Nonrespiratory Lung Function Introduction 1. Mucociliary Clearance ...

64 XAO100099Nonrespiratory Lung Function

Toyoharu Isawa, M.D.

Introduction

The function of the lungs is primarily the function as a gas exchanger; the venousblood returning to the lungs is arterialized with oxygen in the lungs and the arterial-ized blood is sent back again to the peripheral tissues of the whole body to be uti-lized for metabolic oxygenation. Besides the gas exchanging function which we call"respiratory lung function" the lungs have functions that have little to do with gasexchange itself. We categorically call the latter function of the lungs as "non-respiratory lung function".

The lungs consist of the conductive airways, the gas exchanging units like thealveoli, and the interstitial space that surrounds the former two compartments. Theinterstitial space contains the blood and lymphatic capillaries, collagen and elasticfibers and cement substances. The conductive airways and the gas exchanging unitsare directly exposed to the atmosphere that contains various toxic and nontoxic gases,fume and biological or nonbiological particles. Because the conductive airways areequipped with defense mechanisms like mucociliary clearance or coughs to get ridof these toxic gases, particles or locally produced biological debris, we are usuallyfree from being succumbed to ill effects of inhaled materials. By use of nuclearmedicine techniques, we can now evaluate mucociliary clearance function, and othernonrespiratory lung functions as well in vivo.

1. Mucociliary Clearance Mechanism

Mucociliary clearance mechanism is the first line of defense in the respiratorysystem. By coordinated beating of the cilia of the airway epithelia the mucous over-lying the epithelial surface is propelled upward towards lthe larynx. The cilia growon the airway epithelial surface from the trachea down to the terminal bronchioles.In and distal to the terminal bronchioli the cilia are either poorly developed or ab-sent [1].

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1) Cilia

The airway epithelium has 200 cilia on its surface facing the airway lumen fromthe trachea as far as down to the distal bronchi just proximal to the terminal bron-chiole [2]. The length of a cilia is 6-7 micron and its diameter, 1 micron. Theyare dipped in the periciliary fluid above which there is a mucous layer. By a coor-dinated ciliary motion at the rate of about 1000/min the mucous layer is transportedupward toward the pharynx.

Each cilium has a characteristic structure consisting of 9 pairs of peripheral doublets(A and B) and two central tubules. Each doublet is connected by a bundle callednexin. From A of the doublet two dynein arms (outer and inner) are protruded.The dynein arms themselves contain ATPase (an enzyme to degrade adenosinetriphosphate (ATP) to derive energy) with which ATP is utilized as an energy sourcefor ciliary motion. There is a radial spoke extending from A toward the centriole[1]. When the dynein arms are deficient, ciliary motion is disturbed. Afzelius calledthis pathological state "immotile cilia syndrome" [3]. Nowadays even arrangementdisturbance of the peripheral doublet or missing radial spokes are included in thissyndrome and another more rational name of "dyskinetic cilia syndrome" is pro-posed [4].

2) Mucus

Airway mucus is composed of the secretions from the submucosal glands andthe goblet cells in addition to the tissue fluids. The total amount of bronchial secre-tions per day is from about 10 to 100 ml. The cilia are immersed in the serousfluids of lower viscosity (periciliary fluid) and when ciliary motions occur, the tipsof the cilia during the effective or effector stroke of the cilia touch the base of themucous layer covering the periciliary fluid and propels the layer upward. With thereturn stroke the cilia return to the original position and the effective stroke is re-sumed. By repetition of the effective and return strokes a metachronal wave isproduced in the upper mucous layer and the actual mucous transport results. Thetime required for the effective and the return stroke is about 1 to 4 in ratio [1].The periciliary layer is also called "sol" layer, while the upper mucous layer, "gel"layer [5].

