Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.59 (MIP)
 4,906 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We measured maximal inspiratory and expiratory pressures (MIP and MEP, respectively) in 23 male patients with cystic fibrosis (CF), 16 to 35 yr of age (22.1 +/- 3.7), and in a control group of 33 male volunteers, 17 to 39 yr of age (22.5 +/- 6.8), to evaluate the effects of chronic hyperinflation and malnutrition on MIP and MEP in the patients with CF. Routine pulmonary function tests and skeletal muscle indexes, such as the force generated by the adductor pollicis muscle with supramaximal ulnar nerve stimulation at a frequency of 10 Hz as percentage of force at 100 Hz (F10/100) and midarm muscle circumference as a percentage of predicted (MAMC), were also measured in the patients with CF. Severe hyperinflation in this study was defined as a ratio of residual volume to total lung capacity above 50% and malnutrition as a ratio of actual weight to the ideal weight for the patient's age and height of 90% or less. The severely hyperinflated subgroup of patients with CF had significantly reduced MIP values in comparison with those in the other patients with CF. The malnourished subgroup, which was also severely hyperinflated, differed from the well-nourished one in both skeletal muscle indexes; MAMC was reduced, whereas F10/100 was elevated, and respiratory muscle pressure generation, MIP, and MEP were reduced. We conclude that patients with CF who are malnourished and/or severely hyperinflated have reduced maximal respiratory pressures.
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PMID:Maximal inspiratory and expiratory pressures are reduced in hyperinflated, malnourished, young adult male patients with cystic fibrosis. 405 13

Indices of respiratory muscle strength, pulmonary function, and pulmonary diffusing capacity were measured in 11 malnourished children (age 10 to 17 years) with cystic fibrosis, before and after improvement of nutritional status with supplemental parenteral nutrients for 1 month. During this time, the children received 120% of estimated energy requirements (either 3.75% or 22.5% as lipid) and amino acids 2.5 gm/120 kcal by central venous catheter, plus as much of their usual diet as desired. With nutritional supplementation, body weight, triceps skinfold thickness, and mid-arm muscle circumference increased (mean 15%, 62%, and 95%, respectively). Maximum inspiratory airway pressure also increased (mean 29%; P less than 0.01), suggesting improvement in respiratory muscle strength. However, none of the indices of pulmonary function improved. Pulmonary diffusing capacity did not change during parenteral nutrition regardless of the amount of parenteral energy intake supplied by lipid, but arterial oxygen saturation decreased (mean of 93.5% to 91.5%; P less than 0.005). During the month following parenteral nutrition, weight, skinfold thickness, and mid-arm muscle circumference, but not MIP, decreased and arterial oxygen saturation returned to the initial value (P less than 0.01).
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PMID:Short-term pulmonary effects of total parenteral nutrition in children with cystic fibrosis. 642 80

Replication-deficient adenovirus vectors (Avs) have shown high-efficiency gene transfer in a variety of animal models, but demonstrated lower than expected efficiency in the intensely inflammatory milieu of the respiratory tract of individuals with cystic fibrosis (CF). Specific acquired immune responses directed at adenovirus capsid proteins are known to limit the duration of transgene expression and the effectiveness of vector readministration. In these models, however, nonspecific inflammation is also frequently noted to accompany specific immune responses. Because inflammation can occur early after Av administration, we hypothesized that inflammation may block Av-mediated gene transfer in the lung independent of specific immune responses. To evaluate this hypothesis, we measured pulmonary gene transfer and expression in the absence or presence of the potent antiinflammatory agent dexamethasone. To address and eliminate concerns over the potentially confounding effects of systemic, vector-specific acquired immune responses, evaluations were confined to a 3-day period following Av administration and were carried out, in parallel, in normal and immunodeficient (athymic) mice. Dexamethasone significantly reduced Av-associated inflammation in all animals as measured by a significant reduction of blinded, quantitative lung histopathology scores and by reduced proinflammatory cytokine release. Concomitant with reduced inflammation, gene transfer efficiency was significantly increased in both normal and immunodeficient animals as measured by transgene product activity (beta-galactosidase) in total lung homogenates 3 days after vector administration. This finding could not be explained by a direct effect of dexamethasone on transgene specific activity. To begin to understand the molecular mechanisms of Av-induced inflammatory responses, lung levels of the chemoattractive chemokines MIP-2, MIP-1alpha, and MCP-1 were quantified. All were elevated significantly in Av-exposed animals. Dexamethasone reduced levels of MCP-1 and MIP-1alpha, but not MIP-2, consistent with the observed pattern of inflammatory cell changes. Expression of several proinflammatory cytokines including TNF-alpha, IL-6, IL-1beta, and IFN-gamma were also elevated in Av-exposed animals and modulated by dexamethasone. These observations demonstrate that nonspecific inflammation is an important determinant of the efficiency of in vivo pulmonary gene transfer and expression independent of specific immune responses and may have important implications for human gene therapy for diseases of the lung.
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PMID:Nonspecific inflammation inhibits adenovirus-mediated pulmonary gene transfer and expression independent of specific acquired immune responses. 979 5

