Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Macrophage migration inhibitory factor (MIF) was one of the first cytokines to be identified. In the early 1990s it was 'rediscovered' as a hormone that is secreted by the anterior pituitary gland and counter-regulates the anti-inflammatory effects of glucocorticoids. We now know that glucocorticoids stimulate the release of MIF from T cells and macrophages; this appears to be a physiological response to override the effects of glucocorticoids at the inflammatory site. However, this response can become pathological in acute respiratory distress syndrome (ARDS), in which high concentrations of MIF in the alveoli might contribute to ARDS pathogenesis. New insights into the structure and function of MIF, and the possibility of increasing the efficacy of glucocorticoids in the clinic by inhibiting MIF, are discussed in this review.
Mol Med Today 1997 Nov
PMID:Macrophage migration inhibitory factor: a regulator of glucocorticoid activity with a critical role in inflammatory disease. 943 Jul 86

Synthetic surfactant peptides SP-B1-78 and SP-C1-31 in a standard phospholipid mixture have been employed to examine the correlation between in vitro surface activity and in vivo function of synthetic surfactant preparations in the isolated rat lung and premature rabbit models of respiratory distress syndrome. Monolayer techniques showed that SP-B peptides have a high propensity for association with a phospholipid structure. By dynamic respreading, synthetic SP-B and SP-C showed rapid spreading and attained low surface tensions. Used as replacement surfactants in two animal models, these synthetic surfactant preparations partially restored lung compliance in lavaged rats and premature rabbits better than a pure phospholipid preparation and to a degree comparable to clinical surfactant, measured by pressure/volume curves. Our data confirm that in vitro functional determinations of synthetic surfactant peptides are instrumental in the preparation of replacement surfactants, and that dispersions thus selected represent viable therapeutic alternatives to current treatments for respiratory distress syndrome.
Mol Genet Metab 1998 Feb
PMID:Synthetic mimics of surfactant proteins B and C: in vitro surface activity and effects on lung compliance in two animal models of surfactant deficiency. 956 65

Mutations and polymorphisms within the human SP-B locus have been linked to fatal congenital alveolar proteinosis (CAP) and associated with respiratory distress syndrome (RDS), respectively. In the present study we used PCR and direct sequence analysis of the SP-B gene of three individuals from a family with CAP to search for additional SP-B mutations resulting in CAP and/or polymorphisms that could be used as markers in association studies of RDS and/or CAP. We found three novel mutations/polymorphisms in this family. One is a C/A substitution at nt 1013 at the splice junction of intron 2-exon 3. A second one is a single base T deletion at nt 1553 in exon 4. The single base (T) deletion at nucleotide 1553 (1553delT) shifts the reading frame at amino acid 122(122delT) and creates a premature termination codon at amino acid 214 in exon 6. The mutated gene produces no mature SP-B protein. Genotype analysis from the nuclear family carrying this mutation showed that both parents and three of the four living children are heterozygous for the mutation. One of the four living children is homozygous for the normal allele and a child that died in the perinatal period from CAP is homozygous for the mutation. A third change is a C/T substitution at nt 1580 in exon 4 that changes amino acid 131 from threonine to isoleucine (Thr131Ile). The location of a previously reported mutation, 121ins2 (1), is only 4 nt upstream of 122delT, and the missense mutation Thr131Ile (exon 4) is only 27 nt downstream of 122delT. These changes are within or in close proximity to a CCTG sequence and a poly(C) tract, both of which are shown in other systems to be mutation hotspots. The 122delT occurs within the CCTG and the poly(C) tract sequences, the Thr131Ile occurs 26 nt downstream from the CCTG sequence, and the 121ins2 occurs 2 nt upstream from CCTG sequence and within the poly(C) tract. The present observations suggest that the short SP-B sequence containing the CCTG motif and the poly(C) tract is a mutation hotspot.
Mol Genet Metab 1998 May
PMID:An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4. 968 15

