American Journal of Medical Genetics 35126-131 (1990)

Mouse Major Histocompatibility Complex (H-2) and Fetal Lung Development: Implications for Human Pulmonary Maturation Ching-Chun Hu, Tina F. Jaskoll, Cedric Minkin, and Michael Melnick Graduate Program in Craniofacial Biology and Department of Basic Science, School of Dentistry, University of Southern California, Los Angeles

Using C57/10Sn (B10, H-2b) and BlO.A/SgSn (BlO.A,HJ") congenic mice, we measured 1) the level of endogenous pulmonary corticosterone during mouse development;2)the degree of lung morphological maturation on gestation day 17, with or without corticosteroid treatment; and 3) the maternal influence on normal lung development and fetal response to corticosteroids. The results of our study indicate that there was a progressive increase in the level of endogenous hormone with time in fetal B10 (H-2b)and BIO.A (H-2") mice; throughout mid- to late gestation, the detectable amount of hormone was almost identical in lungs of both strains. Evaluating the degree of lung maturation by morphometry, BIO.A mouse lungs were found to be less mature than B10 mouse lungs. Following corticosteroid treatment on day 12 of gestation, H-2"lungs were equal to or more mature than H-2blungs. We also compared heterozygous mouse lungs from reciprocal crosses (B10. BlO.A, b/a and B1O.A-BlO, a/b). Mice with a maternally derived H-2" haplotype had less mature lungs than those with a maternally derived H-2b haplotype, suggesting a maternal effect. When exogenous hormone was administered, all heterozygous mouse lungs increased in maturity regardless of the origin of the H-2" haplotype. The treated a/b or bia lungs were more mature than homozygous b/b and less mature than homozygous d a lungs. We conclude that progressive lung maturation is associated with a gene(s) at or near

the H-2 complex, as is the ability to respond to corticosteroids.

KEY WORDS: congenic mice, lung maturation, endogenous corticosterone, morphometry, respiratory distress syndrome

INTRODUCTION The lung is critical to extrauterine life because of the immediate need to achieve oxygenation and ventilation a t birth. Insufficient prenatal maturation of the respiratory system is the leading cause of respiratory distress syndrome (RDS), also referred to as hyaline membrane disease. RDS, an acute pulmonary disorder characterized by generalized atelectasis, develops almost exclusively in premature infants during the first few hours of life and leads to early respiratory failure. Supportive ventilation, administration of artificial surfactant, and corticosteroid treatment have significantly reduced the morbidity and infant mortality rate. Specifically, the administration of corticosteroids has been shown to promote morphologic and physiologic pulmonary maturation, surfactant synthesis, and enhanced nonsurfadant-related tissue compliance [Kresch and Gross, 19871.Clinically, the incidence of RDS appears t o be reduced from about 25% t o 9% after corticosteroid treatment; yet, there remains a group of infants who develop RDS despite receiving apparently optimal therapy [Kresch and Gross, 19871. It has also been demonstrated that different human lymphocyte antigens (HLA, chromosome 6 )of the major histocompatibility complex (MHC) are associated with differential responsiveness to corticosteroids [Becker et al., 19761. It is reasonable to hypothesize, then, that the Received for publication March 31, 1989; revision received July HLA type of infants who do not respond to hormone 21, 1989. Address reprint requests to Dr. Tina F. Jaskoll, Craniofacial treatment differs from that of responsive infants. BeBiology, School of Dentistry DEN-4321, MC-0641, University of cause of this, they are unable to benefit from corticosteroid therapy and require a different treatment regimen. Southern California, Los Angeles, CA 90089-0641.

0 1990 Wiley-Liss, Inc.

H-2 and Mouse Lung Development

Since the murine H-2 gene complex (mouse MHC, chromosome 17) is homologous to the HLA complex in humans, we can investigate the association of the MHC, lung maturation, and corticosteroid responsiveness using congenic mice which are genetically identical except at the H-2 complex.

