Pathophysiology The 9th lecture

These processes are happening in .. They are interconnected, First we have the accumulation CC and
MM , accumulating of the lipids intra and extra cellular, especially cholesterol and this cholesterol is
especially bound aquapin.. , very important this combination. This accumulation of lipids in intra and
extra cellular in the vessel wall secondatet.. this will affect the endothelial cells, the endothelial cells
could be activated so we will have element of inflammation because endothelial cells being activated
will express adhesion molecules so will be interconnected with the macrophages and the neutrophils
and we will have another process the migration of the monocytes, becoming after that macrophages. So
monocyte migration from the circulation into the subendothelial spaces, so these monocytes if they are
migrating they are already started to be activated, so again we have elements of inflammation and we
will see if we have inflammation and endothelial cells are signaled so we have also Hemostasis so we
have all the time to turn back to those basics themes of inflammation and hemostasis in
morphopathology.
Other processes for atermatosis/aterogenesis . Endothelial cells lesions, injury without repairation, the
presence of membrane attack complexes and we will see that it will be an immunological involvement
in the aterogenesis.
Another process will be related to inflammation, the thrombi formation microthrombi, and this is
related to the endothelial injury, endothelial dysfunction, because the property which offer the balance
between procoagulant and anticoagulant activity of the endothelial cells will be disturbed so will be
favorized the thrombosis .
Another process, will be the proliferation of the smooth muscular cells in the arterial wall and occurs the
accumulation of the CT by collagen fibers and cuboidal tubules!, protocglycans, mucopolysaccharides,
for the accumulation of the cholesterol in the vascular wall in conditions of high LDL, because LDL is the
transporter of the cholesterol be high as the cholesterol.. , so the endothelial cells will containing these
cholesterols, but the the most important cells which are take the cholesterol from the circulation are
macrophages, and monocytes already migrated into the subendothelial spaces and these macrophages
take especially the modified particles by glycosylation, oxidation, peroxidation, acetylation,
subcellilation, myelinization, there are a lot of reactions modifying these particles, because these
reactions modify the lipid part with also the protein part of the alial..!, and we will take 2 processes for
instance the alial could be glycosylation, so glycosylation of the alial will occur in the hyperglycemia,
long term hyperglycemia, oxidation is done by some enzymes in some tissues for instance the leseloxidase.. , an enzyme contained in the extracellular fluid of tendons and aorta wall. The peroxidation is
done because of the production of the free oxygen radicals, these cells become activated, these
proinflammatory cells will produce and will deliver free oxygen radicals. So these modified lipids ,
modified ApoB , because not only the lipids, the cholesterol, the phospholipid, which are entering in the
composition of the LDL, but especially ApoB will be modified, and ApoB because contains lysine, lysine
oxidase will attack lysine, the peroxidation, attacks especially the lipids, the glycosylation will attack also
the proteins . so the oxidized LDL stimulate the production of prostaglandins and leukotriens, and these
modified LDL have a high electron negativity charge. All these features stimulated the uptaken of the

