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Circulation Research MARCH 1982

VOL. 50 NO. 3

An Official Journal of the American Heart Association

BRIEF REVIEWS

Metabolic Functions of the Pulmonary Circulation

Sami I. SaidFrom the Departments of Internal Medicine and Pharmacology, University of Texas Southwestern Medical School, Dallas, Texas,

and the Dallas Veterans Administration Medical Center

THE primary function of the pulmonary circulationis to bring the blood in contact with alveolar gas, forthe purpose of gas exchange. In addition to this vitalfunction, in which the lung may be said to play a"passive" role, the pulmonary circulation has another,more recently recognized function. This is an "active,"or metabolic, function, in which the lung takes up,inactivates, or activates certain circulating com-pounds, and synthesizes and releases others. Thesemetabolic activities help determine and regulate suchimportant functions as pulmonary vascular and air-way smooth muscle tone, pulmonary microvascularpermeability, regional and total pulmonary bloodflow, and systemic arterial blood pressure.

In the few past years, the pace of research on lungmetabolism has accelerated, and several reviews andmonographs have been published on the subject(Said, 1968; Vane, 1969; Bakhle and Vane, 1974, 1977;Junod, 1975; Said, 1979; Ciba Symposium, 1980). Thispaper focuses on the metabolism and release of va-soactive hormones and neurotransmitters and the rolethat these activities may play in the physiologicalregulation and the pathophysiological responses ofthe pulmonary circulation.

Uptake and Metabolism of Biologically ActiveCompounds

Compounds That are Taken Up and Degraded byIntracellular Enzymes (Fig. 1)

Serotonin (5-Hydroxytryptamine). Possibly thefirst indication of the metabolic potential of the pul-monary circulation was the observation in 1925, byStarling and Verney, that a "serum vasoconstrictorsubstance was detoxicated" on passage through aheart-lung preparation. This vasoconstrictor sub-stance was identified later as serotonin (5-hydroxy-tryptamine) (Rapport et al., 1948), which was subse-quently shown to be inactivated by perfused cat lungs(Gaddum et al., 1953). Efficient removal of serotoninby the lung has since been confirmed in many mam-malian species, including humans (Thomas and Vane,1967; Alabaster and Bakhle, 1970; Alabaster, 1977;

Gillis and Roth, 1977). The extent of this removal, byisolated lung or in vivo, has been estimated to be asmuch as 98% (with intravenous infusion) or as low as33% (with a bolus injection) of the serotonin reachingthe pulmonary circulation, with most estimates beingclose to the higher figure.

The pulmonary handling of serotonin depends onuptake, followed by enzymatic degradation (Pickett etal., 1975). Because the inactivating enzyme, mono-amine oxidase (MAO), is an intracellular (mitochon-drial) enzyme, serotonin must cross the cell mem-brane to be acted upon. Only one metabolite, 5-hydroxyindoleactic acid, is detected in lung perfusateafter infusion of serotonin through isolated lungs,confirming the MAO is the only metabolizing en-zyme. The rate-limiting step in the pulmonary re-moval of serotonin, however, is not its enzymaticinactivation but its uptake into the cell. This processof uptake is saturable, energy dependent, and involvesa sodium carrier system (Junod, 1972). If the processof uptake alone is inhibited, as by cocaine or by oneof the tricyclic antidepressant drugs (which also in-hibit its uptake in platelets), the pulmonary removalof serotonin is greatly reduced. If, on the other hand,monoamine oxidase activity is inhibited, as by me-banazine, iproniazid, or paragyline, serotonin still istaken up and reappears slowly in the effluent fromthe lung.

By contrast to the uptake of serotonin by the lung,which is followed by rapid enzymatic degradation,serotonin taken up into platelets and neurons isbound and stored in intracellular membrane-boundgranules. Reserpine, which inhibits the accumulationof serotonin in platelets and in neurons, does notaffect its removal by the lung.