MOUSE MAJOR HISTOCOMPATIBILITY GENE COMPLEX The MHC of mammals is a multigene family whose members encode cell surface glycoproteins involved in the recognition of and immune response to foreign antigens [Flavell et al., 19861. The MHC of mice (H-2) and humans (HLA) have been extensively studied [Becker et al., 1976; Hood et al., 1983; Goldman, 19841. Recently, attention has been focused on possible non-immune functions of MHC associated genes, particularly as they relate to embryonic and fetal mouse development [Melnick et al., 1981a; Goldbard and Warner, 1982; Warner et al., 19871. This includes timing of the first cleavage division [Goldbard and Warner, 1982; Goldbard et al., 1982a,b], corticosteroid receptor level and responsiveness as it relates to normal development and teratogenesis [Melnick et al., 1981b; Gupta and Goldman, 1982; Bonner, 1984; Goldman, 19841, morphogenesis of the mandible and other facial structures LBailey, 1986; Ciriani and Diewert, 19861, and overall fetal growth and survival [Melnick et al., 1981al. Phenotypic variation for all of these traits appears to be associated with H-2 haplotype. It is known t h a t there are major genes at or near the H-2 complex in mice that influence pre- and post-implantation development. H-2 antigens are synthesized by pre-implantation mouse embryos [Goldbard and Warner, 19821 and these antigens have been detected earlier in the embyros of congenic strains with the H-2b haplotype than with the H-2” and H-2khaplotype lCozad and Warner, 1981, 19821. A major developmental gene (Ped) that influences early mouse development has been demonstrated [Goldbard et al., 1982a,b; Warner et al., 19871. Mouse strains with the b or d haplotype develop faster than those with the k haplotype. Melnick et ai. [1981a] have also shown that the H-2 haplotype is associated with fetal weight and survival. B10 (H-zb) and B10.D2 (H-2d) had significantly smaller litters and greater fetal weight than B1O.A (H-2”, a recombinant between the k and d haplotype, i.e., KkDd). Several investigators have conclusively demonstrated that a strong association exists between H-2 haplotype and corticosteroid-induced cleft palate LMelnick et al., 1981b, 1983; Bonner, 1984; Goldman, 19841. H-2“ mice are more susceptible to corticosteroid-induced cleft palate than H-2bmice; H-2 haplotype differences alone are sufficient to alter the response to corticosteroids. The gene associated with corticosteroid susceptibility to cleft palate has been mapped between the H-2S and H-2D region ofthe H-2 complex [Gasser et al., 19891and is independent of the Ped gene, which is probably located near the D end in the Qa-2 region [Warner et al., 19871. These studies suggest that there are at least 3 or 4 major genes associated with the H-2 complex which could influence mouse development. The manifestation of these

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“developmental” genes can be modified by the genetic background [Goldbard et al., 198213;Warner et al., 19871 and the environment [Melnick et al., 1981b; Goldman, 19841.

CORTICOSTEROIDS AND LUNG DEVELOPMENT It has been shown that administration of corticosteroids to fetal animals accelerates lung development, resulting in pulmonary type I1 cell differentiation and subsequent surfactant synthesis and secretion [Ballard, 19821. In mice exposed transplacentally to dexamethasone, increases in air space size were observed [Kauffman, 1977al; these morphologic alterations occur earlier and at lower steroid concentrations than those which initiate type I1 cell maturation [Kauffman, 1977bl. Honig et al. L19841, using in vitro methods, detected differences in response to corticosteroid-stimulated choline incorporation into phosphatidylcholine between lungs of congenic BlO.A(H-2”) and B10 (H-2h) mice, suggesting t h a t the H-2 haplotype may influence lung morphogenesis and cytodifferentiation. Goldman and his coworkers [Gupta and Goldman, 1982; Goldman and Katsumata, 19861 measured the number of corticosteroid receptors in mouse lung cytosol and observed a n association between the H-2 haplotype and the number of receptors. H-2” mouse strains had a significantly higher receptor number than H-2b strains. Since the H-2 complex appears to play a n important role in normal mouse development and in the response to exogenous corticosteroids, we investigated the relationship between H-2 haplotype and lung morphogenesis. Using H-2 congenic mice, we determined 1) the levels of corticosterone in embryonic and fetal H-2” and H-2bmouse lungs, 2) the association of lung maturation with fetal H-2 haplotype with and without exogenous corticosteroid treatment, and 3) the extent of H-2 related maternal effects on fetal lung development. Our results suggest that a gene or genes a t or near the H-2 complex influences mouse lung development and its responsiveness to corticosteroid treatment.

