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Query: UNIPROT:P06889 (Mol)
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Pulmonary surfactant is a lipid-protein complex involved in maintaining alveolar stability. SP-A is the major surfactant-associated protein of 26 to 38 kD. A human SP-A gene (SP-A I) and two distinct SP-A cDNAs, MPSAP 1A and MPSAP 6A, have been reported previously. We have isolated and characterized a second human SP-A gene (SP-A II), which appears to code for the mRNA corresponding to the previously described MPSAP-1A cDNA. Both genes consist of five exons, a consensus recognition sequence for initiation, TATAAA, and a polyadenylation signal sequence. Significant divergence in the two genes is observed throughout. The divergence is highest in the upstream region, intron I, exon III, and noncoding portion of exon V. The coding regions of all other exons and the introns show much lower divergence. Transcripts from both genes were found in adult human lung, using gene-specific oligonucleotide probes in Northern blot analysis.
Am J Respir Cell Mol Biol 1992 Apr
PMID:Characterization of a second human pulmonary surfactant-associated protein SP-A gene. 137 11

Pulmonary surfactant is a lipoprotein substance, comprised of approximately 80% phospholipid and approximately 10% protein, that lowers surface tension at the air-alveolar aqueous interface. Surfactant is synthesized and secreted by alveolar type II epithelial cells where it is stored intracellularly in lamellar bodies. In the present study, we used the technique of in situ hybridization to localize the mRNA for two surfactant-associated proteins, SP-A and SP-B, in developing rabbit fetal lung tissue. We found that SP-A mRNA was first localized in rabbit fetal lung alveolar type II cells on day 26 of gestation, the time at which lamellar bodies are first observed within fetal lung type II cells. On day 28 of gestation, a very small amount of SP-A mRNA was also detectable in the epithelial cells of some bronchioles. In neonatal and adult rabbit lung tissue, SP-A mRNA was primarily restricted to alveolar type II cells; however, the epithelial cells of some bronchioles contained small amounts of SP-A mRNA. SP-B mRNA was first detected in cuboidal epithelial cells in the prealveolar region of the rabbit fetal lung tissue on day 24 of gestation, i.e., at least 2 days before the appearance of SP-A mRNA and lamellar bodies within differentiated alveolar type II cells. SP-B mRNA was detected in most bronchiolar epithelial cells of the rabbit fetal lung tissue at day 28 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)
Am J Respir Cell Mol Biol 1992 Sep
PMID:Localization of surfactant-associated proteins SP-A and SP-B mRNA in rabbit fetal lung tissue by in situ hybridization. 152 Apr 94

The expression of the surfactant-associated proteins in bronchiolar cells remains to be defined. We used in situ hybridization to identify sites of message expression of the surfactant-associated proteins A, B, and C (SP-A, SP-B, and SP-C) in adult and fetal rat lung. The expression of these messages by in situ hybridization was also compared with the localization of SP-A by immunocytochemistry. The localization of SP-A was used to identify type II cells and nonciliated bronchiolar epithelial (Clara) cells in these sections. The cRNA antisense probes for SP-A, SP-B, and SP-C appeared to hybridize over type II cells. Sense probes showed no localization or apparent specific hybridization. Messages for both SP-A and SP-B were also found in nonciliated bronchiolar epithelial (Clara) cells. However, no message for SP-C was observed in these cells. Clara cells from terminal to large bronchioles lacked detectable mRNA for SP-C. Expression of surfactant protein mRNAs was not detectable in type I cells, alveolar macrophages, interstitial cells, or vascular cells. Similarly, in fetal rat lung the messages for SP-A and SP-B but not SP-C were detected in bronchiolar cells. We conclude that rat Clara cells do not express SP-C mRNA, and thus SP-C can be regarded as a specific marker for rat type II cells.
Am J Respir Cell Mol Biol 1992 Jun
PMID:Surfactant protein C is expressed in alveolar type II cells but not in Clara cells of rat lung. 159 Oct 8