LDL by the macrophages through a cellular receptors specialezid for LDL and there is an important
feature for these receptors because the uptake of the modified LDL is not controlled, so as higher is the
amount of the LDL as much is the uptaken by the macrophages , so the macrophages could accumulate
lipids LDL although coming there is a possibility of metabolization, so they will become modified cells
these macrophages, in morphopathology there is a name for these cells, Foamy cells. There are some
control mechanisms for this uptaken of LDL by macrophages, but could be ineffective in LDL with high
concentration. So macrophages which had already taken the LDL they will leave the arterial wall and
they will reenter in circulation so they will arrive in the reticular endothelial system in the spleen and in
the lymph nodes and the lipids could be metabolized there but we have to take in account that the high
contained of the lipids inhibits the mobility of the macrophages . another possibility of control is related
to HDL, the others lipoprotein which offer the transport of cholesterol from the tissues to the liver, we
know that cholesterol from LDL is hydrolyzed, so in the cell LDL brings acetyle 5 cholesterol.., and this is
a dominant form in the composition of LDL . the cells through an enzyme delivered by the lysosome ,
this enzyme is the acidcholesterolester hydrolase will transform the cholesterol from the esterfied form
in the free cholesterol which will be included in the membrane structure so if we have an excess of LDL
we will have an excess of free cholesterol in the cellular membrane so HDL will take this cholesterol and
will transport it to the liver but in cases with very high free cholesterol in the membrane the activity of
HDL is overcomed so the remained excess of cholesterol will be reesterefied by ACA, AceylcoenzymeA
cholesterol acid acel transferase , and again this cholesterol esterfied will be accumulated and the cells
will be transformed in a foamy cells. So as we see, the control mechanisms are not enough for this
uptaking of the LDL by the macrophages.
Another process , the endothelial cells first will be signaled by lipids accumulation but lipids
accumulation will have as a consequence increasing thicker of the vascular wall and increasing its rigidity
so if the blood flow is variable could injure this rigid and thick wall, so these lesions will stimulate more
the endothelial cells and the endothelial cells become activated will express adhesion molecules and we
have inflammation . this endothelial dysfunction will activate also the macrophages and macrophages
becoming activated will produce interlukines and the most important interlukin produced by the
macrophages is IL1, so IL1 will activate in a additious circle! That endothelial cells so in this case the
endothelial cells will expose adhesion molecules will expose tissue factors so prohemostatic processes
and will expose inhibitors plasminogen activators so we will have an imbalance between prohemostatic
and antihemostatic properties, so the prohemostatic properties of endothelial cells will be favorized so
will have tendency to thrombosis for this reason and also for other reasons .
Other possibility for endothelial lesions, we said that there are an immune process attacking the
endothelial cells and attacking the structers of the vessels wall. The excess of LDL will be attacked by
the free oxygen radicals, will be attacked by the cellular lipooxygenase, so into the cell this LDL will be
attacked of macrophages become to be activated so will produce free oxygen radicals and from the
lysosomes some enzymes will be delivered, for instance Lipooxygenase, and in this way the LDL will
become more and more modified they will become oxidized, because of this high content of oxidized
LDL the macrophages have lower mobility and there is a possibility from the phospho membrane
phospholipids to formation of lysolistin, and lysolistin propagate between the peroxidation process , we

have leusineoxidase , lipooxygenase, free oxygen radicals and we have a favorable process for
peroxidation so these process will affect the lipids and also the apoproteins in the structural LDL into the
macrophages.
Whats happening with these ApoB ?
Will be modified, because of peroxidation and all these processes there is a degradation of ApoB and
another processes is a processes of conjucation of fragments from oxidized fatty acids with an amino
termination, amino groups, from ApoB . in this way ApoB will be a large protein, transformed protein, a
modified protein and in this way the macrophages will process this transformed protein generating
epitopes, antigens, and will express this antigen, epitopes through the MHC molecule, so an immune
response will be initiated producing antibodies against these antigens, Ab will attack circulating LDL,
because LDL circulating modified LDL containing these epitopes against the antibodies were produced
and we will have circulating immune complexes and they will activate complement producing lesions on
the endothelial cells surfaces. So we can have an immune involvement in the aterogenesis and ofc it
was noticed that the infiltration of T lymphocytes in the zones of ateromatos plaque.
The most important element in the evolution of athermatos plaque Is the mitral thrombic formation.
The endothelial cells is signaled from the begin of injure and will be activated so the procoagulant
property will be enhanced compliant to the anticoagulant property, in another way the activated cells
like macrophages and endothelial cells will express factors which will activate platelets which will
activate clotting factors so clotting cascade and in this ways the small thrombi could be formed on the
endothelial layer, there is a tendency including of this microthrombi in the subendothelial space, so the
microthrombines added to the athermatos plaque will increase the thickness and will increase the
rigidity and in the same time the blood flow could distruct this thrombi and the disruption of this
thrombi from the atheramtos plaque could produce in the plaque a deep lesion like an ulcer, so this
deep layer lesion will enhance more and more inflammation and hemostasis .
There is another phenomena, the corperation of the smooth muscle cell, ofc if we have inflammation we
have proinflammatory factors discharged at the site of the athermatosis and among the
proinflammatory factors there is also cloin factors, for instance PDGF, growth factors derived from the
activated endothelial cells, derived from the activated macrophages so the smooth muscle cells will be
stimulated to hypertrophy and to proliferate and during this stimulation the hypertrophy and the
proliferation of the SMC the arterial wall are associated by other modifications by the modifications of
their properties , these SMC which are proliferated and hypertrophied they are taking properties of
macrophages they can emphasize now properties like macrophages, for instance they could by their
own take LDL from the circulation, and another modified property of these SMC is that they could
synthesize and deliver fibers and proteoglycans so they will participate like in repairatory process they
will toxicipate to the increasing thickness of the vessel wall and rigidity.
So starting from lipid accumulation we can have many processes, immune involvement, hemostasis
involvement, inflammation involvement, and all of them are interconnected in fact driving to the

