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