Lung injury is a frequent consequence of oxygen (O2) therapy administered to newborns and adults with respiratory distress. Acute exposure to hyperoxia results in a well-described pathophysiologic response in the lungs. Because inflammation is an important component of pulmonary O2 toxicity, we have an interest in identifying the inflammatory mediators that increase during hyperoxia. Platelet-endothelial cell adhesion molecule-1 (PECAM-1), a member of the immunoglobulin superfamily that is expressed at the junctions between endothelial cells, is essential to the transendothelial migration of leukocytes. We hypothesized that increased expression of PECAM-1 occurs in pulmonary endothelial cells during hyperoxic lung injury. Adult mice were exposed to 100% O2 for up to 96 h. We analyzed PECAM-1 expression by RNA blot hybridization, in situ hybridization, and immunohistochemistry. A increase in PECAM-1 mRNA was seen as soon as 2 d of hyperoxia relative to unexposed control mice. PECAM-1 mRNA and protein were found in endothelial cells of both large and small arteries. The expression of PECAM-1 in capillary vessels was further confirmed using in situ hybridization at the electron microscope level. This increase in PECAM-1 expression coincided with the appearance of leukocytes in lung tissue. These observations suggest that PECAM-1 expression is a relatively early step in the inflammation cascade, and intervention at this phase may be critical to the prevention of further damage.
Am J Respir Cell Mol Biol 1998 Oct
PMID:Increased endothelial cell expression of platelet-endothelial cell adhesion molecule-1 during hyperoxic lung injury. 976 50

Infants born to heroin- and cocaine-addicted mothers have been reported to have a lower incidence of respiratory distress syndrome (RDS) compared with nonaddicted infants. However, it is not known whether these are direct drug-mediated effects or secondary phenomena. We therefore investigated the effect of opioids and cocaine on fetal rat lung maturation in vitro. Using 18- to 20-d fetal rat lung explants and 20-d fetal type II cells, we measured the effect of varying concentrations (1 x 10(-8) to 1 x 10(-3) M) of heroin, morphine, methadone, and the nonopioid cocaine on the rate of choline incorporation into phosphatidylcholine (PC) and disaturated PC. We also analyzed the morphology of 19-d explants after exposure to opioids. Significant increases in rate of choline incorporation were noted in 19- and 20-d explants using 1 x 10(-3) M heroin, 1 x 10(-3) M morphine, and 1 x 10(-4) M methadone (P < 0. 005). No acceleratory effect was seen with cocaine. Morphologic analysis of the three opioid-treated groups revealed a significant (192 to 251%) increase in type II pneumocytes and lamellar bodies per alveolar lining cell (P < 0.01). Choline incorporation into PC by type II cells was also significantly increased by opioids (P < 0. 01); lactate dehydrogenase release and cell viability were not affected by opioid treatment. These data indicate that high-dose opioids have an acceleratory effect on biochemical and morphologic parameters of fetal lung maturation in vitro. The lack of in vitro acceleration with cocaine suggests that any cocaine-related reduction in the incidence of RDS is a secondary effect.
Am J Respir Cell Mol Biol 1999 Mar
PMID:Opioids accelerate fetal rat lung maturation in vitro. 1003 Aug 50

During late pregnancy, the fetal lung stores surfactant in preparation for extrauterine life. Surfactant deficiency, most often due to prematurity, precipitates respiratory distress syndrome (RDS) of the neonate. Although vitamin A (retinol) and retinoic acid have been shown to enhance the synthesis of phospholipid surfactant components, their effect on surfactant-specific proteins is unclear. No attempt has been made to evaluate the consequences of vitamin A restriction on surfactant phospholipid storage or on the expression of the life-essential surfactant protein-B (SP-B). We induced in rats a partial vitamin A deficiency leading to a 30-60% reduction in blood retinol, a status compatible with maintenance of gestation and absence of gross abnormalities in offspring. At term, lung surfactant phospholipids were reduced by 21%, and the major surfactant phospholipid, disaturated phosphatidylcholine (DSPC), was reduced by 27% in vitamin A-deficient (VAD) fetuses. The decrease in surfactant phospholipids and DSPC correlated linearly with plasma retinol, and reached about 50% in fetuses with the lowest retinol concentrations; it was accompanied by reduced expression of the gene for fatty acid synthase, a key enzyme in the synthetic pathway for surfactant-phospholipid lipid precursors. The amounts of SP-A, SP-B, and SP-C messenger RNAs were decreased by 46%, 32%, and 28%, respectively, in VAD fetuses. Consistently, amounts of SP-A and SP-B proteins were diminished as assessed by Western blotting. The proportion of type II cells determined after SP-B labeling was unchanged in VAD as compared with control lungs. Vitamin A deficiency is therefore a cause of lung maturational delay. In view of its rather large incidence in human populations, it may represent an increased risk for RDS and an aggravating factor for prematurity.
Am J Respir Cell Mol Biol 1999 Jul
PMID:Mild vitamin A deficiency delays fetal lung maturation in the rat. 1038 96

