Respiratory Disease (2) Smooth Muscle, Inflammation, & Remodelling in the respiratory system Flashcards
- Lung airway architecture - Airway resistance - Airway smooth muscle location, morphology and functions - Factors affecting bronchomotor tone - Mechanisms of airway contraction and relaxation - Key inflammatory and remodelling mediators - Comparative remodelling in asthma, COPD and Idiopathic Pulmonary fibrosis (IPF)
Lung airway architecture
- Number of airways doubles at each airway branch
- 23 generations
- Terminal bronchiole
>important area, particularly in COPD
>it’s where gas slows down
>gas moves by diffusion, particles start to fall out of the bulk flow and impact on the surface of the terminal bronchioles
Airway resistance (1)
50% resides in nose, pharynx, larynx
>e.g. airway resistance increases when you have the common cold because of swelling
80% of remaining resistance is in trachea and bronchi of more than 2mm diameter - cartilaginous airways
>cartilage protects against collapse’
>can still narrow e.g. during cough
>you can afford to have some airways collapse and still survive because we have 2^9 amt
Airway resistance (2)
Small bronchi/bronchioles
>generations 7-14
>Cross-sectional area is still relatively small compared to distal regions, so still contributes to resistance
>critically, this resistance is variable
(Neuronal innervation of the airway muscle in the smaller airways, sensitive to mediators released like histamine and leukotriene, causing shortening of smooth muscle)
> > little to no supporting cartilage
presence of innervated smooth muscle
influence of vasomotor tone
influence of disease
Airway resistance (3)
Beyond generation 16
>rapid increase in airway numbers in subsequent generations
>offsets decrease in diameter (and potential increased resistance) of individual members
> > disease can progress for quite some time before a patient presents with a decrease in FEV1 or total lung volume
> > Beyond gen 16
silent zone
airway resistance not detected by standard lung function tests
Airway smooth muscle - Location
Arranged circumfrentially around the airways
>muscles shorten, lumen narrows, increase resistance, reduced FEV1
Extensive network of nerves (green)
>parasympathetic nerves (flight or fight)
>in humans, airway smooth muscle is Nor served by sympathetic nervous innervation
>tends to have a donminaince of parasympathetic constrictor influence
Different muscle types
ASM
>don’t see same level of rigid organisation unlike skeletal or cardiac muscle
>much more plasticity
>reason for the plasticity is that it has to adjust itself to the different roles in the organs that it functions in
> not just lungs
e.g. bladder as well, needs to expand and shorten up to 10x original size
plasticity is required
ASM is plastic as well
Airway Smooth Muscle - Function
Regulates airway calibre by active force development
>Developing force against a load
>causes movement
>Movement of airway wall
>ASM is oxotonic = can shorten and develop force
Function affected by many mediators, neurotransmitters and drugs
>mostly via receptors expressed on cell surface
Most interest centres on function in disease (e.g. asthma)
>related to more of the physiology than pathology of asthma
Neural mechanisms
Contractile tone depends on
>Parasympathetic vagal efferent (ACh, M3R)
>Excitatory NANC efferent (SP, NK)
(Non-adrenergic non-cholinergic)
> > Inhibitory NANC efferents
(Vasoactive intestinal peptide, Nitric Oxide)
Excitatory NANC efferents
(Substance P, Neurokinin)
Relaxation depends on
>Sympathetic efferents to adrenal medulla, increasing circulating adrenaline, acts on B2-ARs
(A1-ARs mediate modest constriction)
>Sympathetic efferents to parasympathetic ganglia
>Inhibitory NANC efferents (VIP, NO)
(Only neuronally-mediated bronchodilator pathway in human)
Mediators and ASM - Balance
Think about airway muscle tone as a balance between excitatory and inhibitory NANC efferents
>functional antagonism
Contraction (constrictors)
>ACh, HA, LTC4, LTD4
Relaxation (dilators)
>PGE2 (made in large amts in epithelium and muscle cells itself, act as hand break on tendency of the muscle to narrow)
>Adrenaline
>PGI2
The contractile mechanism (1)
>increase in intracellular calcium >Ca2+ binding to calmodulin >Activation of myosin light chain kinase >Myosin light chain phosphorylation (Actomyosin ATPase activated, allows cross bridge Cycling to happen)
> cross bridges between actin and myosin break and reform
sliding past each other
(In a polar way, only slide in 1 direction in a criss-cross pattern)
overall cell shortening (and force development)
The contractile mechanism (2)
Regulation of intracelllular calcium
> Mechanisms increasing free [Calcium}
>voltage operated calcium channels
(less important in ASM)
>Phospholipase C/inositol triphosphate (IP3)
(More important in ASM, modulated by ATP dependent pumps, plasma Ca2+ ATPase, release from intracellular stores)
>Mechanisms decreasing free [calcium] >>plasma Ca2+ ATPase (Extrusion across plasma membrane) >>Sarcoplasmic reticulum Ca2+ ATPase (SERCA) >>uptake into internal stores
Regulation of smooth muscle tone
Activation by contractile mediators of GPCRs
>Ca2+ oscillations
»Activate Myosin Light Chain Kinase
»Convert MLC to MLC-P (active)
»>Contraction via actomyosin crossbridge formation
Activation by inhibitory mediators of GPCRs >Protein Kinase A (PKA) >Activate Myosin Light Chain Phosphatase >>Convert MLC-P to MLC (inactive) >>>Stops crossbridge cycling
PKC and Rho Kinase
>Inhibit MLC-Phosphatase