Evidence from radioautographic experiments andfluorescence microscopy suggests that the sites ofuptake of serotonin in the lung are in the endothelialcells of pulmonary vessels, especially pulmonary ar-terioles and capillaries (Strum and Junod, 1972). Thelung is also capable of forming serotonin, by decar-boxylation of 5-hydroxytryptophan. This biosyn-thesis occurs in cells which apparently do not partic-

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326 Circulation Research/ Vol. 50, No. 3, March 1982

®

SEROTONINNOREPINEPHRINE,

LEUKOTRIENES

fNOREPINEPHRINE

LEUKOTRIENESy

PGE2PGF2a

FIGURE 1. Pulmonary handling of bio-logically active compounds: Serotonin,norepinephrine, PCE2, PCF>,,, andprobably also the leukotrienes (slow-reacting substance), are taken up fromthe circulation and metabolized by in-tracellular enzymes (see text).

ipate in removing serotonin. They are found in thetracheobronchial tree, and can be identified by fluo-rescence and other characteristic histochemical fea-tures (Pearse, 1968; Lauweryns and Cokelaere, 1973).

The actions of serotonin include airway constrictionand pulmonary vasoconstriction. Its efficient uptakeand inactivation by the lung is thus a useful protectivemechanism that minimizes its untoward effects whenit is released under abnormal conditions, such aspulmonary embolism.

Catecholamines. Approximately 30% of norepi-nephrine is removed in the pulmonary circulation byan uptake process similar to that of serotonin.

Unlike neuronal uptake of norepinephrine (Uptake1),* pulmonary uptake is followed by metabolism, bythe intracellular enzymes MAO and catechol-O-methyltransferase. In this respect, the uptake by thelung resembles that by extraneuronal tissues, such asthe heart (Uptake 2),* but differs in having a higheraffinity (lower Km) (Gillis and Roth, 1976). Further,although epinephrine and isoprenaline are better sub-strates for the extraneuronal Uptake 2 process, neitherof these catecholamines is taken up by the lung(Alabaster, 1977).

As for serotonin, the uptake of norepinephrineoccurs mainly in pulmonary vascular endothelium,with preferential uptake in the pre- and postcapillaryvessels and in veins (Nicholas et al., 1974). Pharma-cological evidence suggests that the uptake sites fornorepinephrine and for serotonin are distinct andseparable (Iwasawa and Gillis, 1974).

The possible physiological significance of the dif-ferential handling by the lung of norepinephrine on

* Uptake 1 refers to neuronal, and Uptake 2 to extraneuronal,uptake of catecholamines. Uptake 2 differs from Uptake 1 in beingunaffected by cocaine and metaraniinol, but inhibited by meta-nephrine and normetanephrine, and in having a higher Km andVm, for norepinephrine (Alabaster, 1977).

the one hand (20% removal) and epinephrine or iso-prenaline on the other (no uptake) is at present un-known.

Histamine. The lungs of different species containhistamine-metabolizing enzymes, including imid-azole-A/-methyltransferase and diamine oxidase.Therefore, it is not surprising that homogenized orchopped lung readily inactivates histamine. Relativelyfew reports are available on the clearance of histamineby intact lungs; most of these reports conclude thatremoval of histamine is ineffective, probably becauseof the lack of a specific transport (uptake) mechanism.A recent paper, however, showed that 14C-histaminecould be taken up and metabolized by rat lungs invivo (Krell et al., 1978).

If pulmonary inactivation in vivo is, in fact, inade-quate, it means that the airways and pulmonary (andbronchial) vessels are vulnerable to the actions ofendogenously released histamine, including broncho-constriction and increased microvascular permeabil-ity.

General Comments on the Uptake of VasoactiveAmines

The foregoing discussion underscores the criticalrole of the uptake process in the pulmonary handlingof vasoactive amines. Compounds for which thismechanism is lacking may be inactivated by lunghemogenates in vitro, but not by perfused lungs orlungs in vivo. As examples, perfused lung does notinactivate epinephrine, dopamine, or tyramine, eventhough all are good substrates for intracellular en-zymes from the lung. The uptake mechanism thusenables the lung to exercise selective control over themetabolism of these compounds (Youdim et al., 1980).

