regulates inflammation and fibrosis

What are the key stages of wound healing?

Haemostasis → Inflammation → Proliferation → Granulation → Scar → Remodelling → Contraction → Maturation

What is healing by first intention?

Healing of clean, sutured wounds with minimal tissue loss and no infection.

What is healing by second intention?

Healing of open wounds with tissue loss, devitalised margins, or infection.

When does regeneration begin in first intention healing?

around day 3

When does early scarring appear?

7-10 days

When can scar maturation take place?

Over 1 month to 2 years

What is the wound coagulum?

a fibrin meshwork containing clot and blood components; acts as a scaffold for cell migration

Why is fibrin meshwork essential in wound healing?

mammalian cells cannot swim—need physical substrate to migrate into wound

Phases of Healing by Second Intention. Phase 1: Haemostasis. What are the first responses during haemostasis?

vasoconstriction of arterioles and platelet plug formation

[Phase 1: Haemostasis.] What mediators do platelets release?

PDGF, TGF-β, IGF-1, EGF, serotonin, vWF

Phases of Healing by Second Intention. Phase 2: Inflammation. What is the priority during inflammation phase?

eliminate pathogens and debris ("worst-case scenario" assumption)

[Phase 2: Inflammation] What do neutrophils do in healing?

kill bacteria and secrete inflammatory cytokines (6-48 hrs)

[Phase 2: Inflammation] What do monocytes/macrophages do?

arrive at 48-72 hrs, become macrophages, initiate proliferation

Phases of Healing by Second Intention. Phase 3: Proliferation. When does proliferation start?

Day 2-3 after wounding

[Phase 3: Proliferation] What are the key processes in the proliferative phase?

angiogenesis, fibroplasia, and epithelialisation.

[Phase 3: Proliferation] What drives angiogenesis?

growth factors from macrophages (e.g., FGF, TGF-α, TNF), hypoxia, fibronectin, hyaluronic acid

[Phase 3: Proliferation] What is the role of fibroblasts?

migrate on fibrin scaffold, stimulated by growth factors, produce collagen

[Phase 3: Proliferation] How does epithelialisation occur?

basal cells flatten, dedifferentiate, migrate via integrins, and divide to re-form mature epithelium

[Phase 3: Proliferation] What delays epithelialisation?

infection, necrosis, protein-rich exudate; clean moist wound facilitates it

Phases of Healing by Second Intention. Phase 4: Remodelling. What happens in the remodelling phase?

myofibroblast-driven wound contraction, collagen remodelling, and scar maturation

[Phase 4: Remodelling] What controls collagen synthesis/degradation?

metalloproteinases from macrophages, fibroblasts, etc.

[Phase 4: Remodelling] What is final tensile strength of scar tissue?

~70% of normal skin.

What is the relationship between healing time and wound size?

logarithmic — larger wounds take disproportionately longer to heal

What systemic factors affect healing?

nutrition, vitamin deficiency, age, immune status, comorbidities

What local factors affect healing?

necrosis, infection, blood supply, apposition of wound edges, foreign bodies, wound mobility

What are major complications of healing?

Infection, Keloids (hypertrophic scarring), Poor blood supply, Diabetes (microvascular/metabolic issues), Presence of foreign bodies, Oxygen-deprived leukocytes = poor bacterial killing