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Abnormal Lung Surfactant Related to Essential Fatty Acid Deficiency in a Neonate

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Abnormal

Lung

Surfactant

Related

to Essential

Fatty

Acid Deficiency

in a Neonate

Zvi Friedman, M.D., F.R.C.P.(C), and Abraham Rosenberg, Ph.D.

From,, tlt’ 1)Eiartmllents of Pediatrics and Biological Clienistry, TI,e Milton S. Ilershey ‘stedieal Ce,,ter of tle

Penn.sylrania St(It(’ t mirersity College of %fedicine, Hershey, Pen n.sylrania

ABSTRACT. A low-birth-weight infant, suffering from

chronic bronchopulmonar dysplasia following hyaline

mcI1l)rane disease and recurrent episodes of necrotizing

enterocolitis, developed biochemical evidence of essential

fatty acid (EFA) deficiency in the plasma. Fatty acid

(01111)OsitiOfl of phosphatidlcholine and

phosphatidlglcer-ol in the lung lavage fluid was abnornial. Plasma changes

includcd a decrease in the level of linoleic acid and an

increased level of palmitic, palniitoleic, oleic, and

5,8,11-eicosatrienoic acids, the ratio of 5,8,1 1-eicosatrienoic acid to

arachidonic acid being >0.4:1. A lower than normal level of

palmitic acid and an increased level of palmitoleic and oleic

acids were SCCII in )ulmonar surfactant phospholipid

C0IU1)OfleIlts. U1)()n treatment and recovers’ from EFA

deli-ciencv, the fatty acid pattern both in plasma and surfactant

l)1i5l)110l ipids returned to normal along with clinical

improvement. Au association l)etween EFA deficiency and

altered fatty acid composition of pulmonary surfactant

phospholipids is suggested. Pediatrics 63:855-859, 1979,

(‘s.s(’nti(Il fatty (1(i(l (lefu-iency. lung surfactant.

The presence of a surface tension-lowering material in lung alveoli was first suggested by von Neergaard in 1929.’ In 1946, Thannhauser et al2

observed the high content of saturated lecithin in

lung tissues. Soon others’ began to realize that

the lung is an active site of lipid synthesis and that, in the alveolar lung fluid, an insoluble film

forms at the air-liquid interface and modifies its surface tension. Clements et al later

demon-strated that this interfacial material reduces the

pressure across the alveolar interface, thereby

promoting alveolar stability. King and Clements7

also have shown that 85% of this surfactant

material is lipid, of which approximately 75% by

weight is phosphatidlcholine. The major molec-ular species of phosphatidylcholine in the lung

and lung lavage fluid is dipalmitoyl glycerophos-phocholine, which plays an important role in determining the surface properties of pulmonary surfactant .

Essential fatty acid deficiency is reported to

cause respiratory disease syndrome in chickens”;

in rats, it results in a significant reduction in the patmitate content of lung surfactant. These changes have been associated with impaired surface tension-lowering activity of this materi-al.i)2 Development of EFA deficiency has been described in infants and children who have been maintained on fat-free diets’ and fat-free intraye-nous alimentation.’

The present studies were undertaken to ascer-tam in a human subject, an EFA-deficient infant with chronic bronchopulmonary dysplasia

follow-ing hyalmne membrane disease, whether there was

a reduction in palmitate content of the lung lavage phospholipids and to investigate the time

course of reversal of this alteration once the infant is fed a diet containing linoleic acid. The results

show a decrease in palmitate content of lung lavage phospholipids during the EFA-deficiency

state in a human infant. On feeding the infant a

lmnoleate-containing diet, reversal was completed within one month.

MATERIALS AND METHODS

Case Report

The infant was born to a 22-year-old gravida 3, para 2

black woman after spontaneous labor associated with

al)rup-tio placentae at 30 weeks’ gestation. Apgar scores were 2 at

one and ten n#{236}inutes,respectively. The infant was

resusci-tated vigorously and later transferred to the Neonatal

Intensive Care Unit at MSHMC. Birth weight was 1,300 gin

(40th percentile); length, 41 cn (60th percentile); and head

circumference, 27.5 cm (40th percentile). The infant

devel-oped respiratory distress that required endotracheal

intuba-Received July 20; revision accepted for publication October

19, 1978.