3) Mucociliary Clearance

By interaction of the coordinated ciliary beating and the mucous, the mucous con-taining various extrinsic or intrinsic biological and nonbiological materials lying overthe airway epithelium is transported toward the larynx to be swallowed into thestomach and the airways are thus kept "clean" in the normal lungs. In variouspathological states this cleaning process is deranged. Various methods have beendeveloped and applied to elucidate this function as follows;

66 Nonrespiratory Lung Function

a) BronchoscopyMovement of a dye like india ink placed over the trachea was observed by bron-

choscopy or cine-bronchoscopy in dogs [6]. The direct measurement of mucociliaryclearance in man without anesthesia is, however, technically so difficult that themeasurement has been done using only animals or excised tracheal segment.

b) X-raysRadiopaque materials like barium sulfate placed over the trachea were sequen-

tially x-rayed and an estimation was made regarding tracheal velocity of mucociliaryclearance by measuring the distance of the tracer over a certain time interval [7].A cinebronchofiberscopic technique was also developed following blowing stan-dardized teflon discs through the inner channel of the bronchofiberscope onto thetracheal mucosa and their motion was filmed [8]. The latter is invasive and notapplicable to the routine clinical practice. An improvement was made by renderingthe teflon discs radiopaque with bismuth trioxide [9],

c) Radioisotopic methodBy the same token radioactive materials were placed over the trachea, and se-

quential imaging was made [10-12]. Acute toxicity of cigarette smoke to mucociliaryclearance could be easily evaluated by this method in dogs [12]. The droplet migra-tion or transport on the trachea is disturbed by forced smoking in the dog in a dosedependent manner [12]. Taking a hint from this droplet migration, we proposed"radioaerosol inhalation lung cine-scintigraphy" in order to visualize the actual mucousflow or transport in vivo as described later [13].

In static images, whether or not a hot spot seen on the subsequent sequential im-ages is the same hot spot with that on the previous image is extremely difficult totell. In this sense sequential static images are not adequate means to tell mucociliaryclearance mechanisms. Transport velocity or direction can be determined only whenan adequate hot spot is seen.

Inhaled aerosol deposits on the airways by impaction, sedimentation and diffu-sion. When turbulence occurs in the airways at the sites of stenosis or narrowingcaused by mucous deposition, cancerous protrusion of the airway mucosa, exces-sive narrowing of the airways in obstructive airways diseases, etc, excessive depo-sition of inhaled aerosol or "hot spots" occur regionally in the stenotic lesions [14].

4) Measurement of Mucociliary Clearance

The measurement of mucous transport on the airways can be performed prin-cipally by two methods; measurement either of 1) the transport of the mucous globon the trachea or 2) the disappearance rate of deposited particles in the lungs. Theformer to visually evaluate how mucous is transported on the large ciliated airwaysand the latter to quantitatively evaluate the overall disappearance from the intrapul-monary ciliated airways.

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a) Tracheal transportEither bronchoscopic or cine-fiberscopic observation or sequential radiologic ob-

servation of the movement of a marker dye or radiopaque materials placed on thetrachea has been done as described earlier.

The transport pathway of a radioactive bolus placed on the trachea can also befollowed by external measurement. Placement of a radioactive bolus itself, however,requires bronchoscopic insertion that makes anesthesia of the oropharynx and thetrachea indispensable. In other words, the method could be invasive and not direct-ly applicable routinely to human subjects. We use instead radioactive aerosols forinhalation. Inhalation of aerosol is not an invasive procedure and can be done intidal respiration without giving any discomfort to any examine. If inhaled aerosolforms a bolus or a "hot spot" of excessive radioactivity and radioactivity is se-quentially measured, the migrating distance of radioactive globs on the trachea canbe used as an index to measure mucous transport velocity. Actually tracheal mu-cous velocity was reported as 1.14 ± 0.38 [9], 2.15 ± 0.55 [15], 0.44 ± 0.13[16], and 12.0 ± 1.0 mm/min [12].

This method can be used only when tracheal mucous transport is linear, cons-tant, steady and cephalad in direction. Even in normal subject, however, mucoustransport is not necessarily linear in direction. Especially in smokers mucous globstransiently stop and start moving on their pathway to the oropharynx [17]. In patho-logical states as described later, regurgitation or backward migration, stasis, stray-ing, or spiral or zigzag movement of mucous globs are seen [18]. Under thesecircumstances this method cannot be applicable, because the radioactive peaks de-tected at different sites on the trachea by making windows cannot be identified to betruly the radioactive globs of interest. Recently a computer analysis of a mucousglob movement has been made in a detailed fashion by "condensed mode" and/or"trajectory mode" and even in normal nonsmokers fractions of backward move-ment were found to be present but the transport of tracheal mucous as a bulk wascephalad in direction toward the oropharynx [19].