Surfactant protein-A (SP-A), the major pulmonary surfactant-associated protein, is a developmentally and hormonally regulated sialoglycoprotein of about 35,000 mol wt. In previous studies we observed that dexamethasone has dose-dependent biphasic effects on the levels of SP-A and its mRNA in human fetal lung in vitro. At concentrations of 10(-10)-10(-9) M, dexamethasone increased the levels of SP-A and its mRNA over those of control tissues, whereas at concentrations greater than or equal to 10(-8) M, the steroid was markedly inhibitory. Our findings suggest that the inhibitory action of dexamethasone (greater than 10(-8) M) on SP-A mRNA levels was mediated by an effect to reduce SP-A mRNA stability, since the steroid caused a dose-dependent increase in the rate of transcription; however, an effect to increase transcription with premature termination leading to instability of mRNA transcripts could not be ruled out. In the present investigation we have studied in detail the mechanisms underlying the biphasic effects of glucocorticoids on SP-A mRNA levels in human fetal lung tissues in vitro. Our findings indicate that dexamethasone (10(-7) M) has no adverse effect on the elongation of nascent mRNA transcripts throughout the SP-A gene; elongation of SP-A mRNA transcripts in dexamethasone-treated tissue explants was similar to that observed in tissues incubated in control medium or medium containing (Bu)2cAMP. Therefore, premature termination of SP-A mRNA transcription leading to the instability of SP-A mRNA can be ruled out. On the other hand, we found that dexamethasone (10(-7) M) had a pronounced effect to reduce the apparent half-life of SP-A mRNA; in control explants maintained in the presence of actinomycin-D to block gene transcription, the SP-A mRNA half-life was estimated to be 11.4 h, whereas in tissues also treated with dexamethasone, the SP-A mRNA half-life was reduced by more than 60% to 5.0 h. Dexamethasone also was found to have dose-dependent effects on the degradation of SP-A mRNA. After 12 h of incubation in the presence of actinomycin-D and dexamethasone at 10(-9) and 10(-7) M, the levels of SP-A mRNA were reduced by 50% and 80%, respectively, compared to those in tissue incubated with actinomycin-D alone. The inhibitory effects of glucocorticoids on SP-A mRNA levels were completely reversible and were blocked by the glucocorticoid antagonist RU486.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Endocrinol 1991 Mar
PMID:Posttranscriptional regulation of surfactant protein-A messenger RNA in human fetal lung in vitro by glucocorticoids. 165 95

The differentiated phenotype of the alveolar type II cell is rapidly altered in vitro. To evaluate factors that might influence this process, we isolated and plated rat type II cells in serum-supplemented media to promote adherence and then maintained the cells in a simple nutrient medium in the absence (S- cells) or presence (S+ cells) of serum for 5 to 7 d. The type II S- cells remained metabolically active. Despite protein synthesis that was 50% that of S+ cells, S- cells continued to synthesize a broad spectrum of proteins and to express several features of type II cell differentiation. They synthesized an apical integral membrane glycoprotein, Maclura pomifera agglutinin (MPA)-gp200, and a cytokeratin, No. 19, while S+ cells did not. When supplemented with linoleic acid, S- cells contained lamellar and multivesicular bodies, incorporated cell surface MPA into these structures, and secreted their phosphatidylcholine (PC) in response to mastoparan. Despite the relative synthesis of higher levels of total and saturated PC in S- cells supplemented with linoleic acid, phosphatidylglycerol remained diminished. A surfactant protein (SP-A) was present in S- cells, but synthesis was not detected. These studies demonstrate that serum accelerates the loss of type II cell differentiation in vitro and that the expression of type II cell markers of differentiation is not inherently linked.
Am J Respir Cell Mol Biol 1990 Oct
PMID:Serum accelerates the loss of type II cell differentiation in vitro. 169

SP-A is the most abundant, surfactant-associated protein isolated from lung lavage. Genomic blot analysis of total human cellular DNA with SP-A cDNA demonstrated the presence of multiple hybridizing fragments that are not accounted for by available SP-A gene sequences. In this report, we have cloned and characterized human genomic DNA fragments that account for some of the other hybridizing fragments. These clones contain nucleotide sequences that are highly homologous to the fourth intron and fifth exon of the human SP-A gene. Sequences upstream from these SP-A-like sequences are not detectable by Northern blot hybridization of SP-A-expressing cells and the SP-A-like sequences contain premature stop codons, consistent with the interpretation that these clones represent an SP-A pseudogene. Restriction fragments consistent with this pseudogene and the functional SP-A gene are present in a human chromosome 10 genomic library made from a single chromosome, showing that the functional SP-A gene and the pseudogene are syntenic.
Am J Respir Cell Mol Biol 1991 May
PMID:A portion of the human surfactant protein A (SP-A) gene locus consists of a pseudogene. 182 27