ADDRESS FOR REPRINTS: (Z.F.) Department of

Pediat-ncs, Baylor College of Medicine, 1200 Motirsund Avenue,

(2)

3000

25001-:

2000 I

1500

1000L

150

125

100

75

50

25

0

Parenteral

I

Nutrition

Portagen

I I I I I I . . ‘

1

1 2 3 4 5 6 7 8 9 10 11 12 13 14

WEEKS OF LIFE

Nutritional regimen and weight gain in patient during postnatal life.

C’,

---S-0 -o1:)

tiol3 and mechanical ventilation. Hpotension and anemia

were corrected with blood transfusions. The clinical course

was complicated l)\ patent ductus arteriosus, convulsions,

chronic bronchopulmonar dsplasia, and cor pulmonale.

Recurrent episodes of necrotizing enterocolitis required the

administration of parenteral nutrition. The intravenous

solu-tions included dextrose, electrolytes, a parenteral

alimenta-tion mixture containing a synthetic solution of aniino acid,

trace minerals, and vitamins. Fluid intake varied between 75

and 220 ml/kg/24 hr and caloric intake between 18 and 135

kcal/kg/24 hr. Oral feeding included Portagen, a formula

containing lipid mainly in the form of medium-chain

trigly-cerides (MCT) and a sniall amount of corn oil containing

linoleic acid.

The feeding regimen is illustrated in the Figure. The

infant died at 3#{189}nonths of age. Permission for postmortem

examination was refused.

Lipid Analysis of Plasma and RBC

Whole blood, anticoagutated with EDTA, was obtained via a central line or peripheral veni-puncture and centrifuged at 4 C. The plasma and

RBCs were frozen and stored in 100% nitrogen

until lipid extraction was begun. The various lipid fractions-phospholipids, cholesterol esters, tn-glycerides, and free fatty acids-were separated

by thin-layer chromatography, and the fatty acid composition of each lipid fraction was then

deter-mined by gas-liquid chromatography. These methods have been described previously.’

Lung Lavage

Following chest physiotherapy, lung lavage was

obtained using a Fr 6 suction catheter via an

endotracheal tube. Three washes, each utilizing 0.5 ml of normal saline, were collected. The material was centrifuged within 30 minutes at 101 x g for 15 minutes and pellet (A) and float (B) were removed. The remaining supernatant was centrifuged at 10

x

g for 60 minutes and pellet

(

C) was separated from supernatant (D). These

fractions were extracted with choloroform and methanol. ‘ The phospholipids were separated

from neutral lipids by thin-layer chromatography in a variation of a published procedure,” using chloroform, methanol, and water (65:35:8). Spots

were identified by comparison with reference

compounds exposed to iodine vapors. The fatty acid composition of the various phosphotipids was

analyzed by gas-liquid chromatography.”

RESULTS

Plasma and RBC Lipids

The infant was found to have EFA deficiency based on conventional criteria.’7 In addition to a

decrease in the linoleic acid level, there was a charactenisitic increase in 5,8,11-eicosatnienoic

acid (Table I). The ratio of 5,8,11-eicosatnienoic acid to arachidonic acid, the “trienoic/tetraenoic ratio,” is ordinarily less than 0.4:1.’ In this infant, the ratio in plasma was 0.6: 1 during EFA

defi-ciency and less than 0. 1 : 1 during recovery. The

changes in the fatty acids in the RBC phospholip-ids are less obvious than those observed in the

(3)

Lung Lavage

TABLE I

The percentage changes in the composition of the fatty acid methyl esters derived from

phos-phatidylcholine (PC) and phosphatidytglycerol (PG) fractions of the lung lavage during EFA deficiency and upon recovery are shown in Table II. During the period of EFA deficiency, there is a

decrease in palmitate and linoleate in the PC and a decrease in palmitate in the PG fraction.

Smniultaneously, there is an increase in the levels

of palmitoleate and oleate in the PC fraction and

an increase in the level of palniitoleate in the PG fraction. Upon the infant’s recovery from the EFA-deficiency state, an increase in the levels of

palniitate and linoleate and a decrease in the level of palmitoleate are seen in the PC and PG

fractions, and a decrease in the level of oleate is

seen in the PG fraction.