Such selectivity is not exhibited by the liver, wherethese and other amines (including histamine) are me-tabolized equally well by mitochondrial MAO prep-



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Sa/c//Metabolic Functions of the Pulmonary Circulation 327

arations and by the perfused organ. The presence ofa selective uptake mechanism in pulmonary vesselsand its absence in portal vessels may be explained bymorphological differences between endothelial cellsfrom the two organs. Pulmonary capillaries, like thoseof skeletal muscle, have a continuous endotheliumand a continuous basal lamina. The liver on the otherhand, has discontinuous capillaries (sinusoids) pos-sessing a very thin endothelium which displays largegaps (up to hundreds of nanometers in diameter), andits basal lamina is either discontinous or absent (Sim-ionescu, 1980).

The pulmonary uptake of serotonin and norepi-nephrine is sensitive to a number of physiological andenvironmental factors. As already mentioned, the up-take process is inhibited by the tricyclic antidepres-sants and cocaine. It is also inhibited by certain ste-roids, e.g., estradiol and corticosterone, by the anes-thetics halothane and nitrous oxide, and by anoxia,hyperoxia, and hypothermia.

Certain basic drugs (non-biogenic amines) includ-ing tripelennamine, diphenhydramine, mepacrine,imipramine, amphetamine, and methadone, are alsotaken up and accumulated in the lungs. Although thelung does not metabolize these drugs, it appears tohave a selective, saturable, and reversible capacity forbinding some of them (Bakhle and Vane, 1974; An-derson et al., 1974).

Prostaglandins. More work has been done on thepulmonary handling of the "primary" prostaglandins(PCs), especially PGE2 and PGF2U than on the morerecently identified biosynthetic products of arachi-donic acid. Early in the investigation of pulmonaryinactivation of vasoactive hormones, Ferreira andVane (1967) reported that the lung removed 90% ofPGEi or PGF2,, during one circulation. Shortly there-after, McGiff et al. (1969) showed that the pulmonaryremoval of PG's was selective, and that PGA com-pounds passed through the lung with little loss inactivity.

This selectivity was first ascribed to the selectivityof the PG-metabolizing enzymes in the lung, 15-hy-droxy-prostaglandin dehydrogenase and 13,14-reduc-tase, both intracellular enzymes. More recently, how-ever, Bito et al. (1977) and Anderson and Eling (1976)demonstrated the dependence of pulmonary removalof PG's on a carrier-mediated, energy-requiring trans-port process, and Nakano et al. (1969) showed thatthe key inactivating enzyme, 15-OH-PG dehydrogen-ase, exhibits no significant substrate specificity. ForPG's, therefore, as for biogenic amines, an uptakeprocess must procede the enzymic inactivation, andmany pharmacological agents that suppress the re-moval of PG's by the lung probably do so by inhibit-ing PG transport. These agents include highly ionizedorganic molecules such as bromcresol green and di-phloretin phosphate, and less polar compounds ca-pable of reacting with sulfhydryl groups, such asfurosemide and ethacrynic acid.

The cellular sites of PG uptake and inactivation

remain unknown. Ody et al. (1979) found that endo-thelial cell preparations derived from pulmonary ar-tery or aorta failed to degrade either PGF2o or PGAithough they formed the previously demonstratedPGA-glutathione conjugate (Gross and Gillis, 1976).They also found evidence for selective metabolism ofPGAi by smooth muscle from trachea, pulmonaryartery, or aorta.

SRS-A (leukotriene C4 and D4) appears to lose its"biological activity (assayed on guinea pig ileum) dur-ing a single passage through the pulmonary circula-tion (Piper et al., 1981), but the mechanism of thisinactivation remains unknown. The pulmonary me-tabolism of thromboxane A2 has not been investi-gated, owing to the intrinsic instability of this com-pound and because it has generally been availableonly in semipure preparations (Moncada and Vane,1979). Prostacyclin (PGI2) is not significantly metab-olized in the pulmonary circulation (see below).

The efficient, though selective, pulmonary removalof prostaglandins and related lipids has importantpotential implications to pulmonary and systemicfunction. Compounds like PGE2, PGF2,,, and the leu-kotrienes are rendered essentially "local hormones,"acting mainly at the sites of their synthesis andrelease. On the other hand, PGA2 and prostacyclin,which escape pulmonary inactivation, are circulatinghormones capable of influencing organs beyond thosewhere they are released.

