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PubMed1992

Elastase alpha 1-proteinase inhibitor and lactoferrin concentrations in endotracheal aspirates of ventilated newborns.

Bacterial colonization of the tracheo-bronchial tree is common and an established risk factor for infection in ventilated newborns. Elastase, a highly active proteinase, and lactoferrin, an iron-binding protein and potential modulator of the inflammatory process, are both major constituents of either azurophilic or primary granules of neutrophilic granulocytes, released by activation of these cells during the inflammatory response. Since both elastase, complexed with its major inhibitor alpha 1-proteinase inhibitor (E alpha 1-Pl), and lactoferrin (Lf) are indicators of granulocyte activation during bacterial infection, they may indicate infectious inflammation at the tracheobronchial site. To study whether these substances in a single suction probe may serve this purpose, we obtained 82 tracheo-bronchial aspirates routinely from 16 ventilated newborns with a median gestational age of 31.5 (range, 25-39) weeks for laboratory analysis and bacterial cultures. Systemic inflammatory response by differential white blood cell count and C-reactive protein (CRP) was monitored simultaneously. The median E alpha 1-Pl level was significantly elevated in culture-positive aspirates (1,005 micrograms/L; range, less than 30-29,240 micrograms/L) in contrast to culture-negative samples (158 micrograms/L; range, less than 30-1,408 micrograms/L). In addition to a diagnostic sensitivity of 77%, E alpha 1-Pl offered a high specificity of 88%, a positive predictive value of 97%, and a negative predictive value of 73%. In contrast, median Lf concentration (10.6; range, 0.3-58.3 mg/L vs. 11.7; range, 1.6-158 mg/L) showed no correlation with culture results. Of the culture-positive aspirates 36% corresponded with systemic signs of an acute inflammatory response, such as elevated I/T-ratio and CRP.(ABSTRACT TRUNCATED AT 250 WORDS)

Bacterial Infections↗
PubMed2004

The effects of shortening lactoferrin derived peptides against tumour cells, bacteria and normal human cells.

A number of shortened derivatives of the lactoferrin model peptide L12, PAWRKAFRWAKRMLKKAA, were designed in order to elucidate the structural basis for antitumour activity of lactoferrin derivatives. Three tumour cell lines were included in the study and toxicity determined by measuring lysis of human red blood cells and fibroblasts. The results demonstrated a strong correlation between antitumour activity and net positive charge, in which a net charge close to +7 was essential for a high antitumour activity. In order to increase the antitumour activity of the shortest peptide with a net charge less than +7, the hydrophobicity had to be increased by adding a bulky Trp residue. None of the peptides were haemolytic, but toxicity against fibroblasts was observed. However, modifications of the peptides had a higher effect on reducing fibroblast toxicity than antitumour activity and thereby resulted in peptides displaying an almost 7-fold selectivity for tumour cells compared with fibroblasts. The antimicrobial activity against the Gram-negative bacteria Escherichia coil and the Gram-positive bacteria Staphylococcus aureus was also included in order to compare the structural requirements for antitumour activity with those required for a high antimicrobial activity. The results showed that most of the peptides were highly active against both bacterial strains. Less modification by shortening the peptide sequences was tolerated for maintaining a high antitumour activity and selectivity compared with antimicrobial activity. The order of the amino acid residues and thereby the conformation of the peptides was highly essential for antitumour activity, whereas the antimicrobial activity was hardly influenced by changes in this parameter. Thus, in addition to a certain net positive charge and hydrophobicity, the ability to adopt an amphipathic conformation was a more critical structural parameter for antitumour activity than for antimicrobial activity, and implied that a higher flexibility or number of active conformations was tolerated for the peptides to exert a high antimicrobial activity.

Amino Acid Sequence↗
PubMed2000

Antimicrobial peptide of korean native goat lactoferrin and identification of the part essential for this activity.

The antimicrobial activity of lactoferrin isolated from Korean native goat (KN goat) milk was studied and its antimicrobial domain was identified using synthetic peptides. Antimicrobial activity was assayed by a micro-method using 96-well microplates and a microplate reader. The amino acid sequence of the antimicrobial domain was suggested to be YQWQRRMRKLGAPSIT and this sequence corresponds to amino acid residues 20 to 35 of KN goat lactoferrin. Five peptides with certain amino acid residues deleted were synthesized in an effort to identify the residues essential for antimicrobial activity and it was found that the part with the sequence RRMRK (24-28) is the region most important for this activity. On the other hand, the conformation of the peptides did not influence the antimicrobial activity.