DISCUSSION

The patient developed biochemical changes in

the plasma that were compatible with the diagno-sis of EFA deficiency and which were reversible

with oral feedings containing EFAs. Both

arachid-onate and linoleate are effective in the treatment of EFA deficiency’’ but, as linoleic acid is readily

converted to arachidonic acid in vivo,2’ it is the

primary nutrient necesary for the prevention of EFA deficiency. There are two sources of linoleic acid: dietary fat, the prime source, and adipose tissue stores. In the fetus, the proportion of linoleic acid in tissue phospholipids increases with advancing gestational age2’ so that the prematurely born infant is endowed with limited

stores. Because of their limited nonprotein caloric

reserve, these infants must mobilize fatty acids for

caloric needs when faced with deficient dietary intake. Adipose tissue triglycerides undergo constant hydrolysis with the release of EFA and

other fatty acids to the plasma. During

hyperali-mentation, however, the outflow of linoleic acid

froni adipose tissue is blocked, at least in part by

the high insulin levels accompanying glucose

administration. During his first 7 /2 weeks of life, at which time the EFA deficiency was

detected, the patient had gained only 100 gill

over his birth weight. During this time he was

receiving fat-free parenteral nutrition that was

supplemented for a period of two weeks with

Portagen. Although the EFA composition was

deternlined for plasma lipids, tissue levels of

EFAs were likely to be reduced as well.

EFA deficiency has been shown to cause

respi-ratorv disease syndrome in chickens,” and in rats

it resulted in a significant reduction in palmitate

FATTY ACID CONTENT IN PLASMA ANI) RBC PH05PH0LIPID

FRACTION AT 7.5, 11, AND 13 WEEKS OF LIFE#{176}

Fatty Acidst % i

7.5 n Plas 11 ma 13 % 7.5 in RB 11 C 1.3

Palmitic (c16:0) 27.6 23.8 23.2 22.9 21.2 20.8

Palmitoleic (c16:1) 2.7 1.7 1.8 2.1 2.2 2.4

Stearic (c18:0) 12.2 12.6 12.9 9.6 10.8 11.4

Oleic (c18:1 (.o9) 21.0 17.2 16.8 18.7 16.8 15.9

Linoleic (c18:2w6) 6.3 19.5 18.8 8.6 12.2 12.6

5,8,11-Eicosatrienoic 6.0 1.7 0.9 1.0 0.6 0.5

(c20:w 9)

Dihomo-’y-linolenic 4.4 4.4 4.6 2.3 2.8 3.1

(c20:3 Cd6)

Arachidonic (c20:4w6) 10.0 10.8 11.6 14.9 15.2 15.6

‘EFA deficiency was greatest at 7.5 weeks of life, with

‘ecovery taking place between 1 1 and 13 weeks of life.

1The abbreviated formula indicates the number of carbon

atoms and the number of double bonds. The position of the

double bond nearest to the methyl terminus is indicated by

the symbol w.

content of lung surfactant, but not in the total

amount of phospholipids in lung tissue and lavage fluid.”

Our data show that simultaneously with EFA

deficiency in plasma, there is evidence of EFA

deficiency in pulmonary surfactant PC and PG. However, in lung surfactant, EFA deficiency is

associated with a reduction of palmitate content, whereas in the plasma the reverse is true. Once

linoleate-diets containing are fed, the time course for correcting the dietary state in the plasma and

pulmonary lavage PC and PG is similar.

Clinical-ly, upon recovery from the EFA-deficiency state, an improvement in the respiratory illness was

noted in our patient. The infant was extubated for

several days, but superimposed pneumonia and

atelectasis required reintubation and mechanical ventilation. The major molecular species of PC in lung tissue and lavage fluid is dipalmitoyl PC.

This disaturated species of PC is considered to play an important role in determining the surface

properties of pulmonary surfactant.M Reduction

in this species of PC results in surfactant with diminished surface tension-lowering capacity in

EFA-deficient rats. ‘

Beside PC, the surfactant complex contains

other highly characteristic phospholipid

compo-nents. In the adult, the second major phospholipid

is phosphatidylglycerol.2 Ill the fetal rabbit, PC is

absent, appearing first at Y’ Recently, PG deficiency has been demonstrated in infants with

(4)

TABLE II

F:rry Acm CoMPosITIoN OF LUN(; LAVA(;E PHOSPHOLIPIDS DURING

EFA DEFIcIENc- AND RECOVERY0

l1(i(ti()lif (111(1 iiIll(’

of .?l(1liJSiS

I(Itt iJ Acids

(%)1:

--

---Palmnitic Palmitoleic Str’aric Olcie Linolcie

(e16:0) (c16:1) (c18:0) (c18: 1 cv 9) (e18:2 w 6)

