RESPIRATORY SYSTEM
Lung diseases
VLA 1. 12. 2015
BLOOD FLOW VS. VELOCITY OF BLOOD
FLOW
 Ohm´s law:
 BF=BP/R, BP=blood pressure, BF=blood flow, R=
resistance of blood vessels
 BF=BP/R
 Velocity of blood flow (v):
 Π x r2 . v = (constant !!!!!)
 Blood vessels „like“ their natural (physiological)
diameter and they have tendency to do it by
remodelling of blood flow
BLOOD FLOW ENERGY
 Because flowing blood has mass and velocity it has
kinetic energy (KE). This KE is proportionate to the
mean velocity squared (V2; from KE = ½ mV2).
Furthermore, as the blood flows inside a vessel,
pressure is exerted laterally against the walls of the
vessel; this pressure represents the potential or pressure
energy (PE). The total energy (E) of the blood flowing
within the vessel, therefore, is the sum of the kinetic
and potential energies (assuming no gravitational
effects) as shown below.
 E = KE + PE (where KE ∝ V2) Therefore, E ∝ V2 + PE
BLOOD FLOW AS HEMODYNAMIC PRIORITY!!!
 Blood flow is driven by the difference in total energy between two
points. Although pressure is normally considered as the driving
force for blood flow, in reality it is the total energy that drives flow
between two points (e.g., longitudinally along a blood vessel or
across a heart valve). Throughout most of the cardiovascular
system, KE is relatively low, so for practical purposes, it is stated
that the pressure energy (PE) difference drives flow. When KE is
high, however, adding KE to the PE significantly increases the total
energy, E. To illustrate this, consider the flow across the aortic
valve during cardiac ejection. Late during ejection, the
intraventricular pressure (PE) falls slightly below the aortic pressure
(PE), nevertheless, flow continues to be ejected into the aorta. The
reason for this is that the KE of the blood as it moves across the
valve at a very high velocity ensures that the total energy (E) in
the blood crossing the valve is higher than the total energy of the
blood more distal in the aorta.
ENERGY OF BLOOD FLOW AND BERNOULLI'S PRINCIPLE
 Kinetic energy and pressure energy can be interconverted so that total energy
remains unchanged. This is the basis of Bernoulli's Principle. This principle can be
illustrated by a blood vessel that is suddenly narrowed then returned to its normal
diameter. In the narrowed region (stenosis), the velocity increases as the diameter
decreases. Quantitatively, v ∝ 1/D2 because flow (BF) is the product of mean
velocity (v) and vessel cross-sectional area (S) (BF = v ∙ D), and S is directly related
to diameter (D) (or radius, r) squared (from S = π ∙ r2). If the diameter is reduced by
one-half in the region of the stenosis, the velocity increases 4-fold. Because KE ∝ v2,
the KE increases 16-fold. Assuming that the total energy is conserved within the
stenosis (E actually decreases because of resistance), then the 16-fold increase in
KE must result in a proportionate decrease in PE. Once past the narrowed
segment, KE will revert back to its pre-stenosis value because the post-stenosis
diameter is the same as the pre-stenosis diameter and flow is conserved. Because
of the resistance of the stenosis, and the likelihood of turbulence, the post-stenosis
PE and E will both fall.
 To summarize this concept, blood flowing at higher velocities has a higher ratio of
kinetic energy to potential (pressure) energy.
BLOOD VESSEL WALL ENERGY AND STENOSIS
LUNG VESSELS REMODELLING
 Cooperation of actions of HIF-1 AND
MiRNAs???
ASTMA
 3 pathogenetic characteristics:
 Inflammation of airways with the wall
thicking and increased permeability of
capillaries
 Hypersecretion of mucus
 Contraction of smooth muscle cells in
bronchi
PATHOGENESIS OF ASTHMA
 Bronchiols are narrowing.
 Atelectasis is developing (microscopic, segmental
and/or lobar) as a result of complete airways
obstruction by mucous plug and/or as a result of
edema of airways.
 Decrease of ventilation/ perfusion proportion is
leading to decreased of saturation of Hb by O2.