Amino Acid Sequence↗
PubMed1993

Structure of the recombinant N-terminal lobe of human lactoferrin at 2.0 A resolution.

The three-dimensional structure of the N-terminal half-molecule of human lactoferrin, LfN, prepared by recombinant DNA methods, has been determined by X-ray crystallography at 2.0 A resolution. The protein is in its iron-bound form and is deglycosylated. X-ray diffraction data were obtained by diffractometry to 3.2 A resolution and synchrotron data collection, using Weissenberg photography with imaging plates, to 1.8 A resolution. The structure was solved by molecular replacement, using the N-lobe of native diferric human lactoferrin (Lf) as search model. Restrained least squares refinement (program TNT) has resulted in a model structure with an R-factor of 0.184 for all data 34,180 (reflections) in the resolution range 8.0 to 2.0 A. The model comprises 2490 protein atoms (residues 4 to 327), 1 Fe3+, 1 CO3(2-) and 180 solvent molecules, all regarded as water. The structure of LfN is essentially the same as that of the N-lobe of intact Lf, being folded into two similar alpha/beta domains, with the Fe3+ and CO3(2-) bound in a specific site in the interdomain cleft. These details are not affected by either deglycosylation or expression in a non-native system. At the C terminus, however, the conformation of residues 321 to 333 is changed. Whereas in Lf residues 321 to 332 form a helix crossing between the domains at the back of the iron site, in LfN residues 321 to 326 have an extended conformation, forming a third interdomain beta-strand, and residues 328 to 333 appear disordered. The conformational change is attributed to the loss of stabilizing interactions from the C-lobe and is mediated by two Gly residues, at positions 321 and 323. It is further proposed that the conformational change is responsible for the more facile iron release properties of LfN, by its effect on the hinge mechanism and increased solvent exposure of residues near the back of the iron site. Other details of the polypeptide chain conformation and the binding site have also been analysed. Two cis-proline residues are found at positions 71 and 142. The bidentate binding of the CO3(2-) to the metal ion is unambiguous, and a network of hydrogen bonds in and around the binding site links the two domains. Clearly-defined amino-aromatic hydrogen bonds are found for Arg210, near the metal site, and some 31 internal water molecules have been identified, 15 of them in essentially discrete sites, and 16 in a cluster filling a cavity in the interdomain cleft.

Anions↗
PubMed1993

Domain closure in lactoferrin. Two hinges produce a see-saw motion between alternative close-packed interfaces.

Lactoferrin is an iron transport protein. Upon binding iron, the two domains in the N-terminal half of the molecule move together. Previous work has shown that this domain closure involves two hinges. Using the newly refined structure of the open form, the structural mechanism underlying this motion is analyzed here in detail. Upon closure the domains rotate 54 degrees essentially as rigid bodies. The axis of rotation passes through the two beta-strands linking the domains. These strands contain hinges in the sense that three large torsion angle changes are responsible for the bulk of the motion while smaller torsion angle changes in neighboring residues are responsible for the remainder of the motion. The rotation axes of these three torsion angle changes are nearly parallel to the axis of the overall 54 degrees rotation, so the local motion in the hinges can be directly related to the overall motion. A crucial feature of the hinge residues is that they have very few packing constraints on their main-chain atoms. The domains make different packing contacts with each other in the open and closed forms. These contacts form two interdomain interfaces arranged on either side of the hinges. Pivoting about the hinges produces a see-saw motion between the two interfaces. That is, when the domains close down, residues in the interface on one side of the hinges become buried and close-packed and residues on the other side become exposed. The situation is reversed when the domains open up. Lactoferrin provides a particularly clear example of the general features of hinged domain motion. It is compared to other instances of hinged domain closure and contrasted with instances of shear domain closure, where the overall motion is a summation of many small sliding motions between close-packed segments of polypeptide.

Amino Acid Sequence↗
PubMed1997

Three-dimensional structure of diferric bovine lactoferrin at 2.8 A resolution.