MATERIALS AND METHODS Mating Scheme Virgin female C57/1OSn [BlO, H-2b(H-2DbKb)]and its congenic partner BlO.A/SgSn [BlO.A, H-2” (H-2DdKk)l, genetically identical except for a short chromosomal region that includes the H-2 complex, were purchased from Jackson Laboratory (Bar Harbor, Maine). Females were housed in groups of 5 and acclimated to the vivarium for a n initial 2-week period. When the females were 9-12 weeks of age, groups of 3 females were placed overnight with individual males. Each female was examined the next morning for the presence of a vaginal plug; the date of plug detection was designated day 0 of gestation. Pregnant dams were housed in solid-bottom, plastic cages. Alternate 12-hour periods of light (onset a t 9:00 A.M.) and darkness were maintained; mice were fed Wayne’s Mouse Breeder Blox and supplied with drinking water ad libitum. To provide the required maternal-fetal genotype com-

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binations, the following crosses were utilized: BlO? x B106 (H-2b,bib), B1O.AP x B1O.Ad (H-Z", a/aj, BlO? x B10.Ad (H-Zb/H-2",bia), and BlO.A? x B106 (H-2"/H-Zb,db) . Corticosteroid Administration Experimental mice were administered a single intramuscular injection (in the proximal portion of the hindlimb) of triamcinolone hexacetonide (2 mgikg body weight; Aristospan, Lederle Laboratories, Wayne, NJ) at 9 A.M. on day 12 of gestation. The remaining pregnant mice were untreated. Previous investigations in our laboratory demonstrated that there were no significant differences between vehicle injected and untreated controls [Melnick et al., 1981bl. For morphometric studies, 5 to 8 litters of both control and treated mice were collected for each mating type, consisting of a total of 338 fetuses.

Tissue Collection On day 17 of gestation, all dams were lightly anesthetized with metaphane and then sacrificed by cervical dislocation. The uterine horns were examined in situ, each live fetus was carefully dissected out of the decidua, and the trophoblast shell and Reichert's membrane were removed. Fetuses were measured, weighed, and staged according to Theiler [1972]. The left lobe of the lungs was immediately extirpated and fixed in 10% phosphate-buffered formalin overnight, dehydrated in graded ethanol, cleared in xylene for one hour, and embedded in paraplast. The lungs were sectioned at 6 pm, in a plane parallel to the long axis, and stained with hematoxylin and eosin. Morphometric Assays Mid-sagittal sections were selected by morphologic criteria and projected using a Bausch and Lomb microscope slide projector to a total magnification of 150x onto a digitizing tablet linked to an IBM-PC-XT. Air sac space perimeter was measured using the Sigmascan

morphometry program (Jandel Scientific, Corte Madera, CA). Measurements were collected for each fetus (approximately 600 measurements per section), and the summated air sac space perimeters divided by total lung cross-sectional area was calculated for each fetus. This ratio (mrn/mm2)largely corrects for differences in lung size among different fetuses. The ratio for all fetuses within a given litter was then summed and divided by the number of fetuses within that litter. All litters of each cross were then summed and divided by the number of litters for that cross. Thus, each dam was treated as a separate biologic unit [Gaylor, 19781. D a t a Analysis Nested ANOVAs were performed among haplotypes to assess the within litter, among litter within haplotypes, and among haplotype components of variance [Gaylor, 19781. Stepwise multiple linear regression analyses were performed to assess the relationship of lung maturation with several other variables, including H-2 haplotype, fetal weight, and litter size [Sokal and Fbhlf, 1981; Edwards, 19851.

Endogenous Corticosteroid Determination Embryonic and fetal lungs were collected from 12 to 17 days of gestation, pooled, weighed and stored at - 20°C. Corticosteroid concentration was determined by radioimmunoassay using [1,2-3Hlcorticosteroneas previously described [Jaskoll et al., 19881.This assay determined total corticosterone present (bound and unbound hormone) in embryonic and fetal lungs.

RESULTS L u n g Maturation The fetuses selected for each experimental group were all a t Theiler stage 25. Microscopic examination of all lung sections disclosed that most specimens were at the canalicular stage. Table I presents number of litters and fetuses, mean fetal weight, number of implants per litter and mean lung maturation for all crosses. ANOVA

TABLE I. No. of Implants, Fetal Weight, and Lung Maturation in H-2 Congenic Strains of Mice, With and Without Corticosteroid Treatment (Rx)

Cross ( 0 x 8) B10 x B10 B10 x E l 0 (Rx) B1O.A x BIO.A BIO.A x BIO.A (Rx) B10 x BIO.A B10 x BIO.A (Rx) BIO.A x B10 BIO.A x B10 (Rx)

Fetal haplotype bib bib ala a!a

bla bla

am aib

No. of litters

No. of implantsilitter (mean k S.E.)