P!o.spliatidijleholiie

Fraction A

At 7.5 svk of life 53.6 10.3 10.4 17.8 0.4

At 11 wk of life 65.2 6.6 9.9 12.2 1.5

At 13 wk of life 68.4 6.3 9.7 14.5 1.7

Fraction B

At 7.5 wk of life 22.2 16.6 24.3 28.6 1.8

At 11 wk of life 30.9 5.9 23.0 25.1 5.1

At 13 wk of life 62.7 6.0 13.2 9.5 5.6

Fraction C

At 7.5 wk, of life 46.8 12.5 8.9 19.8 ND

1:3 wk of life 62.7 7.3 10.2 9.5 1.2

Fraction D

At 7.5 wk of life 24.1 8.9 11.8 19.5 2.0

At 13 wk of life 56.2 6.8 13.2 13.1 4.2

P!ao.sp!iatidijlglqeerol

Fraction A

At 7.5 wk of life 19.1 8.5 15.0 36.7 3.0

11 wk of life 24.2 6.3 20.0 37.2 3.0

13 wk of life 31.9 4.3 18.6 37.4 3.4

Fraction B

7.5 wk of life 22.6 18.6 19.2 33.0 2.3

At 11 wk of life :36.1 5.4 24.5 24.6 4.4

At 13 wk of life 38.3 7.8 30.1 27.8 4.8

#{176}Materials from tracheal lavage were analyzed at 7.5 weeks of life, which is the period of EFA

deficiency, and at 1 1 and 13 weeks of life, which is the period of recovery.

tAnalysis of tracheal lavage material was performed on the following fractions obtained by

centrifugation: A-pellet, 10

x

g; B--float, 10 X g; C-pellet, 10

x

g; D-supernatant,

10

x

g.

tThe abbreviated formula indicates the number of carbon atoms and the number of double

l)OI1(ls. The position of the double l)ofld nearest to the methyl terminus is indicated by the sym-1)01 CL).

§Nl) = level hot detectable.

fatty acid composition of surfactant PG during the EFA-deficient state may further impair its surface-active tension properties.

Lung structure is not altered by EFA

deficien-cy except for mitochondnial changes confined to type II cells.’ Therefore, the alteration in lung

mechanics in EFA-deficient rats results from impaired surfactant surface tension-lowering activity.’2 Impaired surfactant activity in humans

with EFA deficiency, although likely to occur, has not yet been demonstrated.

The association between EFA deficiency and the impairment of surfactant PC and PG fatty acid composition has been shown in the present study. This alteration niay diminish lung function

and so contribute to the pathophysiolog of hyalmne membrane ‘ chronic

bronchopul-monary dysplasia, cystic fibrosis,272M and other respiratory diseases associated with inadequate

nutrition inviting an EFA deficiency. Prevention of EFA deficiency in such patients may be essential for the maintenance of normal lung function.

REFERENCES

1. Von Neergaard K: Neue Auffassungen uber einen

Grundbegriff der Ateniniechanik. Z Ges Exptl Med

66:373, 1929.

2. Thannhauser SJ, Benotti J, Boncoddo NF: Isolation and

l)roperties of hydrolecithin (dipalinityl lecithin)

from lung: Its occurrence in the sphingoinyelin

fraction of animal tissue. I Biol C!iem 166:669,

1946.

3. NIacklin CC: The pulmonary alveolar mucoid film and

(5)

4. Pattle RE: Properties, junction and origin of the alveolar

lining layer. Nat,re 175:1125, 1955.

5. Clenients J.-, Brown ES, Johnson RP: Pulmonary surface

tension and the mucous lining of the lung: Some

theoretical considerations. I AppI Plzy.siol 12:262,

1958.

6. Clements JA, Hustead RF, Johnson RP, Gribetz I:

Pulmonary surface tension and alveolar stability. I

-“ll’ P!,ij.siol16:444, 1961.

7. King Rj, Clements JA: Surface active materials from dog

lung: II. Comimpositiomi and physiological

correla-tions. Aimi I Pli,.siol 22:3:715, 1972.

8. King RJ: The stirfactant system of the 11113g. lcd Proc

.33:2238, 1974.

9. \Vatkins JC: The surface properties of pure

phospholip-ids in relation to those of lung extracts. Biochin,

Biophijs A(l(I 152:293, 1968.

10. Hopkins DT, Witter RL, Nesheim MC: A respiratory

disease syndrome in chickens fed essential fatty acid

deficient diets. Proc Soc Exp Biol Ied 114:82,

1963.