The three-dimensional structure of diferric bovine lactoferrin (bLf) has been determined by X-ray crystallography in order to investigate the factors that influence iron binding and release by transferrins. The structure was solved by molecular replacement, using the coordinates of diferric human lactoferrin (hLf) as a search model, and was refined with data to 2.8 A resolution by simulated annealing (X-PLOR) and restrained least squares (TNT). The final model comprises 5310 protein atoms (residues 5 to 689), 124 carbohydrate atoms (from ten monosaccharide units, in three glycan chains), 2 Fe3+, 2 CO32- and 50 water molecules. This model gives an R-factor of 0.232 for 21440 reflections in the resolution range 30.0 to 2.8 A. The folding of the bLf molecule is essentially the same as that of hLf, but bLf differs in the extent of closure of the two domains of each lobe, and in the relative orientations of the two lobes. Differences in domain closure are attributed to amino acid changes in the interface, and differences in lobe orientations to slightly altered packing of two hydrophobic patches between the lobes. Changed interdomain interactions may explain the lesser iron affinity of bLf, compared with hLf, and two lysine residues behind the N-lobe iron site of bLf offer new insights into the "dilysine trigger" mechanism proposed for iron release by transferrins. The bLf structure is also notable for several well-defined oligosaccharide units which demonstrate the structural factors that stabilise carbohydrate structure. One glycan chain, attached to Asn545, appears to contribute to interdomain interactions and may modulate iron release from the C-lobe.

Animals↗
PubMed1994

Insertional inactivation of the gene for the meningococcal lactoferrin binding protein.

The lactoferrin binding protein (LBP) of Neisseria meningitidis (the putative meningococcal receptor for human lactoferrin, LF), has been previously characterized as an outer-membrane protein of approximately 105 kDa. Using N-terminal amino acid sequence to generate an oligonucleotide probe, a clone from a lambda gt11 phage library was isolated. This clone was subjected to shuttle mutagenesis, in which an erythromycin mini-transposon was used to interrupt the LBP coding sequence. This insertion mutation was introduced into the meningococcus. A N. meningitidis strain that carried this transposon insertion no longer produced the 105 kDa protein. The absence of this protein was correlated with the inability to bind LF or to use LF as an iron source. The LBP mutant was able to grow with other Fe sources and demonstrated no other visible membrane protein alterations. These data confirm the suggestion that LBP is the meningococcal receptor.

Amino Acid Sequence↗
PubMed2001

Human lactoferrin in the milk of transgenic mice increases intestinal growth in ten-day-old suckling neonates.

Regulatory roles and a signaling receptor have been proposed for the milk protein lactoferrin (Lf), but none has been definitively characterized. Nichols and colleagues (1987) observed that human lactoferrin (hLf) stimulated thymidine incorporation into the DNA of rat intestinal crypt cells. We tested the hypothesis that chronic Lf administration stimulates intestinal growth by studying neonatal mice suckling transgenic dams secreting about 12 mg/mL hLf in their milk. Specifically, nontransgenic litters were adjusted to eight pups each and cross-fostered to transgenic dams. Controls were pups suckling nontransgenic dams of the same strain. On day 10 postpartum pups were weighed, sacrificed, and the small intestines were weighed, measured, and stored for later determination of enzyme activities. The results indicate that intestinal growth was increased in neonates suckling transgenic dams. The weight of the small intestine was increased about 27% when the pups received milk containing hLf. Intestinal length only increased about 6.5% suggesting that Lf in milk enhanced mucosal growth. The ratio of maltase to lactase in the duodenal segment of the small intestine, an indicator of maturation, was also significantly increased in the pups suckling transgenic milks. Our results imply that chronic oral consumption of human Lf promotes the growth and maturation of the intestinal mucosa, and suggest a possible therapeutic role for the agent in premature infants as well as in patients with bowel damage.

Animals↗
PubMed2001

Changes in lactoferrin and lysozyme levels in human milk during the first twelve weeks of lactation.