*

6.34 0.26 7.20k0.24 7.38+0.20 9.20 2 0.06 8.22 0.30 8.50 0.29 6.50 0.34 8.17 +0.20

* * *

No. of fetuses

Fetal weight (g) (mean+-S.E.)

Lung maturation (mean? S.E.)"

41 41 42 45 45 43 40 41

0.9247 t0.0173 0.7932 ? 0.0142 0.8333 t 0.0120 0.8594 0.0156 0.8827 k 0.0246 0.8266 ? 0.0180 0.9050 t 0.0186 0.8540+ 0.0158

2.8127 0.1177 2.5431 k 0.1379 2.1051 2 0.0725 3.4122 & 0.0953 2.8696 2 0.1442 3.9814* 0.1426 1.9352-t 0.1054 3.9339+0.1425

+

*

Where a = air sac space perimeter; n' =total No. of air sac spaces;c = lung cross-sectional area; n = No. of fetuses in a glven litter; N = No. of litters for a given cross. Thus, each dam is treated as a separate biologic unit. Similar calculations were made for mean No. of implants/litterand mean fetal weight.

H-2 and Mouse Lung Development

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TABLE 11. Probability Values of ANOVA F-Tests for Comparisons of Lung Maturation Among Incrosses, With and Without Corticosteroid Treatment B10 x B10 B10 x BlO(Rx) BlOA x BlOA BlOAxBlOA(Rx)

B10 x B10

B10 x BlO(Rx)

BlOA x BlOA

BlOA x BlOA(Rx)

-

n.s.*

P < 0.025 P < 0.05

P < 0.025 P < 0.05 P < 0.001

n.s.* P < 0.025 P < 0.025

-

P < 0.05 P < 0.05

-

P < 0.001

-

*n.s., not significant (P > 0.05).

among incrosses (Table 11; Fig. 1) indicated that B10 untreated lungs were significantly more mature than BIO.A untreated lungs at 17 days of gestation (P < 0.025). Corticosteroid treated BIO.A mice had significantly more mature lungs than untreated BIO.A mice (P < 0.001); there was no significant difference between untreated and treated E l 0 mice (P > 0.05). Further, treated BIO.A mice had significantly more mature lungs than either untreated or treated B10 mice (P < 0.025 and P < 0.05, respectively). When comparing the heterozygous animals from reciprocal crosses, B10.BlO.A (b/a) and BlO.A.Bl0 (a%) with and without corticosteroid treatment (Table 111; Fig. 11, it was observed that untreated bla mice had significantly more mature lungs than a h mice (P < 0.025). Following corticosteroid treatment, bla and d b mice had similar lung maturity and both groups had significantly more mature lungs than either bla or a h untreated mice (P < 0.05). Comparisons between homozygous and heterozygous mice were made (Fig. 1).It was found that untreated bia 5.000 4,500

0UNTREATED

a TREATED

0

4.00Oi

2

3.500

+ -7

c7

Q

g

2.500

1.000 0.500

,

-

0.000

H-2 HAPLCTTE

Fig. 1. Mean lung maturation (mmimm') of corticosteroid treated and untreated fetal mice. b h = B10 x B10; a / a = BIO.A x B1O.A; b/a=BlOxBlO.A: a/b=BlO.AxBlO.