Compounds That are Metabolized at the PulmonaryEndothelial Surface (Fig. 2)

Bradykinin and Angiotensin. Ferreira and Vane(1967) showed that 80% of the bradykinin introducedinto the venous blood was removed in one passagethrough cat lungs. Similarly effective inactivation ofbradykinin by the lung has been demonstrated inseveral other mammalian species. About the sametime, Ng and Vane (1968) reported that conversion ofthe relatively inactive angiotensin I into the potentvasopressor angiotension II occurred more rapidly inthe lung than in blood or other tissues.

The enzymic inactivation of bradykinin in the lungis achieved by kininase II, or dipeptidyl carboxypep-tidase (EC 3.4.15.1). This membrane-bound enzyme,located in pulmonary endothelium and elsewhere,breaks peptidyl-dipeptide bonds from the carboxylterminal end (Erdos and Yang, 1966; Yang and Erdos,1967).

In 1956, Skeggs and co-workers discovered an en-zyme in plasma that removes the carboxyl terminaldipeptide, histidyl-leucine, from angiotensin I, con-verting it to the octapeptide angiotensin II. They calledit angiotensin I-converting enzymes. Several obser-vations suggested that the pulmonary inactivation ofbradykinin and conversion of angiotensin I to angio-tensin II might be catalyzed by one and the sameenzyme. Yang and co-workers, first using partiallypurified enzyme preparations and specific inhibitors,and later using antibody to the enzyme and homo-



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A ,Bkn

FIGURE 2. Pulmonary handling of bio-A2 logically active compounds: Bradyki-

Bkn INACTIVE nin is inactivated, and angiotensin 1 isFRAGMENTS activated, at the pulmonary endothelial

surface, by angiotensin-converting en-zyme (see text).

geneous enzyme, established the identity of angioten-sin I-converting enzyme with kininase II (Erdos,1979a).

In addition to bradykinin and angiotensin I, otherendogenous substrates of this enzyme are the en-kephalins (Erdos et al., 1978) and insulin, at least invitro. Peptides that are not hydrolyzed by this enzymeinclude those with a penultimate proline residue (e.g.,angiotensin II), those lacking a free carboxy-terminalcarboxyl group, and those smaller than a tripeptide(Cushman et al., 1979).

Angiotensin-converting enzyme is located in pul-monary vascular endothelium (Ryan et al., 1976), andto some extent in the endothelium of peripheral vas-cular beds (Caldwell et al., 1976). The enzyme alsooccurs in some epithelial cells, such as the brushborder of the renal proximal tubule (Ward et al.,1977) and intestinal mucosa (Ward et al., 1980). Eventhough the concentration of the enzyme in pulmonaryendothelium is not higher than in all other tissues, thelarge area of the pulmonary vascular bed, to whichthe entire cardiac output is accessible, gives highphysiological significance to the potential for angio-tensin conversion in the pulmonary circulation.

Low levels of kininase II (converting enzyme) activ-ity are found in plasma and other biological fluids(Yang and Erdos, 1967). This activity is elevated insarcoidosis, but not in tuberculosis (Lieberman, 1975);the elevation may result from increased enzyme activ-ity in lymph nodes. Acute hypoxia decreases pulmo-nary kininase II activity in dogs (Stalcup et al., 1979).

The discovery that peptides from the venom ofBothrops jararaca and other snakes potentiate theaction of bradykinin and inhibit the conversion ofangiotensin I has stimulated a lively interest in devel-oping inhibitors of the enzyme for therapeutic use.Inhibitors are now available that have greater speci-ficity and potency (Cushman et al., 1979; Erdos,1979b), and some, including captopril, are effective

by mouth. These inhibitors are now under activeinvestigation for their usefulness as antihypertensivedrugs.

Other Peptides. Substance P, an 11-residue peptidepresent in the central nervous system and peripheralnerves, including those in the lung, intestine and otherorgans, is inactivated by cultured endothelial cellsfrom human umbilical cord and lung (Johnson andErdos, 1977), but inactivation of substance P by wholelung appears to be ineffective. Endothelial cells inculture also inactivate leucine and methionine en-kephalins (Erdos et al., 1978).