b) Disappearance rate of inhaled radioactivity in the lungs [17]When a radioaerosol is inhaled, radioactivity deposited in the extrapulmonary ciliat-

ed airways (A), intrapulmonary ciliated airways (B), in the non-ciliated small air-ways and/or the alveoli (C), or, by being swallowed, in the stomach and/or theGI tract (D) as illustrated in Fig. 1. Disregarding the radioactivity in the stomach(D), the radioactivity in each compartment at time zero or immediately after aer-osol inhalation is over can be written as follows;

Ao + Bo + Co = To (1)

where A, B, C represent the compartments as in Fig. 1, and T, the total radioac-tivity in all three. At time t, radioactivity at each compartment would be


AEROSOL DEPOSITION

Fig. 1. Diagram of aerosol deposition sites. (A) extrapulmonary ciliated airways, (B) intrapulmo-nary airways, (C) nonciliated distal airways including the alveolar space and (D) esophagus andstomach, or GI tract.

T. Isawa 69

At + Bt + Ct = Tt (2)

If radioactivity is corrected for physical decay, the formula (2) becomes

Ate + Btc + Ctc = Ttc (3)

If we define that the radioactivity remaining in the lungs at 24 hrs later is theamount of radioactivity depositing in the non-ciliated space of the lungs, Co, cor-rected for physical decay should be the same with Ctc or Co = Ctc.

Practically speaking, however, it is extremely difficult to measure A without itsbeing contaminated by swallowed radioactivity remaining in the esophagus. In thequantitative estimation of disappearance of inhaled radioaerosol from the lungs thatis nothing less than mucociliary clearance from the intrapulmonary ciliated airwaysradioactivity in the extrapuimonary ciliated airways or radioactivity in the compart-ment A should be neglected. Thus above formulae can be rewritten as follows;

Bo + Co = To (1)'

Bt + Ct = Tt (2)'

Btc + Co = Tte (3)'

The indices to evaluate intrapulmonary mucociliary clearance are as follows:

i) Lung Retention Ratio (LRR)

LRR (%) = Ttc / To X 100

This ratio expresses the amount of radioactivity remaining in the lungs at timet relative to the total radioactivity initially deposited.

ii) Airway Deposition Ratio (ADR)

ADR (%) = Btc / To X 100= (Ttc - Co) / To X 100

This indicates the amount of radioactivity throughout the ciliated airways relativeto the total radioactivity initially deposited in the lungs.


iii) Airway Retention Ratio (ARR)

ARR (%) = Btc / Bo X 100= (Ttc - Co) / (To - Co) X 100

This ratio indicates what percentage of radioactivity initially deposited on the ciliatedairways still remains there at time t.

iv) Airway Clearance Efficiency (ACE)

ACE (%) = (Bo - Btc) / Bo X 100

= (To - Ttc) / (o - Co) X 100

This indicates what percentage of the radioactivity initially deposited on the ciliatedairways has already been cleared by time t.

v) Alveolar Deposition Ratio (ALDR)

ALDR (%) = Co / To X 100

This ratio indicates the percentage of the total initial radioactivity that remainsin the lungs at 24 hrs or in other words the percentage of radioactivity depositedin the non-ciliated space of the lungs.

Normal values using human serum albumin aerosols (activity median aerodynamicdiameter (AMAD): 1.9 /xm with geometric standard deviation of 1.7) have beenestablished [20].

When aerosols of different size are used, normal values of these parameters couldbe different. We should bear this fact in mind.

5) Imaging Mucociliary Clearance

A large field view-camera can image mucociliary clearance in the lungs. Thereare two methods of imaging; 1) Sequential spot imaging and 2) Radioaerosol inha-lation lung cine-scientigraphy.

a) Sequential spot imagingWhen an excessive deposition of radioactivity or a hot spot is present on the air-

ways as in bronchogenic carcinoma invading the main bronchus, sequential lungimaging can tell whether or not the hot spot is cleared with time. This can be knownby repeating sequential imaging of the lungs. But how the radioactivity is clearedwith time is not known. Identification of the particular radioactive globs is usually

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very difficult by simply repeating this spot sequential imaging. Positioning of thepatient at each measurement is also difficult.

b) Radioaerosol inhalation lung cine-scintigraphyIn order to avoid the above drawbacks "cine-scintigraphy" of the lungs follow-

ing radioaerosol inhalation is extremely helpful not only to the visual assessmentof mucociliary clearance but also to the setting of the regions of interest in the lungsand to the interpretation and analysis of time-activity curves over the regions ofinterest. We have coined a name "radioaerosol inhalation lung cine-scintigraphy"for this methodology of imaging [13,17,18].