Changes in the lactoferrin and lysozyme concentration of human milk during lactation were determined by microparticle-enhanced nephelometric immunoassays of 360 milk samples collected from 64 lactating volunteers. These 360 samples were colostrum from days 1 to 5 postpartum (142 samples), transitional milk from days 6 to 14 (106 samples), and 112 mature milk samples obtained from days 15 to 28 (34 samples), from days 29 to 56 (50 samples) and from days 57 to 84 postpartum (28 samples). The concentration and percentage of lactoferrin vs. total protein were found to be significantly higher in colostrum (5.8 g/L, 27%) than in transitional milk (3.1 g/L, 22%) or day 15 to 28 mature milk (2.0 g/L, 19%), then increased in day 29 to 56 mature milk (2.2 g/L, 22%) and day 57 to 84 mature milk (3.3 g/L, 30%). The concentration of lysozyme decreased from colostrum (0.37 g/L) to transitional milk (0.27g/L) and day 15 to 28 mature milk (0.24 g/L), then increased in day 29 to 56 mature milk (0.33 g/L) and was highest in day 57 to 84 mature milk (0.89 g/L). The percentage of lysozyme vs. total protein was found to be always rising during lactation: colostrum, 2%; transitional milk, 2%; days 15 to 28, 2%; days 29 to 56, 3%; and days 57 to 84 mature milk, 8%.

Colostrum↗
PubMed1993

ANCA with specificity for lactoferrin in systemic lupus erythematosus (SLE).

Antibodies to lactoferrin were detected in about 20% of patients with SLE, irrespective of the presence of renal involvement and in 10% of patients with rheumatoid arthritis and in 19% of patients with scleroderma. We conclude that anti-lactoferrin antibodies may be found in different types of connective tissue disease. Their clinical significance in these diseases however remains to be elucidated.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1993

Killing of Candida albicans by lactoferricin B, a potent antimicrobial peptide derived from the N-terminal region of bovine lactoferrin.

Candida albicans was found to be highly susceptible to inhibition and inactivation by lactoferricin B, a peptide produced by enzymatic cleavage of bovine lactoferrin. Effective concentrations of the peptide varied within the range of 18 to 150 micrograms/ml depending on the strain and the culture medium used. Its effect was lethal, causing a rapid loss of colony-forming capability. 14C-labeled lactoferricin B bound to C. albicans and the rate of binding appeared to be consistent with the rate of killing induced by the peptide. The extent of binding was diminished in the presence of Mg2+ or Ca2+ ions which acted to reduce its anticandidal effectiveness. Binding occurred optimally at pH 6.0 and killing was maximal near the same pH. Such evidence suggests the lethal effect of lactoferricin B results from its direct interaction with the cell surface. Cells exposed to lactoferricin B exhibited profound ultrastructural damage which appeared to reflect its induction of an autolytic response. These findings suggest that active peptides of lactoferrin could potentially contribute to the host defense against C. albicans.

Amino Acid Sequence↗
PubMed1994

The bovine lactoferrin gene (LTF) maps to chromosome 22 and syntenic group U12.

Five overlapping lambda EMBL-clones, containing the complete bovine lactoferrin gene (LTF), have been used to map this gene by fluorescence in situ hybridization to bovine Chromosome (Chr) band 22q24. Primers derived from promoter and exon I sequences were applied in polymerase chain reactions (PCRs) to DNA samples of a previously characterized panel of somatic cell hybrid lines, allowing the assignment of the bovine lactoferrin locus to syntenic group U12. These results permit the assignment of syntenic group U12 to bovine Chr 22.

Animals↗
PubMed1984

Lactoferrin in relation to acute phase proteins in sera from newborn infants with severe infections.

Serum lactoferrin concentrations were elevated in 22 out of 49 newborn infants with suspected and verified severe bacterial as well as viral infections, suggesting that this protein resembled an acute phase reactant. In the infants suspected of having septicemia, high concentrations of C-reactive protein appeared to indicate a severe bacterial infection. Like lactoferrin, however, haptoglobin, orosomucoid, alpha 1-antitrypsin and alpha 1-antichymotrypsin discriminated only poorly or not at all between infants with severe bacterial infections and those in which such infections were unlikely. Thus, serum CRP concentrations remained the most valuable of the acute phase reactants tested as an aid in ruling out septicemia in the neonatal period.

Acute Disease↗
PubMed1984

Lactoferrin in benign hypertrophy and carcinomas of the prostatic gland.