Adenine Nudeotides. Adenosine triphosphate(ATP), diphosphate (ADP), and monophosphate(AMP) are removed in one passage through the lung.The metabolizing enzymes, 5'-nucIeotidase and ATP-ase, have been localized on the pulmonary endothelialsurface and within the pinocytotic vesicles of endo-thelial cells (Ryan and Ryan, 1977). Dieterle et al.(1978) have demonstrated the ability of cultured en-dothelial cells of pulmonary and systemic origins tometabolize ATP and adenosine.

Compounds That are Neither Taken Up norMetabolized in the Pulmonary Circulation (Fig. 3)

Compounds for which no uptake (transport) mech-anism exists in pulmonary endothelium or those notmetabolized by enzymes at the endothelial surfaceemerge from the lung without appreciable alterationor loss of activity. Reference has already been madein this review to some of these compounds, includingepinephrine, dopamine, tyramine, and possibly alsohistamine; prostaglandin A compounds (except a pro-portion of which may form an adduct with glutathi-one); and a number of peptide hormones, such assubstance P, oxytocin, vasopressin, angiotensin II(Bakhle and Vane, 1974) and vasoactive intestinalpeptide (VIP) (Kitamura et al., 1975). Some pulmonarydegradation of angiotensin II may occur during pul-



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Sa/d/Metabolic Functions of the Pulmonary Circulation 329

HISTAMINE,EPINEPHRINE

A,,SP, VIP,OTHER

PEPTIDESPGI ,

/HISTAMINE EPINEPHRINE SP.VIP, A, P 6 l 2

OTHER PEPTIDES

FIGURE 3. Pulmonary handling of biologicallyactive compounds: Histamine, epinephrine,angiotensin II, substance, P, VIP and otherpeptides, and PGIi emerge from the pulmo-nary circulation without significant uptake ormetabolism (see text).

monary edema, possibly because of the release ofintracellular metabolizing angiotensinases from en-dothelial and other cells (Kumamoto et al., 1981).

The biological activity of prostacyclin is not sig-nificantly reduced during passage through the lung(Armstrong et al., 1978; Waldman et al., 1978; Dustinget al., 1978), and this conclusion is consistent withbiochemical evidence of only slight metabolic degra-dation of this compound in the lung (Wong et al.,1978). Thus, in contrast to PGE2, PGF2a, and theleukotrienes; prostacyclin is mainly a circulating hor-mone (Moncada et al., 1978; Gryglewski, 1979).

Effects of Physiological and Pathological Factors onPulmonary Metabolism of Vasoactive Hormones

The pulmonary handling of vasoactive amines andof prostaglandins is subject to a variety of physiolog-ical influences. Among these are steroids, pregnancy,and the estrus cycle. Thus, the uptake of monoaminesby rat lung is highest during pro-estrus, and MAOactivity is stimulated by progesterone and estradiol(Youdim et al., 1980). Pulmonary inactivation of PGE2

by rabbit lung is enhanced 3-fold during pregnancyor progesterone treatment (Bedwani and Marley,1975; Boura and Murphy, 1978).

The effects of two types of environmental factorshave been investigated: oxygen and other oxidants,and cigarette smoke. The possible inhibitory effect ofoxygen was first suggested by the finding (Kistler etal., 1967) that pulmonary endothelial cells were par-ticularly vulnerable to damage during the develop-ment of oxygen toxicity. Exposure to 100% O2 for 48hours, or to 46 ppm nitrogen dioxide for 6 hours,inhibited the metabolism of PGF^ by guinea pig lungsin vitro (Chaudhari et al., 1979), and of PGE2 byperfused rat lung (Klein et al., 1978; Bakhle et al.,1979). Hyperoxia (97% O2 for 18 hours or longer) alsoinhibited the uptake of serotonin by perfused rat

lungs (Block and Fisher, 1977). Exposure of rats tocigarette smoke for up to 10 days suppressed theinactivation of PGE2, increased the conversion of an-giotensin I to angiotensin II, but did not affect sero-tonin metabolism in the isolated perfused lung(Bakhle et al., 1979).