Initially following inhalation of ultrasonically generated 99mTc-albumin aerosol intidal breathing through the mouth with the nose clipped, a subject was placed undera gamma-camera in the supine position and radioactivity was measured over theentire thorax including the trachea for 120 minutes in sequential 10 sec frame modewith 64 x 64 matrix. The data was recorded and stored in a computer. The datawas displayed in cine mode on a CRT screen at the rate of 18 frames per secondand the cinematographic display was recorded in a movie camera. Regions of in-terest were set and regional time-activity curves were also obtained following cor-rection for physical half-life.

6) Mucociliary Clearance in Health and Disease

a) Normal subjectIn all 17 normal subjects the deposition of inhaled radioaerosol in the lungs was

homogeneous. In 4 nonsmokers and 2 of 3 ex-smokers, transport of radioactivityin the trachea was always cephalad in direction, steady in its progress, and showedno stagnation of radioactivity in the bronchi or trachea. In all 9 smokers and 1 ofthe 3 ex-smokers, although radioactive transport was still cephalad in direction andtransport velocity nearly constant, temporary collection of radioactivity was seenover the bronchi near the carina or over the carina [17]. Such stasis never persistedlong. There was no visible retrograde migration or retreat, stasis or stagnation ofmucous globs, frequent up-and-down motions of radioactive globs in the tracheaor bronchi or migration into the other regions of the same lung or into the bronchusof the opposite lung.

b) Obstructive airways diseaseContrary to the normal subjects, the deposition of inhaled aerosol in the lungs

was inhomogeneous in all 21 patients studied. Migration of radioactivity over thetrachea and the major bronchi was extremely protean in its direction and transportpatterns. Of the 21 patients, 14 showed temporary but frequent stopping and start-ing of radioactivity in the airways in the course of lung clearance. Even after radi-oactivity begins to migrate up the trachea, it tends to stop on the way. Thus stoppingand renewed migration were repeated many times. Migration was sometimes ac-


celerated by coughing and clearing the throat, with the radioactivity finally swal-lowed or expectorated. Sometimes only cough appears to the major means of upwardpropulsion. In 10 there was reversal of flow, in 5 migration of radioactivity fromone bronchus into the opposite, bypassing the trachea and often followed by shuttlingbetween the right and left bronchi and in four there was spiral or zigzag transportof radioactivity as shown in Fig. 2 [18]. In other series, traveling of mucous notonly in the opposite lung, but also into the different regions of the same lung wasobserved [21].

The airway deposition ratio (ADR) was increased, the airway clearance efficien-cy (ACE) decreased and the alveolar deposition ratio (ALDR) also decreased(Fig. 3) [18].

c) BronchiectasisIn bronchiectatic lung regions, deposition of inhaled radioactivity is diminished

or inhomogeneous. Transport of inhaled radioactivity from the bronchiectatic regionsis deranged. Regional stasis was observed in 12 of the 20 patients studied (12/20),regurgitation or reversed transport in 14/20, straying in 8/20, spiral or zigzag mo-tion in 1/20 and/or various combination of these four abnormal transport patterns.When coughs occur, regurgitation and stray become more marked in the bronchiectaticregions. These regional abnormalities in mucociliary transport seem to be responsi-ble for the development of infections and hemoptysis in the bronchiectatic regions [21].

d) Bronchogenic carcinomaIn bronchogenic carcinoma, abnormal mucociliary transport patterns such as regur-

gitation, stray, stasis and spiral or zigzag motions were seen in most of the cases,especially when obstructive airways disease complicates bronchogenic carcinoma.The frequency of abnormal mucous transport patterns was not related with differ-ent histological diagnoses of lung cancer. The location of the cancerous lesion andwhether or not the mucosal surface is invaded with cancer seem to contribute tothe abnormal mucous transport patterns. "Hot spots" were often formed at the siteof bronchial stenosis or near obstruction due to bronchogenic cancer on the largeairways and mucous transport at the hot spots is greatly disturbed [22].