Chronic pulmonary infection with Pseudomonas aeruginosa is common in cystic fibrosis (CF) patients. P. aeruginosa lipopolysaccharide (LPS), phosholipase C (PLC), and exotoxin A (ETA) were evaluated for their ability to induce pulmonary inflammation in mice following intranasal inoculation. Both LPS and PLC induced high levels of tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta-6, gamma interferon (IFN-gamma), MIP-1 alpha MIP-2 in the lungs but did not affect IL-18 levels. ETA did not induce TNF-alpha and was a weak inducer of IL-1 beta, IL-6, macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-2. Remarkably, ETA reduced constitutive lung IL-18 levels. LPS was the only factor inducing IFN-gamma. LPS, PLC, and ETA all induced cell infiltration in the lungs. The role of interferon regulatory factor-1 (IRF-1) in pulmonary inflammation induced by LPS, PLC, and ETA was evaluated. When inoculated with LPS, IRF-1 gene knockout (IRF-1 KO) mice produced lower levels of TNF-alpha, IL-1 beta, and IFN-gamma than did wild-type (WT) mice. Similarly, a milder effect of ETA on IL-1 beta and IL-18 was observed for IRF-1 KO than for WT mice. In contrast, the cytokine response to PLC did not differ between WT and IRF-1 KO mice. Accordingly, LPS and ETA, but not PLC, induced expression of IRF-1 mRNA. IRF-1 deficiency had no effect on MIP-1 alpha and MIP-2 levels and on cell infiltration induced by LPS, PLC, or ETA. Flow cytometric evaluation of lung mononuclear cells revealed strongly reduced percentages of CD8(+) and NK cells in IRF-1 KO mice compared to percentages observed for WT mice. These data indicate that different virulence factors from P. aeruginosa induce pulmonary inflammation in vivo and that IRF-1 is involved in some of the cytokine responses to LPS and ETA.
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PMID:Pulmonary inflammation induced by Pseudomonas aeruginosa lipopolysaccharide, phospholipase C, and exotoxin A: role of interferon regulatory factor 1. 1185 20

Pseudomonas aeruginosa is a leading cause of hospital-acquired pneumonia, and approximately 80% of patients with cystic fibrosis are infected with this bacterium. To investigate the overall role of complement and the complement activation pathways in the host defense against P. aeruginosa pulmonary infection, we challenged C3-, C4-, and factor B-deficient mice with P. aeruginosa via intranasal inoculation. In these studies, C3(-/-) mice had a higher mortality rate than C3(+/+) mice. Factor B(-/-) mice, but not C4(-/-) mice, infected with P. aeruginosa had a mortality rate similar to that of C3(-/-) mice, indicating that in this model the alternative pathway of complement activation is required for the host defense against Pseudomonas infection. C3(-/-) mice had 6- to 7-fold more bacteria in the lungs and 48-fold more bacteria in the blood than did C3(+/+) mice at 24 h postinfection. In vitro, phagocytic cells from C3(+/+) or C3(-/-) mice exhibited a decreased ability to bind and/or ingest P. aeruginosa in the presence of C3-deficient serum compared to phagocytic cells in the presence of serum with sufficient C3. C3(-/-) mice displayed a significant increase in neutrophils in the lungs and had higher levels of interleukin-1beta (IL-1beta), IL-6, IL-10, KC, and MIP-2 in the lungs at 24 h postinfection than did C3(+/+) mice. Collectively, these results indicate that complement activation by the alternative pathway is critical for the survival of mice infected with P. aeruginosa and that the protection provided by complement is at least in part due to C3-mediated opsonization and phagocytosis of P. aeruginosa.
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PMID:The alternative activation pathway and complement component C3 are critical for a protective immune response against Pseudomonas aeruginosa in a murine model of pneumonia. 1510 2