»Oppose actions of PKA (i.e. pro-contractile)
Pathogenesis of Asthma:
Inflammation, remodelling, hyperresponsiveness
> Increased smooth muscle contraction
Excessive mucus
Inflammation and swelling
Key inflammatory mediators
> IL-1, 6, 8, 4, 13
> TNFalpha
(induce overproduction of mediators, highly proinflammatory, can be pathological in overproduction, induces COX-2)
> Complement and Kinins
(Amplification cascades)
> GM-CSF, G-CSF, M-CSF
(colony stimulating factors: leukocyte survival and priming)
Key induced inflammatory genes
> COX products e.g. prostaglandins
(e.g. PGE2 - pain and dilator of ASM)
> Proteases e.g. MMPS
(Tissue destruction)
Key growth factors
> VEGF
(particularly important for remodelling taking place in tumours to supply more blood to tissue (angiogenesis))
> PDGF and CTGF
(Expanding number of fibroblasts, cause epithelial mesenchymal transition (EMT) where epithelial cells turn into fibroblasts and contribute to scar tissue)
(Tissue scarring)
> TGFbeta
(EMT and scarring)
Asthmatic airways
> Goblet cell metaplasia
(increased mucus production - cause obstruction in small airway)
> Subepithelial collagen thickening
(repair response causes collagen deposition)
> Infiltration of inflammatory cells
Increased mucosal vascularity
(VEGF released from mast cells during allergic inflammation during asthma and other conditions, trigger angiogenesis)
> Increased smooth muscle volume
In Fatal Asthma
Cartilage in asthmatics is smaller (not sure why)
> Mucus glands in the fatal asthma also producing mucus, not just goblet cells
Also has more smooth muscle, greater contraction
Airway smooth muscle - (dys)functions
- ASM does not just constrict and relax
- Contributes to wall volume in airway remodelling and inflammation as well as contraction
>proliferation
>migration
>secretion of cytokines
>secretion of extracellular matrix proteins
> > > Muscle cells are not just structural, they are the target for anti-inflammatory actions by drugs such as steroids
Muscle cells don’t produce a lot of cytokine (IL-8) but we have a lot of muscle cells, combined, produce more IL-8 than T cells
Airway smooth muscle - functions
- ASM does not just constrict and relax
- Contributes to wall volume in airway remodelling and inflammation as well as contraction through secretion of
>growth factors (e.g. PDGF, FGF, TGFb, VEGF)
>Cytokines (e.g. IL-5, GM-CSF)
>Chemokines (e.g. RANTES, eotaxin, CXCL8)
>Lipid mediators (e.g. PGE2)
>Extracellular matrix components (e..g collagen)
> Potential for autocrine effects
Measuring Airway Responsiveness
> Test FEV1
> Increasing severity of airway hyperresponsiveness = greater % fall in FEV1
Pathology of COPD
2 Prominent features of COPD
1) Airway wall is thickened by fibrosis and inflammation
>COPD mainly a disease of small airways and their perinchyma
»>Chronic obstructive bronchitis
2) Alveoli walls damaged, loss of attachments
»>Emphysema
Remodelling in COPD is different
>Occurs in very peripheral airways
>Likely triggered by particulate matter depositing in terminal bronchioles and leading to subsequent loss of tissue, leading to failure of gas exchange (potentially fatal)
Air trapping in COPD (Inspiration)
> Normal
>alveolar attachments in the small airway pulling the airway tubes open during inspiration
> COPD >>inflammation >>thickened airway >>Loss of alveolar attachments >>Loss of elasticity (emphysema)
Air trapping in COPD (Expiration)
Normal
>Perinchyma starts to relax, causing narrowing of the airways
>not narrow enough to close in healthy people
> In COPD, because of loss of perinchymal tethers and those that remain are very loose
>tendency for small airways to close during expiration
>gas not exchanged
>not going to ventilate the alveoli served by those airways with new o2
>reduction in respiratory gas transfer
>decrease in respiratory function
How to treat COPD?
All you can do is to preserve the remaining function as best as possible by using bronchodilators to keep the small airways open
> Bronchodilators dont resolve the fibrosis
this aspect of COPD is treatment resistant
In COPD, PT cannot achieve full lung function with bronchodilator and inhaled steroids
>Vs asthma, can recover ~95% lung function
Idiopathic Pulmonary Fibrosis
- Happens in soft lung tissue
>Fibrosis is invasive
>involves fibroblasts invading air spaces
>Unlike COPD and asthma where fibrosis is limited to ASM
> Fatal interstitial lung disease (median survival 2.8 years)
> Scarring thickens and stiffens alveolar walls
>impaired oxygen transfer
>increased respiratory work
(restrictive disease, lungs need more energy to expand)
>Respiratory failure
> Annual incidence of
>8 per 100,000
>Mainly in 60+ yo
>progressive, relatively poor prognosis, cancer
Lung remodelling in IPF
Fibrotic lung
>collagen deposition
>Thickening of alveolar wall
IPF failed treatments
> Steroids had been standard of care, but when subjected to RCT, combination of Azathioprine and steroids was shown to worsen prognosis
> a lot of drugs showed promise in P2 clinical trials, but then failed in P3
IPF recent successful treatments : Pirfenidone
Pirfenidone
>inhibits TGF-b stimulated collagen production
>reduces fibrogenic and inflammatory mediators including TFG-b and IL-1b
IPF recent successful treatments: Nintedanib
Nintedanib
>Originally developed for lung cancer (multikinase inhibitor)
> Just decelerates the loss of lung functions
There is scope for better treatments
(we want to have a curative drug)
> Very severe adverse effects cause 50% of patients to stop taking it
