Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The tight-skin (Tsk/+) mouse is a genetically determined model characterized by alveolar enlargement and physiologic evidence of emphysema. Morphologic evaluation of the lungs of these animals demonstrated increased numbers of potential protease-secreting cells (alveolar macrophages and neutrophils) in the lower respiratory tract prior to development of the emphysematous lesions. Quantitation of the neutrophils in the lungs of these animals was carried out by bronchoalveolar lavage. In the Tsk/+ mice, neutrophils constituted 3.5 +/- 2% of all inflammatory and immune effector cells present compared with 0.4 +/- 0.1% in control (+/+) mice (p less than 0.01). The Tsk/+ animals had no evidence of infection to explain the presence of the neutrophils and had normal proportions of lung T- and B-lymphocytes, suggesting that their lungs were immunologically normal. There was no evidence that the Tsk/+ mice have an antiprotease deficit; the capacity of serum of Tsk/+ mice to inhibit neutrophil elastase was no different from that of control +/+ animals. However, the fact that these animals have a persistent low level macrophage-neutrophil alveolitis prior to the development of the emphysematous lesion implies that the lung destruction may be associated, in part, with a chronic protease-antiprotease imbalance, similar to that hypothesized for human emphysema.
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PMID:Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis. 656 69

The tight-skin (Tsk/+) mouse represents an autosomal dominant mutation characterized by increased thoracic size, large lungs, and a variety of abnormalities of loose subcutaneous connective tissue, cartilage, tendon, and bone. Because an increase in the size of the lung and thorax may result from destruction of alveolar walls and a loss of elastic recoil of the lung, the present study was undertaken to determine if the Tsk/+ mouse exhibits morphologic and physiologic characteristics of emphysema. In contrast to the lungs of normal mice, examination of the lungs of Tsk/+ mice by light and scanning electron microscopy revealed generalized enlargement of air spaces with numerous subpleural cysts and scattered bullae. In addition, many alveolar walls were either markedly thinned or broken and there was an increase in the number and size of the pores of Kohn. Consistent with these morphologic observations, the lungs of the Tsk/+ mice also exhibited physiologic characteristics consistent with emphysema. Compared to the lungs of normal mice, the lungs of Tsk/+ mice had a markedly increased total lung capacity of (1.8 +/- 0.1 ml versus 3.3 +/- 0.1 ml, p less than 0.001); compliance (0.077 +/- 0.006 ml/cm H2O versus 0.345 +/- 0.025 ml/cm H2O, p less than 0.001), and specific compliance (4.23 +/- 0.34% TLC/cm H2O versus 10.64 +/- 1.01% TLC/cm H2O, p less than 0.001). These findings suggested that the Tsk/+ mouse is a genetically determined model of emphysema that may be useful in determining the pathogenesis of destructive lung disease.
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PMID:Hereditary emphysema in the tight-skin (Tsk/+) mouse. 727 Oct 67

The tight skin (Tsk/+) mouse represents a murine model of heritable fibrosis with some similarities to the skin fibrosis seen in human scleroderma. Tsk/+ animals display alterations in connective tissue in some internal organs. Skin fibrosis can be adoptively transferred to normal recipients with Tsk/+ bone marrow or spleen cells and older Tsk/+ animals develop autoantibodies against topoisomerase suggesting that some of the pathogenesis in the Tsk/+ mouse may be mediated by autoimmunity. To determine the role of T cell subsets in the pathogenesis of fibrotic disease, Tsk/+ mice were bred with CD4- and CD8-deficient (CD4-/- and CD8-/-) mice. Tsk/+ CD4-/- mice showed a marked reduction in skin fibrosis as well as decreased cellularity and only mild collagen disorganization as compared to Tsk/+ CD4+ CD8+ control mice yet did not differ from Tsk controls in the level of serum anti-topoisomerase activity. In contrast, Tsk/+ CD8-/- mice exhibited the same histology in the skin as Tsk/+ controls yet had significantly reduced levels of serum anti-topoisomerase activity. Lung pathology, i.e. emphysema, was unaffected by both the CD4 or CD8 mutations. These data show that only some of the pathological effects of the Tsk mutation are T cell dependent and that different T cell subsets affect different parameters in this multi-organ model of fibrotic disease.
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PMID:A role for CD4+ T cells in the pathogenesis of skin fibrosis in tight skin mice. 791 25