Polymorphonuclear neutrophils (PMNs) are crucial for the outcome of Pseudomonas aeruginosa lung infection in patients with cystic fibrosis. We compared PMNs and inflammatory cytokines in the lungs and blood from susceptible BALB/c and resistant C3H/HeN mice 1 and 2 days after intratracheal challenge with alginate embedded P. aeruginosa. These parameters were correlated with the quantitative bacteriology and histopathology of the lungs. After challenge, the content of granulocyte colony-stimulating factor (G-CSF) and macrophage inflammatory protein-2 (MIP-2) was increased in the lungs and the sera and the percentage of PMNs was increased in the blood. However, 2 days after challenge the concentration of G-CSF and MIP-2 was higher in the lungs and sera of BALB/c mice. CD11b expression was higher on the PMNs of the C3H/HeN mice. The expression of CD62L on PMNs of both strains of mice was decreased 1 day after bacterial challenge, whereas the expression was increased after 2 days of challenge on PMNs of C3H/HeN mice only. These changes were accompanied by a more severe lung inflammation in BALB/c mice and faster clearance of the bacteria in C3H/HeN mice. In conclusion, the rapid early bacterial clearance in the lungs of C3H/HeN mice could be explained by faster activation of the PMNs, as indicated by the higher up-regulation of CD11b. The severe lung inflammation in BALB/c mice may be caused by the early higher content of G-CSF in the sera mobilizing PMNs from the bone marrow and the persistent chemotactic gradient provided by MIP-2 in the lungs.
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PMID:Faster activation of polymorphonuclear neutrophils in resistant mice during early innate response to Pseudomonas aeruginosa lung infection. 1532 Aug 96

Chronic pulmonary inflammation and infection are the leading causes of morbidity and mortality in cystic fibrosis (CF). While the effect of mutation of the cystic fibrosis transmembrane conductance regulator (CFTR) on airways remains controversial, some groups have demonstrated increases in Na(+) and Cl(-) in CF airway surface liquid compared to normal airways. We investigated the consequences of NaCl on pro-inflammatory chemokine and cytokine production by macrophages. Stimulation of mouse macrophages with increasing amounts of NaCl induced macrophage inflammatory protein-2 (MIP-2) and tumor necrosis factor-alpha (TNF-alpha) production. Further, co-incubation of macrophages with NaCl in the presence of either lipopolysaccharide (LPS) or TNF-alpha synergistically increased MIP-2 production. Both the NaCl and NaCl plus LPS responses were partially dependent on endogenous production and autocrine signaling by TNF-alpha. To investigate the role of CFTR in MIP-2 production, we compared the responses of wild-type and DeltaF508 CF mouse macrophages to NaCl and LPS. The responses of macrophages from both strains were indistinguishable. In addition, CFTR mRNA was not expressed in macrophages. Taken together, these findings suggest that NaCl stimulates MIP-2 production by macrophages through a mechanism that is partially dependent on TNF-alpha but independent of macrophage CFTR expression.
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PMID:Regulation of chemokine expression by NaCl occurs independently of cystic fibrosis transmembrane conductance regulator in macrophages. 1681 57