Using immunoperoxidase procedures, the presence of lactoferrin was investigated in benign hypertrophy (40 cases), differentiated adenocarcinomas (20 cases) and undifferentiated carcinomas (10 cases) of the prostate. In benign hypertrophy, the glandular epithelium and the secretory product were consistently negative. Strong staining for lactoferrin was always observed in neoplastic cells of differentiated adenocarcinomas and in their endoluminal material; in contrast, a very slight positivity was noted in undifferentiated carcinomas. These findings are discussed in relation to the different degree of neoplastic glandular differentiation and functional activity of prostatic carcinomas.

Adenocarcinoma↗
PubMed1988

Use of light microscopic immunotechniques in selecting preparation conditions and immunoprobes for ultrastructural immunolabelling of lactoferrin.

Successful postembedding immunolabelling for electron microscopy is sometimes difficult to achieve. We propose that light microscopy can be used (1) to detect quickly processing steps which have an adverse effect on the tissue antigenicity and (2) to check the specific reactivity of the immunogold detecting system normally employed at the ultrastructural level. The individual steps of fixation, dehydration and embedding were tested for their ability to preserve antigenicity by light microscopic peroxidase--anti-peroxidase cytochemistry. Steps that severely reduced antigenicity were replaced by less destructive alternatives compatible with reasonable ultrastructural preservation. The specific reactivity of the immunogold detecting system was assessed by using the light microscopic immunogold-silver staining method. We studied the antigen lactoferrin in human neutrophilic granulocytes from patients with chronic myeloid leukaemia. We obtained strong immunolabelling of specific granules and good ultrastructural preservation using routine methods at room temperature. For lactoferrin the method of choice was to fix in 3% paraformaldehyde/0.1% glutaraldehyde followed by 1% OsO4, dehydrate in 70% ethanol, embed in LR White resin and polymerize at 40 degrees C for 40 h. These conditions may not be suitable for all antigens and we emphasize that for each new antigen a similar study should be carried out.

Fixatives↗
PubMed1987

Inhibition of histamine release in vitro by a blocking factor from human serum: comparison with the iron binding proteins transferrin and lactoferrin.

Recently, we described the presence of a blocking factor (BF) in rat serum, which inhibited the histamine release from rat mast cells in vivo and in vitro. The blocking activity was demonstrated in human serum as well. Qualitative analysis of the purified preparations demonstrated a major component with an apparent molecular weight of 70,000 daltons. In human serum the blocking factor was identified as transferrin (TF) by serological and biochemical methods. BF (DEAE-peak 1) and the iron binding proteins transferrin and lactoferrin (LF) are shown to inhibit the histamine release in vitro. The dose response curves reveal that inhibition by these proteins is dependent on their degree of iron saturation. Furthermore, unlike lactoferrin, the effects of transferrin and BF (DEAE-peak 1) follow the same pattern. Their mechanism of action remains to be elucidated.

Animals↗
PubMed1992

Plasma lactoferrin as a marker of infection in elderly individuals.

To assess lactoferrin as a marker of infection, plasma lactoferrin (LF) levels were determined in elderly in patients with infection and compared with age- and sex-matched healthy and hospital controls and young healthy blood donors. The median LF level in infection (800 ng/mL) was significantly higher than in healthy elderly living in old people's home (300 ng/mL) or elderly hospital controls (298 ng/mL) (p less than 0.01 in each case). Plasma LF correlated significantly with elastase alpha-1-proteinase inhibitor complex (EPIC) (Rs = 0.8, p less than 0.01) and C-reactive protein (CRP) (Rs = 0.45, p less than 0.02), but not with erythrocyte sedimentation rate (ESR) or white blood cell counts. We conclude that plasma LF, like CRP and EPIC, is a marker of infection in elderly individuals.

Adult↗
PubMed2005

Expression of porcine lactoferrin by using recombinant baculovirus in silkworm, Bombyx mori L., and its purification and characterization.

Lactoferrin is a multifunctional glycoprotein that is present in several mucosal secretions. In this study, we exploited the silkworm, Bombyx mori, as host for the recombinant baculovirus harboring the porcine lactoferrin (PLF) gene to produce the recombinant PLF (rPLF). Around 205 mug of rPLF was purified from a single silkworm pupa infected by the virus and the rPLF was proved to be biologically active. This method established in our study will pave the way for efficient industrial production of rPLF on a large scale for further utilization of this protein as a feed additive in the future.

Animals↗