e) Interstitial lung diseaseThe interstitial space of the lung is defined as the space which surrounds or inter-

venes the respiratory units. The ultimate respiratory unit is the alveolus whose base-ment membrane underlies the type I and type II cells, being intimately apposed tothe underlying endothelial membrane [23]. Elsewhere the epithelial and endothelialmembranes are separated by the interstitial space where besides various cell com-ponents and capillaries elastic and collagen fibers are embedded in a proteoglycanmatrix. In interstitial lung diseases like idiopathic interstitial fibrosis or sarcoidosismucociliary clearance mechanisms are well maintained both qualitatively and quan-titatively (Fig. 4) [24]. But as described later pulmonary epithelial permeability isabnormally accelerated in this disease category.

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MUCUS TRANSPORT PATTERNS

I I IV

REGURGITATIONTOWARD

OPPOSITEBRONCHUS

x9/16

STASIS SPIRAL MOTION

5/16 8/16 4/16

Fig. 2. Diagram of mucociliary transport patterns on the trachea and the major bronchi in the ob-structive airways disease. Numbers indicate frequency.

f) Pulmonary vascular diseasesIn pulmonary vascular anomaly like pulmonary artery hypoplasia, pulmonary ar-

teriovenous fistula and aortitis syndrome, and in pulmonary artery occlusive dis-ease like pulmonary embolism, mucociliary clearance was well maintained and withinnormal limits [25].

7) Pharmacological Effects on Mucociliary Clearance

a) Oral beta 2-stimulantSince it is reported that ciliary beat frequency in vitro increases on exposure to

beta 2-stimulants [104-106], it is natural to think that mucociliary clearance in vivois also activated when these agents are clinically administered. We administeredoral salbutamol on 10 patients with various chest diseases in combination with otheragents such as antibiotics and on 9 patients with various chest diseases singly withoutcombining with other agents for one week and studied the 5 parameters for assess-ing mucociliary clearance before and after one week's trial. No changes were ob-served in these parameters after the treatment compared with before treatment,although pulmonary function test showed improvement, indicating that the beta2-stimulant is definitely functioning as a bronchodilator [107].


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Fig. 3. Lung retention ratio (LRR), airway deposition ratio (ADR), airway retention ratio (ARR),airway clearance efficiency (ACE) and alveolar deposition ratio (ALDR) that is equivalent to lungretention ratio at 24 hr (mean + SE) in patients with obstructive airways disease (n= 14). Shadedbands indicate 95 % confidence intervals of normal values [20].

T. Isawa 75

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Fig. 4. Lung retention ratio (LRR), airway deposition ratio (ADR), airway retention ratio (ARR),airway clearance efficiency (ACE) and alveolar deposition ratio (ALDR) that is equivalent to lungretention ratio at 24 hr (mean + SE) in patients with interstitial lung diseases (n= 14, 19 times).Shaded bands indicate 95 % confidence intervals of normal values [20].


b) Inhaled beta 2-stimulant with intravenous aminophyllineUsing bronchial asthmatic patients in remission, salbutamol was inhaled and

aminophylline was injected. Compared with before the treatment, the alveolar depo-sition ratio (ALDR) was improved to nearly normal levels, the penetration indexincreased, the aerosol deposition patterns became more homogeneous throughoutthe lungs and the pulmonary function test showed a definite evidence of bronchodi-lation but the 5 parameters showed little changes [108].

c) Inhalation of a beta 2-stimulator in the midst of the studyIn the previous pharmacological evaluation the comparison was made between

before and after the treatment. A drawback to these approaches was that the alveo-lar deposition ratio (ALDR) could be different before and after the treatment.Because the ALDR is the basis for calculating these parameters, it should ideallyremain the same if possible. To circumvent the drawback, we inhaled a beta2-stimulator, procaterol, while the examine was being measured for radioactivityfollowing radioaerosol inhalation. If some acceleration occurs in mucociliary clear-ance, the time activity curve should be steeper following a beta 2-stimulator inhala-tion. A group of 8 normal subjects and 34 patients with various lung diseases,including 6 with bronchial asthma in remission, were studied. Following inhalationof procaterol, there were neither significant acceleration in mucous transport on thelarge airways by cine-scintigraphy nor significant changes in the slope of time-activitycurves. Quantitative parameters did not show any significant changes, either, althoughspirometry indicated significant bronchodilation [109].