It is not known whether the progressive airway changes in cystic fibrosis (CF) are all secondary to infection and inflammation. The CF mouse nose shares electrophysiologic and cellular properties with human CF airway epithelium. In the present work, we tested the hypothesis that structural abnormalities in the nasal mucosa of CF mice develop independent of infection and inflammation. We performed nasal lavage and subsequent serial coronal section through the nasal tissue of adult CF (mutations Cftr(TgHm1G551D) and Cftr(tm1Unc)-TgN((FABPCFTR))) and wild-type mice raised under normal housing conditions. Nasal tissue was also obtained from Day 17 embryos and newborn pups. Detailed histologic examination of the respiratory and olfactory epithelium within the nasal cavity was performed. Bacterial culture, cell count, and macrophage inflammatory protein-2 (MIP-2) concentration were assessed in nasal lavage fluid. Significantly thickened respiratory epithelium and increased mucous cell density was found in adult CF mice of both mutations compared with wild-type animals. In contrast, the olfactory epithelium was thinner, with a decreased cell density. Areas of lymphoid aggregates were found in CF mice but not in non-CF mice. There were no differences in bacterial growth, cell count, or MIP-2 concentrations. No genotype differences were observed in the embryonic or newborn periods. There are significant histologic changes in the nasal mucosa of adult CF mice, not associated with increased lumenal inflammation or bacterial content, and which are not present perinatally. These may be novel therapeutic targets.
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PMID:Nasal abnormalities in cystic fibrosis mice independent of infection and inflammation. 1823 92

The dominant cause of premature death in patients suffering from cystic fibrosis (CF) is chronic lung infection with Pseudomonas aeruginosa. The chronic lung infection often lasts for decades with just one clone. However, as a result of inflammation, antibiotic treatment and different niches in the lungs, the clone undergoes significant genetic changes, resulting in diversifying geno- and phenotypes. Such an adaptation may generate different host responses. To experimentally reflect the year-long chronic lung infection in CF, groups of BALB/c mice were infected with clonal isolates from different periods (1980, 1988, 1997, 1999 and 2003) of the chronic lung infection of one CF patient using the seaweed alginate embedment model. The results showed that the non-mucoid clones reduced their virulence over time, resulting in faster clearing of the bacteria from the lungs, improved pathology and reduced pulmonary production of macrophage inflammatory protein-2 (MIP-2) and granulocyte colony-stimulating factor (G-CSF). In contrast, the mucoid clones were more virulent and virulence increased with time, resulting in impaired pulmonary clearing of the latest clone, severe inflammation and increased pulmonary MIP-2 and G-CSF production. In conclusion, adaptation of P. aeruginosa in CF is reflected by changed ability to establish lung infection and results in distinct host responses to mucoid and non-mucoid phenotypes.
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PMID:Novel experimental Pseudomonas aeruginosa lung infection model mimicking long-term host-pathogen interactions in cystic fibrosis. 1923 31

Burkholderia cenocepacia is an opportunistic pathogen of major concern for cystic fibrosis patients as well as immunocompromised cancer patients and transplant recipients. The mechanisms by which B. cenocepacia triggers a rapid health deterioration of the susceptible host have yet to be characterized. TLR and their key signaling intermediate MyD88 play a central role in the detection of microbial molecular patterns and in the initiation of an effective immune response. We performed a study to better understand the role of TLR-MyD88 signaling in B. cenocepacia-induced pathogenesis in the immunocompromised host, using an experimental murine model. The time-course of several dynamic parameters, including animal survival, bacterial load, and secretion of critical inflammatory mediators, was compared in infected and immunosuppressed wild-type and MyD88(-/-) mice. Notably, when compared with wild-type mice, infected MyD88(-/-) animals displayed significantly reduced levels of inflammatory mediators (including KC, TNF-alpha, IL-6, MIP-2, and G-CSF) in blood and lung airspaces. Moreover, despite a higher transient bacterial load in the lungs, immunosuppressed mice deficient in MyD88 had an unexpected survival advantage. Finally, we showed that this B. cenocepacia-induced life-threatening infection of wild-type mice involved the proinflammatory cytokine TNF-alpha and could be prevented by corticosteroids. Altogether, our findings demonstrate that a MyD88-dependent pathway can critically contribute to a detrimental host inflammatory response that leads to fatal pneumonia.
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PMID:Lack of MyD88 protects the immunodeficient host against fatal lung inflammation triggered by the opportunistic bacteria Burkholderia cenocepacia. 1953 24


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