increased thickness of the wall and decreasing lumina of the vessel and the possibility of lesions and
disruptions and so on.

The Respiratory Failure

First about respiration, respiration is a large concept meaning respiration moves the essential function
of the gas exchange between the organisms and the environment , and when we say organisms in fact
we mean cells of the organisms, so gas exchange between organisms cells and environment. The most
important gas in respiration is the oxygen, so oxygen obtained and delivery and it is used in the
mitochondria of the cells, so we can say that the respiratory failure represent the disturbance of the gas
exchange between cells and the environment and this disturbance in gas exchange could be emphasized
by decreasing oxygen pressure and increasing carbon dioxide pressure in the mitochondria.
We have other parameters which indirectly will give us data about whats happening between our
mitochondria and the environment , so we classify the mechanisms of the respiratory failure, so
respiratory failure meaning decreased oxygen pressure and increased carbon dioxide pressure in the
mitochondria that means that these parameters will be the first parameters that we are looking for but
we cannot measure these parameters in mitochondria but we can measure them in the arterial blood,
indirectly we can imagine what is happening in the mitochondria, so arterial oxygen pressure in the
tissue means hypoxia and this is the most important feature of the respiratory failure. Decrease arterial
pressure of oxygen means hypoxemia and increase carbon dioxide pressure mean hypercapnia.
The mechanisms of the decrease of oxygen supply for the cells which is the characteristic of respiratory
failure:
At every mechanisms of respiratory failure we will see which are the parameters which could give us
data about the disturbed mechanisms, so we will put only the parameters and here we will animate the
mechanisms so respiratory failure meaning in fact hypoxia.
1.Decreased oxygen pressure in the arterial blood, hypoxemia, so we will see what kind of mechanisms
producing hypoxemia. We have the decreased oxygen in the inhaled air, so the oxygen in the
environment as happening in high altitudes, if there is a discharge of some toxic gases, this locking the
oxygen in a medium, especially in high altitude.
Other possibility of hypoxemia are disturbances in gas exchange between the alveolar air and the
arterial pulmonary capillary blood, and here we can talk about disturbance in neural control of the
respiratory movements, so neural mechanisms. This could be related to the respiratory centers or could
be related to the nervous transmission to the respiratory muscles.
Another aspect here is the respiratory muscle which could be affected in various myopathies, or the
thorax cage could be modified and the activity of muscles could be impaired, exsyphosis, modifications
of the vertebral column, so the modifications of the thorax cage will affect the function of the