Inhaled nitric oxide (NO) is used to treat various cardiopulmonary disorders associated with pulmonary hypertension. The rationale is based on the fact that NO, given by inhalation, only dilates those pulmonary vessels that perfuse well-ventilated lung units. As a result, pulmonary gas exchange is improved while pulmonary vascular resistance is reduced and pulmonary blood flow is increased. Inhaled NO has been successfully applied to treat persistent pulmonary hypertension of the newborn, reducing the need for extracorporeal life support. Although pulmonary hypertension and altered vasoreactivity contribute to profound hypoxaemia in adult and paediatric acute respiratory distress syndrome (ARDS), the benefit of inhaled NO still remains to be established in patients with ARDS. ARDS is a complex response of the lung to direct or indirect insults, leading to pulmonary vasoconstriction and various inflammatory responses. Recent randomized trials suggest that inhaled NO only causes a transient improvement in oxygenation. Whether this effect is important in the long-term management of ARDS remains to be established. NO, measured in the exhaled breath, is an elegant and non-invasive means to monitor inflammation of the upper and lower respiratory tract. In the normal upper airways, the bulk of exhaled NO originates from the paranasal sinuses. Exhaled NO is increased in nasal allergy and decreased in cystic fibrosis, nasal polyposis and chronic sinusitis. That NO production is increased in asthmatic airways is also well established. However, several questions still need to be addressed, in particular evaluation of the sensitivity and specificity of the measurement techniques, and assessment of the bronchodilator action of endogenous NO.
Cell Mol Life Sci 1999 Jul
PMID:Inhaled and exhaled nitric oxide. 1044 91

Membrane-associated tumor necrosis factor (mTNF) has recently been shown to induce inflammatory cellular responses previously attributed to the soluble form. The present study measures for the first time the expression and function of mTNF on the surface of alveolar macrophages (AMs) to determine whether it is associated with the development of acute respiratory distress syndrome (ARDS). TNF expression was determined by flow cytometry, and the function of mTNF on the surface of AMs was determined by an in vitro cytotoxicity assay. Tumor necrosis factor (TNF)-alpha bioactivity was measured by bioassay. Soluble TNF receptor (TNFR) protein and messenger RNA (mRNA) expression were measured by enzyme-linked immunosorbent assay and reverse transcriptase/polymerase chain reaction, respectively. Increased detection of mTNF was observed on the surface of AMs derived from subjects with ARDS (mean percentage increase in fluorescence 22.30 +/- 3.50% for subjects with ARDS compared with 7.09 +/- 1.70% for At Risk subjects [P < 0.003]). mTNF cytotoxicity in the bioassay positively correlated with the mTNF expression determined by flow cytometry (r(2) = 0.97). Although there was increased mTNF expression and cytotoxic function in ARDS, there was no significant increase in soluble TNF expression in the bronchoalveolar lavage fluid or the AM supernatants. Lower levels of CD120b-soluble TNFR were detected in the AM supernatants derived from subjects with ARDS compared with At Risk (mean 0.264 +/- 0.058 versus 0.593 +/- 0.143 ng/ml, respectively [P < 0.05]). By contrast, there was increased CD120b mRNA expression in AMs derived from subjects with ARDS (P < 0.03), suggesting that increased surface expression of this receptor may be important in mediating the signal of mTNF. These data demonstrate for the first time the presence of functionally active mTNF on the surface of AMs in ARDS and highlight a potential mechanism for TNF-mediated lung injury.
Am J Respir Cell Mol Biol 2000 Jan
PMID:Increased expression of functionally active membrane-associated tumor necrosis factor in acute respiratory distress syndrome. 1061 67