The mechanism by which oxygen might diminishserotonin and prostaglandin metabolism could in-volve the inactivation of enzymic SH groups. Thereare eight moles of sulfhydryl (SH) per mol of MAO,and the SH content appears to be important for fullcatalytic activity, since the oxidation of SH to disul-phide bonds leads to a reduction in enzymic activity(Youdim et al., 1980). Indirect evidence suggests that15-hydroxy prostaglandin dehydrogenase, the key en-zyme in the pulmonary inactivation of prostaglandins,also contains SH groups essential for its activity (Han-sen, 1976). The effect of high oxygen pressure on thetransport process for prostaglandins is at present dif-ficult to evaluate (Youdim et al., 1980).

Pulmonary Generation of Biologically ActiveCompounds

Many of the biologically active compounds alreadydiscussed in relation to their pulmonary metabolismmay also be synthesized and released by the lung.Specially mentioned in this review, because of recentimportant discoveries, are histamine, vasoactive pep-tides, and prostaglandins and related lipids. Enzymesand other proteins, e.g., proteases, thromboplastin,plasminogen activator, lymphokines, and comple-ment, are not discussed here.

Histamine

One of the primary mediators of immediate hyper-sensitivity, histamine, is released mainly from pul-monary and other mast cells. The biochemical andcytological mechanisms of this release and pharma-



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cological means of its control have been extensivelyexamined (Lewis and Austen, J1977).

PeptidesIt is not known that normal lung may contain or

generate several active peptides (Said et al., 1980),including those discussed below.

Vasoactive Intestinal Peptide (VIP), a 28-residueneuropeptide occurring in the central and peripheralnervous systems, relaxes airway and pulmonary vas-cular smooth muscle, and induces systemic vasodila-tion, hypotension, and other effects (Said, 1980). Inthe lung, VIP is principally located in nerves supply-ing the airways and pulmonary vessels (Dey et al.,1981) as well as in mast cells (Cutz et al., 1978).

"Spasmogenic Lung Peptides" is a systemic vaso-dilator peptide that contracts airway, pulmonary vas-cular and other smooth muscle, and is distinct fromother peptides with similar actions; it has been puri-fied from normal lung tissue (Said and Mutt, 1977),but its chemical composition has yet to be determined.

Substance P which, like VIP, is mainly a neuropep-tide with pulmonary localization in nerves to airwaysand pulmonary vessels (Dey and Said, 1981); it is asystemic vasodilator but contracts smooth musclestructures in the lung.

A Bombesin-Iike Peptide has been demonstrated inendocrine cells of fetal lungs (Wharton et al., 1978)but not yet in lungs of adult animals. Bombesin, a 14-residue peptide from the skin of the amphibian Bom-bina bombina, has spasmogenic properties on airway,pulmonary vascular, and other smooth muscle. Themammalian counterpart of bombesin is probably the27-residue gastrin-releasing peptide (McDonald et al.,1979).

Bradykinin may be formed (and metabolized) inthe lung, through the action of activated kallikrein ontissues kininogens. Bradykinin, a potent systemic vas-odilator and vasodepressor, is capable of increasingsystemic vascular permeability, but its ability, on itsown, to increase pulmonary microvascular permea-bility has not been established. In combination withhypoxia, however, bradykinin can induce pulmonaryedema (O'Brodovich et al., 1981).

Angiotensin II, generated through the action ofangiotensin I-converting enzyme in pulmonary en-

dothelium, constricts pulmonary as well as systemicvessels (Segel et al., 1960). A role for angiotensin II inthe pulmonary vasoconstriction included by hypoxiawas once proposed (Berkov et al., 1974) but has notbeen confirmed. Inhibition of the conversion of an-giotensin I to angiotensin II has been reported toreduce pulmonary arterial pressure and vascular re-sistance (Niarchos et al., 1979).