From these studies it seems certain that beta 2-stimulators do not facilitatemucociliary clearance mechanisms in vivo as anticipated from in vitro studies andas advertised as such by pharmaceutical companies.

d) BromhexineA clinical dose of a mucolytic agent, bromhexine, was orally administered to

10 patients for 7 days and the 5 parameters were evaluated before and after thetreatment. Airway clearance efficiency (ACE) was statistically significantly increasedafter treatment, although pulmonary function test remained unchanged [110].

Pharmacological evaluation on mucociliary clearance had been made on the ba-sis of changes in subjective complaints of tested subjects. The present method offersa unique and objective methodology to the evaluation of therapeutic or pharmaco-logical effects of a particular medication. The relationship between mucociliary clear-ance mechanism and the nervous system remains to be explored.

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2. Pulmonary Epithelial Permeability

In 1968 99mTc-DTPA (diethylenetriamine pentaacetate) aerosol was first used asa potential agent for inhalation to study regional lung diffusing capacity in patientswith pulmonary sarcoidosis and alveolar proteinosis but the trial was not very suc-cessful because computers to quantitate radioactivity in the lungs were not available[26]. With the advent of computers Taplin and his colleagues evaluated changesin radioactivity in the lungs with time following 99mTc-DTPA aerosol inhalationin 1977 [27]. They found that the disappearance rate of inhaled 99mTc-DTPA aer-osol from the lungs in patients with interstitial lung diseases was accelerated. Mintyand others found that pulmonary clearance of inhaled 99mTc-DTPA aerosol is ac-celerated in smokers [28,29] but that the acceleration is rapidly normalized aftercessation of smoking [30]. 99mTc-DTPA aerosol inhalation method is now widelyaccepted as a useful test to evaluate pulmonary epithelial permeability.

1) Pathophysiologic Basis

The alveolar-capillary barrier consists of the alveolar airway barrier in series withan endothelial barrier and in parallel with the interstitial lymphatic pathways [31].Pulmonary epithelium forms an extremely tight barrier that is one tenth as permea-ble as capillary endothelium for hydrophilic molecules and prevents the alveolarlumen from being flooded [32]. Permeability is likely related to the intercellularjunctions which are certainly the main site of hydrophilic solute crossing the mem-branes. The pore radius of the alveolar epithelial tight junctions is reported to be0.8 - 1.0 nm while that of the capillary endothelium, 4.0 - 8.0 nm [33].

By measuring disappearance of radioactivity following inhalation of this smallsoluble hydrophilic 99mTc-DTPA aerosol, we can know how the 99mTc-DTPA par-ticles depositing on the epithelial surface disappear from the lungs. If the alveolarepithelium is intact, it should produce resistance to 99mTc-DTPA diffusion. If in-tercellular junctions become widened by some pathologic reasons, 99mTc-DTPAshould be cleared faster. Egan (1980) suggested that there is a positive effect oflung inflation on alveolar permeability to instilled solutes and that the increase inpermeability mainly reflects an increase in pore size rather than an increase in al-veolar surface [34]. It is reported that PEEP (positive end expiratory pressure) in-creases pulmonary clearance of inhaled 99mTc-DTPA aerosol [35-38]. In PEEP themost important physiologic effect would be to expand the lungs. It is hard to im-agine, however, that lung inflation by deep breathing analogous to PEEP could in-duce impairment of alveolar permeability. A more likely explanation would be thatthe alveolar lining could be thinner with lung inflation and through the thinner al-veolar lining, 99mTc-DTPA could get access to the intercellular junctions more eas-ily and faster clearance of inhaled 99mTc-DTPA would be facilitated.