Th2 effector cells and asthma pathogenesis. Th2 cells have a central role in
orchestrating the allergen-induced inflammatory response. Th2 derived IL-4
and IL-13 stimulate B cells to synthesise IgE whilst IL-5 is necessary for
eosinophilic inflammation. Th2 cytokines are also involved in mast cell
proliferation and allergic airway remodelling. Key: Eϕ, eosinophil; EpC,
epithelial cell; EMTU, epithelial to mesenchymal tropic unit; ASM, airway
smooth muscle; AHR, airway hyperreactivity.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
Gene environment interactions in asthma. Asthma is an inflammatory disorder of
profound heterogeneity with strong genetic and environmental components. Local
airway susceptibility factors together with allergen-specific immune polarisation
interact both in the induction and subsequent expression of the disease
phenotype. Key: EpC, epithelial cell.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
TO THE PREVIOUS PICTURE:
 Immune cells and the inflammatory cascade in asthma. Initial
exposure(s) to allergen leads to the activation of allergen-specific
Th2 cells and IgE synthesis (sensitisation). Subsequent allergen
exposures cause inflammatory-cell recruitment, activation and
mediator release. IgE-sensitised mast cells expressing the high
affinity IgE receptor (FcRI) degranulate, releasing both pre-formed
and newly synthesized mediators including histamine, leukotrienes
and cytokines, which promote vascular permeability, smooth
muscle contraction and mucus production. Chemokines released
by inflammatory and resident cells direct recruitment of
inflammatory cells characterised eosinophils and Th2 cells.
Eosinophils release an array of pro-inflammatory mediators,
including leukotrienes and basic proteins and mediators such as,
IL-5. Key: APC, antigen-presenting cell; ASM, airway smooth
muscle; EpC, epithelial cell; GM-CSF, granulocyte monocyte
colony stimulating factor; MHC, major histocompatibility; TCR, T
cell receptor; TSLP, thymic stromal lymphopoietin.
Etiopathogenesis of asthma
Mechanisms of acute and chronic inflammation in asthma and
mechanisms of remodelling
Leukotriens in asthma
Relations between pathophysiological mechanisms and clinical state
Clinical relations of airway remodelling in asthma (RBM- basal
membrane, ECM - extracellular matrix)
Airway remodelling in asthma. Activation of airway epithelium by aeroallergens
and pollutants leads to downstream effects including inflammation, dysregulated
repair, activated EMTU and tissue remodelling. Key: ASM, airway smooth
muscle; ECM, extracellular matrix; EMTU, epithelial to mesenchymal trophic
unit; Epc, EpC, epithelial cell; TGF-β, transforming growth factor-β.
Mutat Res. 2010 August 7; 690(1-2): 24–39.
doi: 10.1016/j.mrfmmm.2009.09.005
TYPES OF ASTHMA
 Extrinsic – clear external cause
 Intrinsic (cryptogenic) – it is nit possible to
identify cause.
 Extrinsic asthma in atopic persons with positive
skin prick tests for inhalation allergens (90% of
children with persitent asthma, only 50% of
adulat patients).
 Intrinsic asthma starts in middle age („late
onset“).
ALLERGY AND ATOPY
 Atopy:
 Familial occurrence
 Characteristic reaction to environmental allergens
prostředí
 Circulationg antibodies
 IgE antibodies in 30-40% of population
 Correlation between IgE levels and hyperreactivity of
airways
 Genetic factors and environmental factors influence
IgE levels.
 Candidate genes for IL-3, IL-4, IL-5, IL-9, IL-13 a GM-CSF –
cluster on 5q31-33.
 Hygienic theory of asthma dvelopment
ATOPIC DISEASES
 Atopic rhinitis
 Atopic dermatitis
 Atopic astma
 Combinations (4)
ATOPIC DERMATITIS
• complex interaction between defects in skin barrier function,
immune abnormalities, and environmental and infectious agents.
• Skin barrier abnormalities appear to be associated with mutations
within the filaggrin gene, which encodes a structural protein
essential for skin barrier formation. The skin of individuals with AD has
also been shown to be deficient in ceramides (lipid molecules) as
well as antimicrobial peptides such as cathelicidins, which
represent the first-line of defense against many infectious agents.
These skin barrier abnormalities lead to transepidermal water loss
(passage of water from inside the body through the epidermal
layer of the skin to the surrounding atmosphere) and increased
penetration of allergens and microbes into the skin. The infectious
agent most often involved in AD is Staphylococcus aureus (S.
aureus), which colonizes in approximately 90% of AD patients.
ATOPIC DERMATITIS
• Defective innate immune responses also appear to
contribute to increased bacterial and viral infections in
patients with AD. This interplay of factors leads to T-cell
responses in the skin (initially a predominantly T helper-2
[Th2] response and later a predominantly Th1 response)
with resultant release of chemokines and
proinflammatory cytokines (e.g., interleukin [IL]-4, 5 and
tumour necrosis factor) that promote immunoglobulin E
(IgE) production and systemic inflammatory responses,
leading to pruritic inflammation of the skin.
Probiotics demonstrating a beneficial effect in clinical studies of eczema.