LipidsProstaglandins and Related Lipids. The initial trig-

gering reaction for the biosynthesis of all prostaglan-dins and related lipids is the activation of phospholi-pase A2, which releases free arachidonic acid frommembrane phospholipids. A variety of potent com-pounds may be synthesized by the lung from arachi-donic acid, and their biosynthesis follows one of twomajor pathways: one catalyzed by cyclo-oxygenaseand the other by lipoxygenase enzymes (Fig. 4). Activebiosynthetic products formed through the cyclo-ox-ygenase pathway include the intermediate endoper-oxides, PGG2 and PGH2; the "primary" prostaglan-dins, PGE2, PGF-2,,, and PGD2; thromboxane A2; andprostacyclin (PGI2). With the exception of PGI2, all ofthese compounds are pulmonary vasoconstrictorswith varying potencies. All but PGE2 and PGI2 arealso bronchoconstrictors. There is not direct evidence,however, that any of these products can increasepulmonary vascular permeability. Thromboxane A2induces, and PGI2 inhibits, platelet aggregation. Thenature and relative preponderance of these biosyn-thetic products vary from species to species, (Al-Ubaidi and Bakhle, 1980).

The lipoxygenase system catalyzes the formationof several active compounds, including derivativesof hydroperoxy-eicosatetraenoic acid (HETE andHPETE), with chemotactic activity toward leukocytes,and the leukotrienes, of which leukotriene C4 and D4have the activity of the "slow-reacting substance ofanaphylaxis "(SRS-A)," i.e., slow and prolonged con-traction of airways and other smooth muscle (Kella-way and Trethewie, 1940; Dahlen et al., 1980).

Stimulated pulmonary generation of arachidonicacid, and subsequent biosynthesis of products cata-lyzed by cyclooxygenase and by lipoxygenase, areknown to occur in a number of experimental condi-

ARACHIDONIC ACID

Li poxy genase cyclo-

HPETE, HETELEUKOTRIENFS (SRS)

oxygenase

PG ENDOPEROXIDESFIGURE 4. Transformations of arachidonic acid inthe lung (see text).

PGE2, PGF2a PGI2 (PGXy PROSTACYCLIN) THROMBOXANE A2

PGD,



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Saic//Metabolic Functions of the Pulmonary Circulation 331

tions that mimic physiological and pathophysiologicalstates. Among these are: hyperventilation and respi-ratory alkalosis, pulmonary embolism, pulmonaryedema, endotoxin and hemorrhagic shock, and instil-lation of HC1 in the airways (Said, 1977, 1981; Cooket al., 1980; Aoyagi et al., 1981). The release of pros-taglandins and other lipids in these states probablycontributes to the pathogenesis of lung injury and toaltered pulmonary and systemic function, but theprecise contributions of each compound are still in-completely known. The leukotrienes (SRS-A) are alsobelieved to be important mediators of immediatehypersensitivity.

The anti-inflammatory effects of corticosteroids areattributable, in part, to their ability to inhibit theformation of arachidonic acid, the principal precursorin this system, by inducing the synthesis of an inhib-itory peptide (Flower and Blackwell, 1979).

"Platelet-Activating Factor" (PAF). The PAF factor,recently identified as acetyl glyceryl ether phospho-rylcholine (Hanahan, 1980), is released from sensi-tized rabbit basophils and human neutrophils. As wellas inducing platelet activation, PAF has potent activ-ities, including constriction of airway smooth muscleand the production of edema.

Relation of Metabolic Activities to PulmonaryVascular Responses

The vasoactive hormones metabolized or generatedby the lung are capable of influencing all aspectsof pulmonary hemodynamics, including vascularsmooth muscle tone, vascular pressures, blood flow,and microvascular permeability. Systemic arterialblood pressure and peripheral vascular resistance alsomay be affected.

The following are examples of the participation ofvasoactive hormones and their pulmonary metabo-lism in physiological regulation:

1. Vasodilator prostaglandins (and prostacyclin)released during hyperventilation may promote in-creased pulmonary blood flow to match the aug-mented ventilation (Said et al., 1974a, 1977).

2. Vasoconstrictor prostaglandins and related com-pounds, still incompletely identified, may mediate thehypoxic vasoconstrictor response, at least in somespecies (Said et al, 1974a), whereas vasodilator com-pounds, particularly prostacyclin, may help modulate(or moderate) this response (Gerber et al., 1980; Y.Hamasaki, H.-H Tai, and S.I. Said, unpublished ob-servations).

