6 - lung fibrosis mechanisms Flashcards
variety of cells lining the respiratory airways
ciliated cells goblet cells basal cells alveolar T1 alveolar T2
role of alveolar T1 cells
squamous pneumocytes that make up 90% of lung surface area
forms structure of alveolar walls
flat and thin for gas exchange
role of alveolar T2 cells
secrete lipoprotein called surfactant to reduce surface tension in the alveoli
how much air do we breathe in daily
10, 000 L
factors that may expose the lungs to predispositions for disease
smoking type of workplace (carpenter) oxygen (can produce ROS) genetics viruses breathed in in air
how many viruses do we breathe in a day
500 million
what does IPF stand for
idiopathic pulmonary fibrosis
what is idiopathic pulmonary fibrosis
end stage of a heterogenous group of interstitial lung diseases
accounts for >5000 deaths a year
overall fibrosis aspect of IPF
caused by scar tissue –> collagen (ECM) depositing and building up
which prevents breathing over time
symptoms of IPF
dyspnoea (shortness of breath) coughing fever weight loss clubbing
what is clubbing
thickening of finger tips
dyspnoea
shortness of breath
what does a physical examination look for to diagnose IPF
sounds in the lungs e.g. crackling
overall/general mechanism of IPF development
fibroproliferative response to lung injury
order of steps underlying IPF development from initial injury to organ failure
- epithelial cell injury
- activation of coagulation cascade –> inflammation
- establishment of chemokine networks, leukocyte infiltrations and activation
- fibroblast recruitment, proliferation and differentiation
- loss of organ function
order of events during an active breathing cycle
- diaphragm contracts (flattens, increases thoracic volume)
- external intercostal muscles contract (rip cag moves up and out)
- -> air is sucked in - diaphragm relaxes (dome-shaped)
- internal intercostal muscles contract
what might cause bronchiolar tissue damage
trauma infection physical/chemical agents tissue necrosis foreign bodies (asbestos) immune reactions (hypersensitvity)
how is bronchiolar tissue repaired
by regeneration of damaged tissue by paranchymal cells of the same type
or by replacement by connective tissue (scar formation)
4 steps for tissue repair
- haemostasis
- inflammation
- proliferation
- remodelling
haemostasis and inflammation steps of tissue repair
- haemostasis
- -> blood vessels constrict to keep blood within damaged vessel
- -> platelets stick together, fibrin activated to reinforce plug (clotting cascade)
- -> growth factors and cytokines recruited - inflammation
- -> immune cell recruitment, 1st macrophages then neutrophils
- -> wound debridement (removal of damaged tissue by phagocytes)
which cytokines are recruited during tissue repair
TGF-a
PDGF
VEGF
PDGF
platelet derived growth factor
- regulates cell growth and division.
VEGF
vascular endothelial growth factor
- stimulates formation of blood vessels
proliferation and maturation/remodelling steps for tissue repair
step 3: proliferation
- re-epithelisation –> proliferation of epithelial cells
- angiogenesis
- fibroplasia –> myobibroblasts activated by PAMPs to make collagen
- ECM deposition to make tissue
4: maturation/remodelling
- scar formation
- collagen remodelled from TIII to TII
- collagen realigned along tension lines
- apoptosis removes unneeded cells
aberrant wound healing
not normal
scar formation
cell types important in aberrant wound healing
epithelial cells macrophages fibroblasts myofibroblasts endothelial cells
role of platelets in wound healing
recruit inflammatory cells and growth factors
form fibrin plug
extracellular matrix function
provides structural support
regulates movement and growth of cells
components of extracellular matrix
collagen –> provides tensile strength
elastin –> provides elastic strength and recoil
proteoglycans –> regulate structure and permeability
adhesive glycoproteins
integrins –> cell surface receptor that mediate cell adhesion
importance proper regrowth of ECM
if pattern of ECM remains then restitution of normal tissue structure can occur
keloid scar
thickened/raised scar tissue
viruses implicated in IPF
herpes simplex virus
hep C
types of herpes simplex virus
human herpes virus 7 and 8
cytomegalovirus
epstein-barr virus (EBV)
key physical features of gammaherpesvirus
dsDNA genome
envelope protein e.g. integrins
latency in cell bodies of neurons
immune response to viral infection
Th1 cells:
- activate macrophages –> use MHC I to help cytotoxic T cells using perforins and granzymes
Th2 cells:
- make cytokines to help B cells produce antibodies
problem caused by fibroblasts
tissue is less expandable
problem with herpes virus
reprograms lung epithelial cells to produce fibrotic factors
makes lung more susceptible
mechanism of viral infection
virus enters by endocytosis and replicates
host cell presents viral peptides via MHC I
infected cells release cytokines into blood
viruses kill infected cells —> DC cells recruited
DCs migrate viral peptides to lymphatics and present to naive T cells
CD4 activated via MHC II:
- Th1 –> activates CD8 T cells
- Th2 –> activates B cells to produces antibodies
NK cells –> monitor amount of MHC I on cells
secondary condition usually developed after IPF
interstitial pneumonia
effect of viral infections on IPF
initiate the disease
exacerbate the disease progression
cause rapid decline