lungs were similar in maturation to bib lungs (P > 0.05), with both of them significantly more mature than untreated alb lungs (P < 0.025); untreated a h lungs were similar to untreated a/a lungs (P > 0.05). Corticosteroidtreated mice with d a , bia, and a h haplotypes had similarly increased lung maturation (P > 0.05) and all were significantly more mature than treated b/b mice (P < 0.05). The relationship among mean lung maturation and H-2 haplotype, mean number of implants per litter, and mean fetal weight was investigated by step-wise multiple linear regression analysis. For untreated mice, there was a high and significant correlation between haplotype and lung maturation (r = 0.4730); 22.410of the variation in lung maturation could be accounted for by variation in H-2 haplotype. The inclusion of litter size and fetal weight only accounted for an additional 7.4% and 0.1% of the variation, respectively. When comparing the groups that received exogenous corticosteroids, a high correlation between haplotype and lung maturation was also observed (r = 0.5765). The variation in fetal haplotype accounted for 32.2%ofthe total variation; inclusion of litter size and fetal weight only accounted for an additional 0.7% and 0.1%)of the variation, respectively. Endogenous Corticosteroids We evaluated the level of corticosterone in early embryonic to late fetal stage lungs by radioimmunoassay (Fig. 2). This technique measured total (bound and unbound) corticosteroids.The amount of corticosterone detected in 12-14 day embryonic lungs was below the level of detection of this assay (less than 0.01 ngimg lung protein). There was a progressive increase in the level of endogenous hormone with time in the BIO.A (H-2a)and B10 (H-2b)congenic mice. Multiple linear regression analysis indicated that there was a high correlation between hormone level and gestational age (r =0.9171) and 84% of the total variation in amount of corticosteroid can be accounted for by variation in time. There was no significant difference in immunoassayable endo-

TABLE 111. Probability Values of ANOVA F-Tests for Comparisons of Lung Maturation Among Reciprocal Crosses, With and Without Corticosteroid Treatment B10 x B1O.A BlOxBlO.A(Rx) B1O.A x B10 BIO.A x BlO(Rx)

B10 x Bl0.A B10 x BlO.A(Rx) P < 0.05 P < 0.05 P < 0.001 P < 0.025 P < 0.05 n.s.*

*n.s., not significant (P < 0.05).

BIO.A x B10

BIO.A x BlO(Rx)

P < 0.025 P < 0.001

P < 0.05

-

P < 0.001

n.s.*

P < 0.001 -

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Hu et al.

/'

/t

GESTATIONAL AGE

Fig. 2. Corticosteroid concentration (ng corticosterone pcr mg lung protein) of embryonic and fetal B10 and B1O.A mouse lungs,

genous corticosteroid between B10 and BIO.A mice. Thus, very little of the variation in detectable hormone can be accounted for by the variation in haplotype.

DISCUSSION Genes a t or near the H-2 complex influence embryonic and fetal development, including first cleavage, implantation rate, craniofacial development, litter size, and fetal weight [Melnick et al., 1981a; Goldbard and Warner, 1982; Ciriani and Diewert, 19861. The data reported here furt.her suggest that a gene(s1 in or near the H-2 complex also influences the degree of mouse pulmonary maturation. At the same fetal stage, B10 (H-2")mouse lungs were significantly more mature than lungs of BIO.A (H-2") mice. From the comparison of BlO? x B1O.Ad (bia) and B1O.AP x BlOd ( a h ) fetuses from reciprocal crosses, we observed a maternal effect; mice that received the b haplotype from their mothers had more mature lungs than mice that received the a haplotype. Since both groups of fetal mice had identical genomes, including H-2 haplotypes, the difference in lung maturation could be the result of haplotype related maternal environment, cytoplasmic effects or X-linked inheritance. Since the H-2 gene complex is located on chromosome 17, we can rule out the possibility of X-linkage. When comparing homozygous and heterozygous animals, again it was clear t h a t the lungs of those mice with a maternally derived H-2b haplotype had more mature lungs than those with H-2" haplotype acting by way of the mother. Thus, these data suggest that a faster rate of lung maturation is associated with the maternally derived b haplotype. Backcrosses would be necessary to identify the exact nature of the maternal effect. During preimplantation stages, BIO.A (H-2")and B10 (H-2b)mice develop a t a similar fast rate; Warner et al. 119871 have mapped the Ped gene associated with this phenomenon to the &aregion of the H-2 complex. In the present study, we observed that the B10 and BIO.A mouse lungs develop at significantly different rates. We therefore conclude that the gene(s) associated with the H-2 complex which regulates lung maturation is most probably independent of the Ped gene. As yet, we cannot begin t o approximate the location of this gene within the H-2 complex. Further investigations using other congenic strains are necessary to make this determination.