3. Prostacyclin, a potent inhibitor of platelet aggre-gation that is synthesized by endothelial cells (Wek-sler et al., 1977), may serve to protect the integrity ofpulmonary, as well as systemic, vascular endothelium(Moncada and Vane, 1979).

4. The pulmonary inactivation of the potent vaso-depressor, bradykinin, and activation of the potentpressor, angiotension II, may be important mecha-nisms for maintaining systemic arterial blood pres-sure.

5. VIP, a vasodilator neuropeptide which is presentin nerves supplying the pulmonary vessels (Dey andSaid, 1980), may mediate the nonadrenergic, noncho-linergic relaxation of these vessels. Evidence for theexistance of this system in the pulmonary circulationhas recently been presented (Hamasaki and Said,1981).

On the other hand, impaired pulmonary removalor excessive generation of certain vasoactive hor-mones may be a factor in the mediation of suchpathophysiological responses are pulmonary vaso-constriction, airway constriction, platelet aggregation,increased pulmonary microvascular permeability, andsystemic hypotension.

The biological activities of potential humoral me-diators are generally well known (Table 1), and dataon their release in pathophysiological states and onthe modification of their presumed effects with phar-macological agents are accumulating rapidly. At pres-ent, evidence implicating particular compounds inspecific experimental or clinical conditions remainslargely indirect and, in some cases, tenuous. Beforeascribing a mediator role to a given biological activecompound, the following criteria should be fulfilled:(1) the "candidate mediator" must be capable ofmimicking, alone or with other compounds, the ef-fects it is suspected of mediating, (2) it must bereleased in sufficient concentrations at the site ofaction, (3) its release must be detectable before, or atthe onset of, the suspected effects, and (4) inhibitionof its release or of its actions must reduce or abolishthese effects.

It is likely that, in most instances, release andaltered metabolism affect more than one active com-pound, whether simultaneously or sequentially. Fur-ther, some humoral mediators, including histamine,serotonin, bradykinin, and PG's can activate intrapul-monary irritant receptors, triggering reflex changessuch as bronchoconstriction (Coleridge et al., 1978;

TABLE 1

Major Vascular Responses and Their Likely or PossibleHumoral Mediators

Response Possible mediators

Pulmonary vasoconstrictionand pulmonary hypertension

Pulmonary vasodilation

Platelet aggregation

Increased microvascularpermeability

Systemic hypotension

Serotonin, thromboxane A2,PGF^, PG endoperoxides,spasmogenic lung peptide,bombesin-like peptide, sub-stance P

PGI2, VIP

Thromboxane A2, PG endoper-oxides

Complement, SRS (leuko-trienes G, and D4), others tobe identified

PGI2, PGE2, VIP, bradykinin



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Dixon et al., 1979; Kaufman et al., 1980), that wouldcontribute to the pathophysiological responses.

Concluding CommentsWithin the past few years, the capacity of the lung

for metabolic activity has been well documented.Examples are the selective and efficient removal ofserotonin, bradykinin, and certain prostaglandins, theconversion of angiotensin I to angiotensin II, and thesynthesis and release of a variety of prostaglandins,thromboxane, prostacyclin, leukotrienes, and a vari-ety of peptides and enzymes. The potential implica-tions of these pulmonary activities for the regulationof pulmonary and systemic vascular and airwaysmooth muscle, as well as platelet function, are con-siderable. Similarly, the consequences of impairedmetabolism or excessive release could include pul-monary vasoconstriction, systemic hypotension, air-way constriction, platelet aggregation, and increasedpulmonary microvascular permeability. Firm conclu-sions on the full physiological and pathophysiologicalsignificance of these metabolic lung functions and oftheir alterations in disease must await much additionalinvestigation.

Supported by National Institutes of Health Lung Center AwardHL-14187 and Grant CA-21205.

Address for reprints: Dr. Sami I. Said, Department of Medicine,University of Oklahoma Health Sciences Center, P.O. Box 26901,Oklahoma City, Oklahoma 73190.

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