respiratory muscles, and causes diseases of the respiratory apparatus, means respiratory airwayes,
larynx trachea, bronchi, and the alveoli. The diseases of the respiratory apparatus airways.
These are causes, pathophysiological mechanisms could be especially for .., decrease ventilation
because decrease oxygen environmental air, because of the ..neural control of the respiratory
movements because of the decreased respiratory muscle activity and because of diseases in the
respiratory apparatus, bronchia, or in alveoli.
In the lung, other modification is the perfusion, another group of causes for the respiratory failure is
related to the pulmonary circulation, and here we can have pulmonary stasis, slow peripheral
circulation, and in stasis, so we have no hypoxemia now. Another circulatory disturbances like shunts,
light modification of the pulmonary vascular resistance so the perfusion will be affected.
Related to this 2 processes we will have ventilation perfusion mix match. And another group of
mechanisms related in fact to the alveoli and which will have a directly consequence for the gas
exchange between alveolar air and the arterial pulmonary capillary blood will be the entirety of non
mechanity! Of the alveolar capillary membrane.
Other causes for respiratory failure
Will be anemia, decreased quantity of hemoglobin that transport the oxygen.
Other cause for respiratory failure will be the inability of the cells to use oxygen . we have normal
ventilation, normal perfusion, there is a normal oxygen pressure in the arterial blood but this oxygen is
not used in the cells like it happening in the alcohol intoxication or other intoxications with other
substances.
We have to use another definition. We talked about the respiratory failure, but we use to talk about
pulmonary failure, and this mechanisms into inverse territory causes and all these will delimitate the
pulmonary failure, it means that the respiratory failure are done by causes related to the respiratory
apparatus, usually this consider that the respiratory failure results from the inability of the respiratory
apparatus to perform the gas exchange between the alveoli air and the capillary blood during rest and
exercise, so the pulmonary function is adapting in normal cases, adapting this gas exchange in exercise
compared to the rest but this is only a part of the respiratory disturbances, so this part completly most
be linked ! pulmonary failure and this pulmonary failure will be charachterised by decreased arterial
pressure of oxygen and hypoxemia, and increase carbon dioxide pressure in the arterial blood meaning
hypercapnia, so starting from this 2 first parameters which could charchterise the pulmonary failure
included in the respiratory failure.
classification of the pulmonary failure, depending on these parameters, oxygen and carbon dioxide
pressures we distinguish partial and total pulmonary failure. partial when we have hypoxemia and
normal capnia, so in partial pulmonary failure we have decrease oxygen and normal carbon dioxide. and
total pulmonary failure when both of them are modified.

another creterion for the classification of pulmonary failure depending on the metabolic level of the gas
disturbances, so in this situation we have latent pulmonary failure and manifest pulmonary failure,
latent means that at the rest the pressures of oxygen and carbon dioxide are normal but in exercise, the
hypoxemia occurs and maybe hypercapnia also. the manifest pulmonary failure has also 2 forms,
compensated and decompensated manifest pulmonary failure, compensate both of them has modified
oxygen and carbon dioxide, both of them has decrease oxygen and increase carbon dioxide pressures,
but in the compensate form this modifications are the same in rest and in exercise. in the
decompensated manifest pulmonary failure, in the rest we have modified levels of carbon dioxide level
and oxygen. oxygen decreased and carbon dioxide increased, but in exercise these modifications are
aggravated the oxygens become more decreased and the carbon dioxide more increased ....This could
be acute and a chronic.
The mechanisms of pulmonary failure
we will start with impaired ventilation , now the ventilation is impaired because of these values of
oxygen and carbon dioxide pressures being modified, cannot give us exactly about ventilation or
perfusion or about the alveoli capillary membrane. we have the respiratory volume, The total vital
capacity including the inspiratory capacity and the experatory reserved volume, out of the total capacity
will be also the residual volume, these are the static volumes of the respiration, mechanical parameters,
about parameters that are in dynamic... involved is the forced experatory volume of the 1st second, and
related to these type of measurments we have other 2 or 3 parameters, 25% 75%. so we have a
profound inspiration and with a rapid expiration, in the first second we have F1, and then 25%, 75%
which is the flow of the forced expiratory between 25-75% expiration. regarding to these parameters we
can classify the pulmonary failure in 2 sorts, obstructive dysfunction and restrictive dysfunction and
mixed dysfunction, in the restrictive dysfunction we have decreased pulmonary volumes, vital capacity,
inspired capacity, forced expiratory capacity, we can have increased residual volume. these resrtictive
causes could be done by tumors, by fibrosis, emphysema, tuberculosis, so these are causes related
directly to the lung but we have extrapulmonary causes, thorax cage which impair the respiratory
movements, muscles and neural activity affected and other process which can impair from exterior from
extrapulmonary territory the functions of the lungs.
obstructive dysfunction means obstruction in the small airways, bronchia, bronchioli, and this can be
done in asthma, COPD, emphysema( we have mixed ) there are alveoli walls disrupted and obstruction
because of this emphysema, enlargement of the alveoli could press on the bronchioles and there are
also the production of the mucous, increased SMC proliferation and hypertrophy in the bronchia and
the processes are mixed so in emphysema we have obstruction and restriction.
The perfusion could be affected and could affect the pulmonary function producing pulmonary failure,
we avaluate the perfusion by... we are interested! other parameters. in the perfusion intersted in the
pulmonary arterial pressure which normally arround 15mm!! compared to 9mm!! compared to 90mm
of the aorta pressure !!, we have also a palmunary vascular resistance which could be calculated from
palmunary arterial pressure and other parameters which are measured.