Hemorrhagic shock due to major trauma predisposes to the development of acute respiratory distress syndrome. Because lung fibrin deposition is one of the hallmarks of this syndrome, we hypothesized that resuscitated shock might predispose to the development of a net procoagulant state in the lung. A rodent model of shock/resuscitation followed by low-dose intratracheal lipopolysaccharide (LPS), a clinically relevant "two-hit" model, was used to test this hypothesis. Resuscitated shock primed the lungs for an increased tissue factor and plasminogen activator (PA) inhibitor-1 gene expression in response to LPS, while the fibrinolytic PA was reduced. These alterations were recapitulated in isolated alveolar macrophages, suggesting their role in the process. LPS-induced tumor necrosis factor (TNF) was also augmented in animals after antecedent shock/resuscitation, and studies using anti-TNF antibodies revealed that TNF expression was critical to the induction of the procoagulant molecules and the reduction in PA. By contrast, TNF did not appear to play an important role in neutrophil sequestration in this model, inasmuch as anti-TNF had no effect on lung neutrophil accumulation or chemokine expression. However, treatment prevented albumin leak by preventing alveolar neutrophil activation. The inclusion of the antioxidant N-acetyl-cysteine in the resuscitation fluid resulted in prevention of both the development of the net procoagulant state and lung neutrophil sequestration, suggesting a role for upstream oxidant effects in the priming process. These studies provide a cellular and molecular basis for lung fibrin deposition after resuscitated shock and demonstrate a divergence of pathways responsible for fibrin generation and neutrophil accumulation.
Am J Respir Cell Mol Biol 2000 Apr
PMID:Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: role of tumor necrosis factor. 1074 20

Liquid ventilation using perfluorocarbon has been shown to improve gas exchange in animal models of acute lung injury as well as in children with acute respiratory distress syndrome. This study was designed to define structural features of lung injury following partial liquid ventilation (PLV) using light and transmission electron microscopy in a rabbit model of acute respiratory distress. Animals were treated with either conventional mechanical ventilation (CMV-gas) (n = 6) or PLV (n = 5) for 4 h after the induction of acute lung injury with saline lavage. Control animals were killed after the lung injury. PLV significantly improved alveolar-arterial oxygen tension and the oxygen index compared with CMV (P < 0.05). Morphometric studies using light microscopy show less alveolar hemorrhage, less edema, and fewer hyaline membranes in the PLV group (P < 0.05). Polymorphonuclear leukocyte sequestration in lung capillaries (11.4 +/- 1.5 versus 19.2 +/- 3 x 10(8)/ml, P < 0.05, PLV versus CMV) and migration into airspaces (3.1 +/- 1.2 versus 4.5 +/- 1.1 x 10(8)/ml, P < 0.05, PLV versus CMV) were lower in the gravity-dependent lung regions. There were fewer alveolar macrophages in the PLV group compared with other groups (P < 0.05). Fluorescence microscopy analysis shows fewer type II alveolar epithelial cells in the CMV group and brighter type II cells in the PLV group. Transmission electron microscopy studies show more alveolar wall damage in the CMV group, with type II cells detached from their basement membrane with fewer surfactant-containing lamellar bodies. We conclude that quantitative histologic analysis shows less lung damage and inflammation when perfluorocarbon is combined with CMV in the management of acute respiratory distress syndrome.
Am J Respir Cell Mol Biol 2000 Apr
PMID:Partial liquid ventilation with perfluorocarbon in acute lung injury: light and transmission electron microscopy studies. 1074 25


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