In the lung, steroid action is mediated by specific steroid receptors which bind and translocate the hormone to the cell nucleus, resulting in modulation of de novo protein synthesis [Ballard, 1982; Gross et al., 19831. Two corticosteroid receptors have been identified in the mouse lung: receptor 11, the classical receptor, which binds only corticosteroids, and a non-classical, IBlike receptor which binds both corticosteroids and hydantoin (5,5-diphenylhydantoin) [Goldman and Katsumata, 19861. The number of IB-like pulmonary corticosteroid receptors is influenced by the H-2 haplotype [Gupta and Goldman, 1982; Goldman and Katsumata, 19861. BIO.A mouse lungs have a greater number of IBlike receptors than do those of B10; there is no significant difference in the amount of receptor 11. It is therefore possible that the H-2 haplotype mediates hormonal response by regulating the number of specific receptors. This interpretation is supported by several studies which have demonstrated that various factors can cause either change in the number or in the binding characteristics of steroid receptors [Johnson et al., 1979; Meany et al., 1985; Reul et al., 19871. In the absence of corticosteroid treatment, B1O.A lungs were less mature than B10 lungs. Following steroid administration on gestation day 12, B1O.A lungs became significantly more mature than both the B10 treated and untreated groups. Analysis of heterozygous and homozygous mouse lung maturation in the treated groups indicated that corticosteroids only influenced mouse strains that had a n a haplotype: BIO.A (da), BlOP xB10.Ad (bia) andB1O.AQ x B 1 0 6 (a/b)mice all responded to exogenous steroid with increased lung maturity compared to their respective controls. These findings suggest that pulmonary response to exogenous steroid is associated with the presence of the H-2" haplotype whether homozygous or heterozygous. We found that the total endogenous corticosteroid concentration of fetal B10 and BIO.A mouse lungs was identical in B10 and BIO.A mice from day 14 through day 17 of gestation. This result is consistent with previous observations that concentrations of maternal plasma and embryonic corticosterone do not significantly differ between AiJ (H-2') and C57BLi6J (H-2b) mice [Solomon et al., 19781. Since H-2" lungs have a larger number of receptors [Gupta and Goldman, 1982; Goldman and Katsumata, 19861, the similarity in lung corticosteroid levels which we observed suggests a greater degree of receptor saturation in B10 fetal lungs. The observation that mouse lungs with the b haplotype were more mature and were not affected by steroid treatment indicates that endogenous steroid concentrations are sufficient to saturate lung receptors (or the system in general). Furthermore, the observation that mice with the a haplotype had, a t the same endogenous steroid level, less mature lungs and noticeably responded to exogenous hormone supplements indicates that the corticosteroid receptors are not saturated and might have a lower corticosteroid affinity. Our results have demonstrated that a gene or genes associated with the H-2 complex regulates the rate of mouse pulmonary maturation and t h a t developmentally delayed animals with the a haplotype benefited

H-2 and Mouse Lung Development

from corticosteroid therapy. Different degrees of human responsiveness to corticosteroid is associated with different HLA types [Becker et al., 19761.I t is reasonable to hypothesize that certain HLA haplotypes in human fetuses may be associated with the degree of in utero lung maturation, a greater or lesser risk for RDS andlor the relative ability to respond to in utero corticosteroid treatment. Further, we would predict that the number of functional corticosteroid receptors in newborns would differ based on HLA type and those with fewer receptors or more receptors would be the hormone nonresponsive or responsive newborns, respectively. Based on predicted newborn corticosteroid responsiveness, the clinician could, in the event of a premature birth, more accurately choose among several therapeutic regimens, including corticosteroid treatment, artificial surfactant administration, andlor mechanical respiratory support. A recent paper by Goldman et al. [19871provides clinical evidence supporting the association between receptor number and drug responsiveness. They observed that children with the fetal hydantoin syndrome have a higher level of lymphocyte IB-like receptors, which binds both corticosteroids and hydantoin, than similarly exposed, unaffected control children. This preliminary study identified populations of newborns that were susceptible or resistant to the teratogenetic effects of hydantoin; their response in utero was correlated with their receptor numbers. If we can determine the association between HLA, receptor number and corticosteroidstimulated pulmonary maturation, then we may be able to identify hormone responsive and nonresponsive fetuses in high risk pregnancies by prenatal screening and determine the most appropriate treatment and prognosis.

ACKNOWLEDGMENTS We thank Dr. Greg Mooser for reading the manuscript. This research was supported in part by NIH grants HL 41477 and DE 07006.

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Mouse major histocompatibility complex (H-2) and fetal lung development: implications for human pulmonary maturation.

Using C57/10Sn (B10, H-2b) and B10.A/SgSn (B10.A,H-2a) congenic mice, we measured 1) the level of endogenous pulmonary corticosterone during mouse dev...
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