the difference between pulmonary arterial and palmonary vascular, pulmonary vascular resistance is
done by vasconstriction and includes near and depends on the palmunary arterial pressure and also
depends on caridac output and on the palmunary capillary wedge pressures, so it is not equal to the
palmunary arterial pressure.
we know that in normal cases there is not an uniform distribution of ventillation and there is not a
uniform distribution of perfusion, we know that in apex we have higher ventillation and low perfusion
and in the bases we have high perfusion and low ventilation and these ratios between ventilation and
perfusion is physiological, in some pathological cases, this ratio could be disturbed, and for instance, this
ratio could be disturbed by decrease in ventilation or by effecting perfusion for instance palmunary
vascular resistance could increase by various mechanisms, hypoxia itself but hypoxia which are not by
pulmonary causes, we can have hypoxia by anemia!, hypoxia by vasoconstriction because of the
hypovolemia, hypovolemia itself could produce hypoxia, intoxications, so hypoxia will stimulate the
palmunary vasoconstriction so it tends to produce palmunary hypertension, another possibilty for the
increased vascular resistance could be the cause of thrombi, pulmonary microthrombi,
thrombembolism, and other possibilities of these modifications of pulmonary vascular resistance could
be done by the proliferation of SMC in the vessels wall in the pulmonary circulation, and this is
idiopathic primary pulmonary hypertension. we have also secondary pulmonary hypertension this
including mitral stenosis , increase pressure in the left atrium and this will increase the pressure in the
pulmonary circulation producing pulmonary hypertension.
another cause in disturbances in the perfusion is done by small pulmonary vessel destroy which could be
done by .... of the alveolar wall, so we will have a total cross section area ofhe pulmonary vascular band
diminish, so pulmonary vascular resistance increase.
disturbances in gas exchange, we sow ventilation, perfusion, because of the disturbances of the ratio
between them we have ventilation perfusion mismatch and also we will have disturbances in the
diffusion of the gas through the alveolar capillary membrane and this phenomena is related to
ventilation perfusion mismatch. so this phenomena the gas diffusion depends on the erythrocytes
transit time, the speed, in the circulation, so if erythrocyte transit time in the circulation is shortened the
diffusion will be impaired as it happening in tachycardia. diffusing capacity could be decreased because
of the impairment of capacity, of the integrity, of the alveolar wall capillary membrane. and this is also
related in this part of discussion in the perfusion, circulation modification, shunt. if we have shunt there
is a disaturated blood which effectively bypasses the oxygenation process, so this circulated blood will
enter again in the arterial blood, so bypasses the alveolary capillary level. and for this gas diffusion
which is related to rbc speed and to integrity of capillary membrane, it is also related to the ventilation
perfusion mismatching . how can appreciate if this exchange of gas is normal or not, one of the
parameters is the oxygen saturation of the hemoglobin and we know that because of the aspect of the
curve of oxygen saturation of hemoglobin we know that the possibilities of decompensation when we
have a ventilation perfusion mismatch are very limited, so we know that the hemoglobin has
50%!saturation and 100% saturation with oxygen ( the curve of hemoglobin saturation ), after the level
of semisaturation mast great !! the arterial pressure of oxygen which is when we have more oxygen the
saturation of hemoglin cannot be sublimented, but when when have 95 mmqh arterial pressure of