Type of clinical study Probiotic
Treatment Lactobacillus rhamnosus GG
Lactobacillus rhamnosus HN001
Lactobacillus sakei KCTC
Lactobacillus acidophilus La-5
Lactobacillus acidophilus*
Lactobacillus salivarius LS01
Lactobacillus fermentum VR1
Bifidobacterium lactis Bb12
Bifidobacterium lactis UABLA-12**
Bifidobacterium bifidum
Prevention Lactobacillus rhamnosus GG
Lactobacillus rhamnosus LC705
Lactobacillus paracasei F19
Bifidobacterium breve Bb99
Propionibacterium freudenreichii***
Antigens causing allergic rhinitis and asthma
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
 Symptoms
 Chronic (long-lasting) cough
 A cough that produces mucus
 An increase in respiratory infections (such
as flu and colds)
 Shortness of breath, especially during
physical activity
 A tight feeling in the chest
 Wheezing
Chronic obstructive pulmonary diseases: diagnostic criteria
FEV1 VALUES
 FEV1 greater 80% of predicted= normal
 FEV1 60% to 79% of predicted = Mild
obstruction
 FEV1 40% to 59% of predicted =
Moderate obstruction
 FEV1 less than 40% of predicted = Severe
obstruction
FEV1- expiratory volume exhaled in the first second of forsed
expiration.
FVC - forced expiratory vital capacity
Volume- pressure
loops in a/ healthy
persons, b/
patients woth
COPD
Epidemiology of COPD
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
 Two main forms
 Chronic bronchitis is an ongoing inflammation of
the airways.
 Pathophysiology: chronic irritation of airways by
smoking (including second-hand smoke), air
pollution, chemical fumes, gases, vapors, or mists,
dust) leading to damage of mucociliar escalator.
 Pathology: hyperplasia of mucus glands
 Pneumology: bronchial irritation, increased
secretions and a productive cough lasting at
least three months, two years in a row.
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
 Emphysema
 Is the permanent widening of the
structure of pulmonary gas
exchange that is distal to the
terminal bronchioles,
accompanied by destruction of
alveolar walls.
 Inhalation of cigarette smoke or
pollutants stimulate cells in the
lung macrophages and
neutrophils to produce elastase
and collagenases. These enzymes
are able to damage the fibers of
elastin and collagen, which form
the framework of the alveoli and
acini in order not to collapse.
EMPHYSEMA: TYPES
 Centriacinar Emphysema: The abnormal permanent enlargement
of air spaces distal to the terminal bronchioles, accompanied by
the destruction of the walls and without obvious fibrosis. It begins in
the respiratory bronchioles and spreads peripherally.
 Panacinar Emphysema: Panacinary (or panlobular) emphysema is
related to the destruction of alveoli, because of an inflammation
or deficiency of alpha 1-antitrypsin.
 Paraseptal Emphysema: Paraseptal emphysema is a type of
emphysema( as abnormal permanent enlargement of air spaces
distal to the terminal bronchioles) which involves the alveolar
ducts and sacs at the lung periphery.
Pathological signs of chronic bronchitis and emphysema
CHRONIC OBSTRUCTIVE PULMONARY
DISEASE (COPD)
 Emphysema
 Smoking also inhibit the action
of alpha-1-antitrypsin, an
enzyme that protects elastin
fibers against proteases.
In the lung there is a balance
between destroying enzyme
(protease) and protective
enzymes (alpha-1-antitrypsin).
Due to destruction of fibers of
the lung elastin & collagen
elastic recoil loss will occur.
 Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
 Pathophysiology of the small airways in chronic obstructive pulmonary
disease.
 Baraldo S, Turato G, Saetta M.

INFLAMMATION
 One of the earliest histological abnormalities that
can be detected in cigarette smokers is the
presence of an inflammatory reaction in the
peripheral airways.
 This inflammatory reaction consisted
predominantly of the infiltration of mononuclear
cells in the airway wall and clusters of
macrophages into the airway lumen. It is
conceivable that this early inflammatory infiltrate
which has been observed in smokers’ airways,
probably represents a nonspecific response to
the insult from cigarette smoke.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
SMOKING EFFECTS
 Each puff of a cigarette contains more than 2,000 xenobiotic compounds and 1015
free radicals, which increases the oxidant burden in the lung. This burden,
associated with the decrease in endogenous antioxidant defenses which occurs
with aging, will result in reduced protection against oxidative stress and increased
damage to lung epithelial cells and connective tissue proteins. The products
released during this process may possibly activate the immune system. The tissue
damage that is associated with the infection that will alert the immune system to
respond, rather than the microbial antigens themselves. Tissue damage with the
resulting cellular stress will cause the release of endogenous damage-associated
molecular pattern (DAMP) molecules, such as alarmins, which alert the host to
danger by triggering immune responses and activating repair mechanisms through
their interaction with pattern recognition receptors. Among these danger signals,
high-mobility group box 1 (HMGB1) and the receptor for advanced glycation end
products (RAGE) are upregulated in the lungs of smokers and have the potential
to activate an immune response by interacting with Toll-like receptors.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
INCREASE IN SMOOTH MUSCLE
 Increase in smooth muscle correlates with the degree of airflow limitation;
the greater the amount of smooth muscle, the lower the FEV1 and the
more severe the airway obstruction. So, increased smooth-muscle mass is
an important component of airway wall thickening, which can be due to
several mechanisms including hypertrophy and hyperplasia, possibly due
to the activity of inflammatory mediators, cytokines and growth factors.