11. Kvriakides EC, Beeler DA, Ed,nonds RH, Balint JA:

.lterations iii phosphatidvlcholine species and their

reversal in pulmonary surfactant during essential

fatty acid deficiency. Bioehim Biophijs ;%ct(I

4:31::39), 1976.

12. Bimrnell JM, Kvriakides EC, Edmonds RH, Balint JA:

The relationship of fatty acid composition and

surface activity of lung extracts. Re.spii- P!ay.siol

:32:195, 1978.

1:3. HaIlseli AE, Wiese HF, Boelsche AN, et at: Role of

linoleic acid in infant nutrition: Clinical and

chemn-ical stud of 428 infants fed on milk mixtures

varying in kind and amount of fat. Pediatrics 31:171,

1963.

14. Frieclmuan Z, Danon A, Stalilmia,i Mt, Oates JA: Rapid

onset of essential fatty acid deficiency in the

newborn. Pediatrics 58:640, 1976.

15. Rosenberg A: Light-independent stoichomiietry of

galac-tosvl diglceride and chlorophl accretion during

light-induced chloroplast membrane synthesis in

Luglena. Bioc!,en, Biophys Res Commun 73:972, 1976.

16. Barton NW, Rosenberg A: Metabolism of glycosyl [‘H]

ceranuide by human skin fibroblasts from normal

and glucoslceran-midotic subjects. I Biol Chem

250:3966, 1975.

17. Holmiman RT: Essential fatty acid deficiency, in Holmnan

RT, et at (eds): Progress in the Chemistry of Fats and Other Lipids. Elmsford, NY, Perganion Press mc,

1968, vol 9, pp 275-348.

18. Holmnan RT: The ratio of trienoic-tetraenoic acids in

tissue lipids as a measure of essential fatty acid

requirement. I Niitr 70:405, 196().

19. Mohrhauer H, Holman RT: The effect of dose level of

essential fatty acids upon fatty acid con3position of

the rat liver. I Lipid Res 4:151, 1963.

20. Mead JF: The metabolism of the polyunsaturated fatty

acids, in Holinan RT, et al (eds): Progress in the

Claeniistry of Fats and Ot!,er Lipids. Elmsford, NY,

Pergamon Press Inc. 1968, vol 9, pp 159-192.

21. Bruce A, Svennerholni L: Skeletal mmmscle lipids: I.

Changes in fatty acid composition of lecithin in

man during growth. Bioel,in, Biophy.s’ Aria 239:393,

1971.

22. \Vene JO, Connor WE, DenBesten L: The development

of essential fatty acid deficiency in healthy man fed

fat-free diets intravenously and orally. I Cli,, lot-es!

56:127, 1975.

23. Rooney SA, Canavan PM, Motoyamria EK: The

identifi-cation of phosphatidylglycerol in the rat. rabbit,

monkey and human lung. Bioe!aim Biophy.s’

360:56, 1974.

24. Hallmiian NI, Gluck L: The biosynthesis of

phosphatidl-glycerol in the lung of the developing rabbit. ted

Proc 34:274, 1975.

25. Hallman NI, Feldman BH, Kirkpatrick E, Cluck L:

Absence of phosphatidlglvcerol in respiratory

distress syndrome in the newborn. Pediatr Re.s

11:714, 1977.

26. Edmnonds RH, Beeler DA, Trebler DH, et al:

Morpho-logical alterations in type II alveolar cells in

essen-tial fatty acid deficiency. Exp .\Iol Pai!,o! 23:276,

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27. Rivers JPW, Hassam AG: Defective essential fatty acid

metal)olismil in cystic fibrosis. Lance! 2:642, 1975.

28. Sanjurjo P, AIltie X, Rodriguez-Soriano J: Fatty acid

composition of lecithin fraction of mucus in cystic

fibrosis. L(1fl(’et 1 :752, 1977.

ACKNOWLEDGMENT

This investigation was supported by grants No. 1 ROl HD

11255 from the National Institute of Child Health and

Human Development and No. NS08258 from the National

(6)

1979;63;855

Pediatrics

Zvi Friedman and Abraham Rosenberg

Abnormal Lung Surfactant Related to Essential Fatty Acid Deficiency in a Neonate

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1979;63;855

Pediatrics

Zvi Friedman and Abraham Rosenberg

Abnormal Lung Surfactant Related to Essential Fatty Acid Deficiency in a Neonate

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