oxygen we have, we have very low oxygen saturation of hemoglobin, it mean that between ventilation
and perfusion there is a physiological ratio, other way one cannot decompensate the other, for instance
if we have high ventialted regions thats what happen in the apex, and a bad perfusion regions in bases
so because of them we have low arterial pressure of oxygen and we have low level of hemoglobin
saturation of oxygen, so this high ventilation in the apical regions cannot compensate even here the
arterial pressure of oxygen is very high, this arterial pressure of oxygen cannot saturate too much the
hemoglobin so cannot produce a supplemental of that oxygen to compensate the decreased saturation
from perfusion causes.
another parameter which could be very important in the evaluation of this perfusion ventilation
mismatching will be the so called alveolar arterial oxygen gradient so that means these pressures,
pressures of the oxygen in the alveolar air, and pressure of the oxygen in the arterial blood , the
difference between the 1st and 2nd mains the gradient, the alveolar arterial oxygen gradient which is
normal arround 15mmhg!. so if we have decrease arterial pressure of oxygen we will have increase
gradient ..... because of a disturbance in the perfusion we can have decreased arterial pressure of the
oxygen for instance,in shunt, shunt means bypassing the oxygenation, so even if we have alot of oxygen
in the alveolar air, this exchange is not produced. another cause to be, the lesions, increased thickness in
the alveolar capillary membrane, so this exchange is not properly, ........ near the saturation of the
oxygen saturation of hemoglobin will give us data about perfusion, about the ventilation perfusion
mismatching and also about the diffusion of the gases through the alveolar capillary membrane. we
have also other parameteres, which are very important to evaluate, which are telling us data for this
phenomena, this mechanism, ventilation perfusion, ventialtion perfusion mismatch and alveolar
capillary membrane possibility to diffuse, this poor ox.... post vacidine!!. so this oxymethene! in diffusing
capacity of the lungs for carbon monoxide, hosmetidine.... is assesing the oxygenation which is a ideal
for closing monitoring of as,...... alternative mean for assesing oxygenation. and the force oxymeter
measures oxygen saturation using a drop usually clipped over a finger which is the device measures the
absorbtion of 2 wave! lungs , by hemoglobin, one is the oxygenated hemoglobin and the other one is
the disaturated hemoglobin and the difference between them gives the saturation of the possibilty of
hemoglobing to transport oxygen.
diffusing capacity is very important to measure in fact directly the alveolar capillary membrane to be
passed by the gas. so the ability of gas to pass through the alveolary capillary membrane is ordinarily
assested by the diffusing capacity of the lung with carbon monoxide, a small quantity of carbon
monoxide 0.3% is inhaled during one respiration 10 seconds during a single breath, so in this time the
carbon monoxide is diluted in the alveolar gas and this is also taken by the hemoglobin and will be
transported and eliminated later and part of this carbon monoxide still remain in the alveolar gas and
will be eliminated for one breath so we can measure the, calculate, the difference between carbon
monoxide it was inhaled and that which was escaped, so in this way we know how much carbon
monoxide was taken by hemoglobin, so know the diffusion capacity of the alveolar capillary membrane.
the diffusing capacity of the alveolar capillary membrane will be affected by decreasing its surface area,
scars, tumors, another cause will be increased thickness of this membrane like inflammation, another
possibility is the decreased hemoglobin level, so this is not related to the membrane, another cause will

be the disturbance in ventilation perfusion mismatch, and the pathological variation of the pulmonary
capillary blood volume, we saw which are the most important parameters which could evaluate the
pulmonary failure to establish why these pressures are modified, another thing very important, if we
talk about increased carbon dioxide pressure we have to make the bind to the acid base balance, when
know which kind of parameters are used to evaluate .....