Pulmonary surfactant phospholipids may assume several different structures including tubular myelin, unilamellar and multilamellar vesicles, and others. These populations of materials appear to have similar phospholipid compositions but may differ in their association with surfactant proteins SP-A, SP-B, or SP-C. We have used electron microscopy to determine the changes in structure of simple lipid mixtures (phosphatidylglycerol, dipalmitoylphosphatidylcholine) produced by adding one or combinations of the three proteins. Adding SP-A to lipids generated multilamellar structures composed of membranes with fuzzy or particulate surfaces. In contrast, SP-B or SP-C generated discoidal particles and structures that appeared to be sheets of membrane formed by associated particles. Used together, SP-A and SP-B reorganized some of the lipid into tubular myelin, a structure that was not observed in SP-A, SP-C recombinants. These observations confirm the in vitro formation of tubular myelin reported by others and support the possibility that surfactant materials with defined structure can be produced in vitro for analyses of their molecular organizations.
Am J Respir Cell Mol Biol 1991 Jul
PMID:Changes in lipid structure produced by surfactant proteins SP-A, SP-B, and SP-C. 187 52

Surfactant proteins have key roles in regulating surfactant secretion, in recycling, and in the assembly of the surfactant monolayer but little is known about their regulation in vivo. Surfactant proteins SP-A, SP-B, and SP-C have been shown to be upregulated by glucocorticoids in vitro, but the role of glucocorticoids in the physiologic regulation of surfactant protein synthesis remains unknown. We have studied the effects of exogenously administered glucocorticoids on the regulation of steady-state surfactant protein mRNA accumulation. We have also studied the effects of adrenalectomy on the accumulation of the surfactant protein mRNAs. Surfactant protein genes appear to have quantitatively different responses to exogenously administered glucocorticoids, with SP-C mRNA increasing at the lowest dose, SP-A and SP-B mRNA increasing in response to similar glucocorticoids doses but with SP-B yielding the highest maximum response. Adrenalectomy, however, does not alter surfactant protein mRNA levels. These observations support a minor role for glucocorticoids in maintaining the steady-state accumulation of surfactant protein mRNA. Adrenalectomy decreases total pulmonary SP-A when compared to sham-operated animals in the absence of changes in its mRNA. Therefore, glucocorticoids may have translational or post-translational effects that regulate total pulmonary SP-A accumulation, but the effects appear to be minor. These findings support a potential role for the adrenal in the pulmonary response to stress and demonstrate for the first time differential accumulation of the surfactant protein mRNAs to glucocorticoids in vivo.
Am J Respir Cell Mol Biol 1991 Jul
PMID:In vivo regulation of surfactant proteins by glucocorticoids. 187 53

The physiologic response of the lung to oxygen toxicity is complex, and similar among all mammals studied. Acute exposure to 100% O2 results in severe decreases in respiratory function and is accompanied by alterations in pulmonary surfactant metabolism, including the regulation of surfactant proteins A, B, and C (SP-A, SP-B, SP-C). Because surfactant proteins and their mRNAs can be expressed in alveolar epithelial type II cells, and nonciliated bronchial epithelial (Clara) cells, we were interested in determining if alterations in the abundance of SP-A, SP-B, and SP-C mRNAs occurred differentially in these two cell types during hyperoxic lung injury. Using quantitative in situ hybridization, we found that hyperoxic lung injury resulted in nearly 20-fold increases in SP-A and SP-B mRNAs in Clara cells, with relatively small (2-fold or less) increases in type II cells. Immunohistochemical analysis suggested a commensurate increase in SP-A protein in Clara cells. SP-C mRNA was only detected in type II cells, and changed little in hyperoxic lung. Because Clara cells are not known to produce surfactant, and appear to lack SP-C mRNA, these observations suggest that increased SP-A and SP-B may serve nonsurfactant functions in hyperoxic lung.
Am J Respir Cell Mol Biol 1991 Dec
PMID:Differential accumulation of surfactant protein A, B, and C mRNAs in two epithelial cell types of hyperoxic lung. 195 77

The pulmonary surfactant-associated protein SP-A is encoded by presumably two different genes, resulting in slightly different amino acid sequences. Both gene products were expressed in Chinese hamster ovary cells. Their macromolecular structure differed significantly. SP-A alpha 3 exhibited a much higher amount of tetrameric to hexameric structures than SP-A alpha 2, for which dimeric structures predominate. These differences may be caused by the higher expression rates of SP-A alpha 3 presumably due to the presence of introns in the sequence. The occurrence of irregular disulfide links between individual oligomeric SP-A molecules composed of alpha 3-chains together with the demonstrated presence of both gene products in natural human SP-A suggest that the subunits of SP-A are heterotrimers of one alpha 2- and two alpha 3-chains.
Am J Respir Cell Mol Biol 1991 Jan
PMID:Structural comparison of recombinant pulmonary surfactant protein SP-A derived from two human coding sequences: implications for the chain composition of natural human SP-A. 198 81


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