The most appropriate airway device for use in EMS systems staffed by basic skilled EMTs with (EMT-Ds) or without (EMT-Bs) defibrillation capabilities is still a matter of debate. The purpose of this study was to assess the feasibility, safety and effectiveness of the Esophageal Tracheal Combitube (ETC) when used by EMT-Ds in cardiorespiratory arrest patients of all etiologies. The EMTs had automatic external defibrillator (AED) training but no prior advanced airway technique skills. The prehospital intervention was reviewed using the EMTs cardiac arrest report, the AED tape recording of the event and the assessment of the receiving emergency physician. The patients' hospital records and autopsy report were reviewed in search of complications. Eight hundred and thirty-one adult cardiac arrest patients were studied. Placement was successful in 725 (95.4%) of the 760 patients where it was attempted and ventilation was successful in 695 (91.4%). Immediate complications encountered, but not necessarily related to the use of the ETC, were; subcutaneous emphysema (18), tension pneumothorax (5), blood in the oropharynx (15), and swelling of the pharynx (three). An autopsy was done in 133 patients; no esophageal lesions or significant injury to the airway structures were observed. Our results suggest that EMT-Ds can use the ETC for control of the airway and ventilation in cardiorespiratory arrest patients safely and effectively.
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PMID:Use of the esophageal tracheal combitube by basic emergency medical technicians. 1180 52

Immunostimulatory CpG motifs can preferentially induce Th1 immune responses and have been applied to treat Th2-dominant disease. In this study, we investigated whether a plasmid with the addition of 20 copies of an immunostimulatory CpG motif (pB-CpG20) might prevent the development of scleroderma-like syndrome in tight-skin (Tsk/+) mice. Administration of pB-CpG20 to Tsk/+mice every 3 weeks starting at the age of 1 week reduced skin thickness and collagen content compared to that of pB or saline. The reduction was long lasting even after halting the treatment. Furthermore, this treatment partially reduced the production of anti-nuclear antibodies although it did not decrease the incidence of lung emphysema. pB-CpG20 increased the number of spleen cells secreting IFN-gamma and reduced that of the cells secreting IL-4 in vivo and in vitro compared to saline. These results suggest that repeated administration of a CpG-enriched plasmid can ameliorate scleroderma-like syndrome by biasing Th1 immunity in young Tsk/+mice.
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PMID:Therapeutic effect of CpG-enriched plasmid administration on the tight-skin mouse model of scleroderma. 1584 40

Tight-skin (Tsk/+) mice develop a disease similar to human scleroderma, characterized by the spontaneous appearance of cutaneous hyperplasia, anti-nuclear antibodies, and emphysema. T helper (Th) 2 cells secreting interleukin (IL)-4 are known to play a critical role in the etiopathogenesis of this disease. Th2-mediated responses can be blocked by treatment with synthetic oligodeoxynucleotides (ODN) containing immunomodulatory CpG motifs. Thus, we examined whether CpG ODN might be of therapeutic benefit in Tsk/+ mice. Administering CpG ODN to Tsk/+ mice every 3 wk starting at 1 wk of age abrogated skin fibrosis. This reduction in skin thickness persisted even after the cessation of therapy, and was accompanied by increased serum levels of IL-12 and an increased ratio of T cells available to secrete interferon-gamma rather than IL-4. CpG ODN therapy also reduced autoantibody production, but did not inhibit the incidence of lung emphysema. Delaying the initiation of CpG ODN treatment until 6 wk of age failed to prevent skin disease. These results indicate that by preferentially promoting the development of a Th1-biased immune milieu in young Tsk/+ mice, CpG ODN can ameliorate Th2-driven scleroderma-like syndrome.
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PMID:CpG oligodeoxynucleotides prevent the development of scleroderma-like syndrome in tight-skin mice by stimulating a Th1 immune response. 1595 88

We have recently established a new bone marrow transplantation (BMT) method in which bone marrow cells are injected into the intrabone marrow (IBM). In the present study, we used an animal model for emphysema (tight-skin [Tsk] mouse) to examine whether IBM-BMT could be used to treat emphysema in Tsk mice. IBM-BMT was carried out from C3H mice into Tsk mice (8-10 weeks old) that had already shown emphysema. Six months after transplantation, the lungs of all the Tsk mice treated with IBM-BMT [C3H-->Tsk] showed similar structures to those of normal mice, whereas the [Tsk-->Tsk] mice showed emphysema, as seen in age-matched Tsk mice. Next, we attempted to transfer emphysema from Tsk mice to C3H mice by IBM-BMT. Six months after IBM-BMT, the [Tsk-->C3H] mice showed emphysema. These results strongly suggest that emphysema in Tsk mice originates from defects of stem cells in the bone marrow.
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PMID:Treatment and transfer of emphysema by a new bone marrow transplantation method from normal mice to Tsk mice and vice versa. 1670 77