2) Alveolar Epithelial Permeability in Health and Disease

a) Normal subjectsIn normal non-smokers clearance half-times (tl/2) of the left and the right lungs

were 55.5 ± 22.3 min and 61.4 ± 23.6 min when 99mTc-DTPA aerosols ofAMAD of 1.00 jim with og of 1.78 were inhaled [39]. They were 59.4 ± 1 1 . 2and 80.1 ± 26.4 min, respectively, when 99mTc-DTPA aerosols of AMAD of 0.86/xm with <7g of 1.75 were inhaled [40]. Normal non-smokers who were subjectedto these tests were different. The difference in normal values was statistically notsignificant by unpaired Student t-test. Normal values could be different in differentregions of the world due to the degree of air pollutions.

b) SmokingDisappearance of 99mTc-DTPA has been found faster in smokers [28,29]. In our

study, too, when 7 smokers (average cigarette consumption 16 pack-year or 160Brinkman Index) inhaled aerosols of AMAD of 0.86 jtm with og of 1.75, half timeclearance (tl/2) was 23.6 ± 15 and 27.8 + 16.6 min in the left and right lungs,respectively. These values were significantly smaller than those of non-smokers [40].The reason why smoking induces faster clearance of inhaled 99mTc-DTPA is notknown. In dogs horseradish peroxidase tagged with transferrin instilled into the al-veoli was observed to increase in the intercellular junctions after smoking indicat-ing widening of the junctions [41,42]. It is reported that the acceleration of permeabilitybecomes normalized in 3 weeks or so after cessation of smoking [30].

c) Interstitial lung diseaseIt has been found that biopsy-proven patients with idiopathic interstitial pneumo-

nias (HP) showed significantly accelerated clearance of inhaled 99mTc-DTPA aero-sol as compared with non-smoking normal subjects, but there was no correlationbetween abnormal clearance of 99mTc-DTPA aerosol and abnormal diffusing ca-pacity (DLCO) measured by using carbon monooxide [39]. Not only in HP but alsoin pneumonias of known origin like sarcoidosis [27], systemic sclerosis [35], radia-tion pneumonitis or fibrosis, clearance is also accelerated [43].

There are speculations that the intercellular junctions are widened by increasedretractive forces due to fibrosis [35], and that the increase may precede alveolitisor a residue of subsiding active disease in sarcoidosis [44]. According to our ex-perimental fibrosis induced in rat by bleomycin, clearance of inhaled 99mTc-DTPAaerosol definitely increased 2 weeks after instillation of bleomycin, but no definitetendency was discernible thereafter because there was partial recovery and partialfibrosis in the same lung. Microscopical examination indicated that there were thin-ning, detachment or denudation of the alveolar epithelium and that the basementmembrane was directly exposed to the alveolar surface. We could not confirm by

T. Isawa 79

electron microscopy the widening of the intercellular junctions. We think that theepithelial damage and loss of epithelial covering from the basement membrane wouldcontribute to the faster clearance of inhaled 99mTc-DTPA aerosol to some extent[45].

d) Pathological changes of alveolar fluid retentionIn adult respiratory distress syndrome (ARDS) and infantile respiratory distress

syndrome (IRDS) the consistent increase in pulmonary clearance of inhaled 99mTc-DTPA is reported [46-50]. These are classified as noncardiogenic pulmonary ede-ma. In cardiogenic edema the increase is not a uniform finding. Pathogenesis ofincreased permeability in respiratory distress syndromes may be associated with deple-tion of surfactant [51]. There is a suggestion that the actual site of clearance couldbe respiratory bronchioli where clearance is accelerated because the alveoli are al-ready flooded with edema fluid and because alveolar absorption of 99mTc-DTPAshould be decreased [49].

Interesting findings in radiation pneumonitis in which lung injury may be dueto alveolar cell damage and edema [52] is that clearance is accelerated not onlyin radiation pneumonitic lesions but also in the contralateral lung where no radio-logical abnormalities are recognized [43]. When radiation pneumonitis recovers withsteroid therapy, clearance of 99mTc-DTPA gradually becomes slower. We do notknow why this is so but we are of the opinion that frequent measurement of pulmo-nary epithelial permeability can be a good indicator to know the development ofradiation induced pulmonary epithelial damage.

In hyaline membrane disease [53], long-term free base cocaine users [54], glue-sniffers [55], and pneumocystis carinii pneumonia complicated AIDS or HIV-positivehemophiliac nonsmokers [56-59] increased pulmonary epithelial clearance is reported.Especially in the latter, clearance returned toward normal with response to therapy[56] and 99mTc-DTPA clearance study is reported more useful than 67Ga chestscans for detecting lung disease when chest x-rays and/or PaCh are normal [60].

3) Regarding Methodology

It was reported in 1987 that less than 10 % of 99mTc-DTPA remains in bound-ed form after nebulization with an ultrasonic nebulizer [61], and this finding wassurprising. The report was not confirmed [62].