 The airways of smokers can react to nonspecific stimuli by constricting,
and this results in increased resistance and decreased FEV1.
 The major functional consequence of the increase in smooth-muscle
mass is that, in airways with thickened walls, the same degree of smoothmuscle
shortening may cause considerably greater lumenal narrowing
than in the normal airways.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
PERIPHERAL WALL FIBROSIS
 Another important component of remodeling is
fibrosis of the airway wall. The cigarette smoke
induces oxidative stress in human lung fibroblasts,
which may then initiate a process of repair and
collagen deposition. Furthermore, the interaction
between fibroblasts and inflammatory cells may
also play a role in fibrotic remodeling. Along with
this is the observation that mast cells, which have
important profibrotic and prorepair properties, are
increased in the airways of smokers with COPD,
particularly in those with centrilobular emphysema.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
PERIPHERAL WALL FIBROSIS
 Fibrosis, along with an increased airway
smooth muscle and other inflammatory
components, ought to increase the airway
wall thickness and change the mechanical
characteristics of the airway to decrease
the luminal diameter.
 The total thickness of the airway wall was
the parameter found to correlate best with
airflow limitation in smokers across the
different stages of severity.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
THICKNESS OF THE AIRWAY WALL
 Inflammation, fibrosis and smooth-muscle hypertrophy, by increasing the
thickness of the airway wall, may facilitate uncoupling between airways
and parenchyma, therefore promoting airway closure. In addition,
airway wall inflammation could contribute to the destruction of alveolar
attachments (i.e. the alveolar walls directly attached to the airway wall),
further reducing the tethering effect of lung parenchyma, thus allowing
the airway wall to deform and narrow. This hypothesis is supported by the
observation that, in smokers, the destruction of alveolar attachments is
correlated with the degree of inflammation in the peripheral airways. This
finding suggests a pathogenetic role for airway inflammation in inducing
the destruction of alveolar attachments. It is possible that mediators
released by inflammatory cells may weaken the alveolar tissue and
facilitate its rupture, particularly at the point where the attachments join
the airway wall and the mechanical stress is maximal.
Respiration. 2012;84(2):89-97. doi: 10.1159/000341382. Epub 2012 Aug 6.
Pathophysiology of the small airways in chronic obstructive pulmonary disease.
Baraldo S, Turato G, Saetta M.
Potential pathogenetic mechanisms involved in COPD Exogenous inhaled
noxious stimuli such as tobacco smoke, noxious gases or indoor air pollution and
genetic factors are proposed to be the major factors related to the pathogenesis of
COPD. These factors may influence protease activity and may also lead to an
imbalance between pro-inflammatory and anti-inflammatory mediators.
Groneberg and Chung Respiratory Research 2004 5:18 doi:10.1186/1465-9921-5-
18
TYPES OF RESPIRATORY INSUFFICIENCY
Type A is „pink puffer“. Symtoms:
1. Severe exspiratory dyspnoe (PaO2 and PaCO2 in
blood near to normal values
2. Cor pulmonale -no
3. Higher proportion of emphysema Partial respiratory
insufficience
Type B is „blue bloater“. Symtoms:
1. Small or none dyspnoe
2. Arterial hypoxia and hypercapnia
3. Secondary polycytemia
4. Cor pulmonale.
5. Higher proportion of chronic bronchitis
6. Global respiratory insufficiency (no pure O2!!!)
Interaction of cells and cytokines in the airway inflammation
of chronic obstructive pulmonary disease.
is an important risk factor for disease progression and
exacerbation risk. Relative pulmonary artery enlargement on
computed tomography scan, defined by a pulmonary artery to
aortic (PA:A) ratio >1, has been evaluated as a marker of
pulmonary vascular disease.
In healthy patients a PA:A ratio >0.9 is considered to be abnormal.
The PA:A ratio has been compared with invasive hemodynamic
parameters, primarily mean pulmonary artery pressure in various
disease conditions and is more strongly correlated with mean
pulmonary artery pressure in obstructive as compared with
interstitial lung disease.
In patients without known cardiac or pulmonary disease, the PA:A
ratio is predictive of mortality, while in COPD, an elevated PA:A
ratio is correlated with increased exacerbation risk, outperforming
other well established predictors of these events.
PULMONARY VASCULAR DISEASE
Factors influencing the state of pulmonary circulation
Thank you for your attention