Pulmonary emphysema is a major cause of mortality and morbidity in chronic obstructive pulmonary disease (COPD). Cigarette smoking is a major risk factor in the development of pulmonary emphysema. In this study, we investigated the acute effect of cigarette smoke in vitro on the production of tumour necrosis factor-alpha (TNF-alpha) using differentiated U937 cells, a macrophage model system. We found that stimulation of the macrophages with cigarette smoke media (CSM) leads to a rapid activation of extracellular-regulated kinases 1 and 2 (erk1/2), p90RSK and a transient decrease in phosphorylation of PKB/akt. The CSM also caused the subsequent induction of TNF-alpha release. Our studies revealed that U0126, an inhibitor of the erk1/2 pathway, markedly suppressed CSM-induced TNF-alpha release. Consistent with this finding, U0126 blocked CSM-stimulated erk1/2 phosphorylation, as well as phosphorylation of the downstream kinase, p90RSK. On the other hand, the PI3-K inhibitor, LY294002, and epidermal growth factor receptor (EGFR)-specific inhibitor, AG1478, did not suppress the release of TNF-alpha. Thus, CSM induction of TNF-alpha production by differentiated macrophages is regulated primarily via the erk1/2 pathway.
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PMID:Acute effect of cigarette smoke on TNF-alpha release by macrophages mediated through the erk1/2 pathway. 1677 89

The tight skin 2 (Tsk2) mutation is an ENU induced dominant mutation localized on mouse chromosome 1. While the molecular defect is unknown, Tsk2/+ mice display cutaneous thickening associated with excessive matrix production and are used as a model of scleroderma. The purpose of this study was to examine the cellular mechanisms associated with the excessive synthesis of matrix macromolecules using a collagen promoter GFP reporter transgene (pOBCol3.6GFP) as a marker of Col1a1 expression. This analysis of pOBCol3.6GFP expression in Tsk2/+ skin showed an increase in transgene activity compared to wild-type (+/+) samples. In addition, an increased area of "high" GFP fluorescence in Tsk2/+ dermis in both 1- and 4-month-old mice was observed that was also associated with an increased number of dermal fibroblasts per unit area of dermis. These data collectively suggest an important mechanism of Tsk2/+ skin fibrosis; an increased number of collagen expressing cells as well as elevated collagen expression on a per cell basis. During this study it was noted that Tsk2/+ mice appeared consistently smaller than wild-type (+/+) siblings and measurements of body length revealed a decrease (5-10%) in 1- and 2-month-old Tsk2/+ mice as well as a decrease in body weight in both age groups as compared to wild-type (+/+) control mice. Femur length was also decreased (2-9%) in Tsk2/+ mice. Finally, in contrast to Tsk/+ mice that display an emphysema-like lung pathology, histological sections of lungs from Tsk2/+ mice were normal and indistinguishable from wild-type (+/+) controls.
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PMID:Regulation of collagen gene expression in the Tsk2 mouse. 1796 May 58

In otolaryngology, CO2 laser is the first and most commonly applied device. Such lasers as Ny:YAG generating visible light having wavelength 532 nm referred to as KTP laser due to the Name of the crystal where infrared light is converted to visible light. Such wavelenght, having green colour, due to strong absorption in haemoglobin is applied in treatments on tissues having dense blood vessels. The object of the work is to analyze larynx microsurgery laser treatments performer between 1994-2008 in the Otolaryngology Department of the Military Medical Institute CSK MON in Warsaw. The examination covered 445 patients including 142 women (31.9%) and 303 men (68.1%) aged between 12 and 80 (the average age of 48.2 year olds) who Were qualified in 1994-2003 for endoscopic laser surgery of the larynx. The operations field was watched using OPMI-11 operating microscope (Zeiss, Germany) allowing 4-16 times blow-up. Larynx laser microsurgery was performer using white laser beam: CO2 Illumina 40 (Heraeus LaserSonics, Germany) and green laser beam using KTP AURA XP laser (AMS, USA). The total of 445 larynx laser microsurgeries were performer. In recent years our clinic has seen an increase in the number of operations using this technique. The largest group were patients with recognized precancerous conditions (33.0%) and larynx carcinoma (26.4%). The next group in terms of the number of patients were 114 patients (20.6%) with recognized juvenile papilloma. Complications were observed in 180 patients. Table III show the type of recognized complications. The most commonly observed was swelling of the mucous membrane (48.3%), the rarest type was subcutaneous emphysema (3.3%). It was concluded that larynx laser microsurgery is a safe method and a valuable tool in treatment of larynx diseases, especially precancerous conditions and early forms of larynx carcinoma; that complications following procedure are relatively rare, usually mild, not life-threatening, and most often subsiding after a few days.
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PMID:[Application of lasers in treatment of larynx diseases]. 2056 6


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