Clearance of inhaled 99mTc-DTPA is partly influenced by pulmonary arterial cir-culation [63], but contribution of either bronchial arterial or lymphatic circulationis very little [63,64]. Correlation with diffusing capacity is poor [39].


4) Using Other Agents

Another agent like 99mTc-HMPAO (hexamethyl propylene amine oxide) has alsobeen tried to evaluate permeability of the pulmonary epithelium [65-67]. This agentis lipophilic and believed to pass through the pulmonary epithelium intracellularly.Half-time clearance is very rapid with half time clearance of about 1 to 3 sec inthe normal subjects [65]. There is no difference between smokers and nonsmokers.Yeh and others report that the clearance of 99mTc-DTPA and 99mTc-HMPAOchanges in an opposite direction in interstitial pulmonary fibrosis [66]. Clinical use-fulness remains to be explored. 99mTc-pertechnetate and 123I-IMP have also beentried as inhalation agents but their clinicopathological significance remains unknown[65,67].

3. Lung Uptake of IMP123I-IMP (N-Isopropyl-[123I]p-Iodoamphetamine) was originally described as a

brain scan agent in 1980 [68]. When it was intravenously injected, it was soon foundthat the agent accumulated in the lungs right after intravenous injection and sugges-tions were made regarding a possibility of its depicting amine receptors in the lungs[69]. The incidental finding that the agent accumulated in the regions of broncho-genie carcinoma triggered interest of many people [70]. The true reason why andwhere it is accumulated in the lungs is not known but it is documented that 123I-IMP accumulates in the inflammatory and atelectatic lesions surrounding broncho-genie carcinomatous lesions [71-73], in lung lesions where perfusion lung imagingusing "nlTc-MAA showed deficient perfusion or inside carcinomatous lesions [74],in diffuse interstitial lung diseases [75] and in adenocarcinoma of the lung [76].

4. Lung Uptake of Gallium-67 Citrate

Gallium-67 citrate was first described as a tumor scanning agent in 1969 [77].As is well known this agent has been widely used for imaging of various epithelialand lymphoreticular neoplasms [78,79] as a tumor scanning agent, but soon inves-tigators noted concentration of the isotope in inflammatory lesions as well as in tumors[80,81]. Gallium citrate binds to serum transferrin [82] which acts primarily as acarrier protein for the 67Ga, transporting it from the site of injection to the cellu-lar localization. The intracellular localization occurs in lysosomes or lysosome-likegranules of the cell [83]. There has been disappointment, however, that the infor-mation afforded by 67Ga-citrate does not exceed that provided by conventional chestradiography [84[, as far as the detection of the primary site of bronchogenic cancer

T. Isawa 81

is concerned. An interest has been gradually directed to the application of this agentas a useful means of knowing "activity" of interstitial lung disease [85,86]. Thetrue mechanism of gallium uptake is not clear, but it is speculated that activatedmacrophages might be taking up the isotope [86,87]. Gallium-67 uptake is reportedin crypotogenic fibrosing alveolitis and hypersensitivity pneumonitis [88], extrinsichypersensitivity pneumonia [89], rheumatoid lung [90], pneumocystis carinii pneu-monia [60, 91-95]. In a comparative study Rosso and others found that of 100investigations in 88 patients infected with the human immunodeficiency virus, a pul-monary infection mainly with pneumocystis carinii was diagnosed in 39 and a nonin-fectious disorder in 42, mainly with Kaposi's sarcoma and lymphocytic alveolitis.Gallium scan and DTPA clearance was abnormal respectively in 74% and 92 %of infectious complications, and in 12 % and 60 % of noninfectious disorders. Theysay that a gallium scan is indicated to distinguish progressive Kaposi's sarcoma froma superimposed second process when radiological abnormalities of pulmonary Ka-posi's sarcoma are present [60]. The usefulness of 67Ga-citrate is also reported inoccupational lung disease especially asbestosis [96-98], pneumoconiosis [99], radi-ation pneumonitis [100], sarcoidosis [101,102] and neoplastic angioendotheliosis ofthe lung [103]. When the disease process is in active stage, the uptake is high, butwhen it is in recovery or regression, the uptake becomes less marked, making theclinical decision to treat further or not easier, especially in sarcoidosis.


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