Differential expression of VEGF-Axxx isoforms is critical for development of pulmonary fibrosis

RATIONALE Fibrosis after lung injury is related to poor outcome, and idiopathic pulmonary fibrosis (IPF) can be regarded as an exemplar. Vascular endothelial growth factor (VEGF)-A has been implicated in this context, but there are conflicting reports as to whether it is a contributory or protective factor. Differential splicing of the VEGF-A gene produces multiple functional isoforms including VEGF-Aa and VEGF-Ab, a member of the inhibitory family. To date there is no clear information on the role of VEGF-A in IPF. OBJECTIVES To establish VEGF-A isoform expression and functional effects in IPF. METHODS We used tissue sections, plasma, and lung fibroblasts from patients with IPF and control subjects. In a bleomycin-induced lung fibrosis model we used wild-type MMTV mice and a triple transgenic mouse SPC-rtTATetoCreLoxP-VEGF-Ato conditionally induce VEGF-A isoform deletion specifically in the alveolar type II (ATII) cells of adult mice. MEASUREMENTS AND MAIN RESULTS IPF and normal lung fibroblasts differentially expressed and responded to VEGF-Aa and VEGF-Ab in terms of proliferation and matrix expression. Increased VEGF-Ab was detected in plasma of progressing patients with IPF. In a mouse model of pulmonary fibrosis, ATII-specific deficiency of VEGF-A or constitutive overexpression of VEGF-Ab inhibited the development of pulmonary fibrosis, as did treatment with intraperitoneal delivery of VEGF-Ab to wild-type mice. CONCLUSIONS These results indicate that changes in the bioavailability of VEGF-A sourced from ATII cells, namely the ratio of VEGF-Aa to VEGF-Ab, are critical in development of pulmonary fibrosis and may be a paradigm for the regulation of tissue repair

Vascular Endothelial Growth Factor (VEGF) isoform expression and activity in human and murine lung injury

<p>Abstract</p> <p>Background</p> <p>The properties of vascular endothelial growth factor (VEGF) as a potent vascular permogen and mitogen have led to investigation of its potential role in lung injury. Alternate spliced VEGF transcript generates several isoforms with potentially differing functions. The purpose of this study was to determine VEGF isoform expression and source in normal and ARDS subjects and investigate the expression and regulation of VEGF isoforms by human alveolar type 2 (ATII) cells.</p> <p>Methods</p> <p>VEGF protein expression was assessed immunohistochemically in archival normal and ARDS human lung tissue. VEGF isoform mRNA expression was assessed in human and murine lung tissue. Purified ATII cells were cultured with proinflammatory cytokines prior to RNA extraction/cell supernatant sampling/proliferation assay.</p> <p>Measurements and Main Results</p> <p>VEGF was expressed on alveolar epithelium, vascular endothelium and alveolar macrophages in normal and ARDS human lung tissue. Increases in VEGF expression were detected in later ARDS in comparison to both normal subjects and early ARDS (p < 0.001). VEGF₁₂₁, VEGF₁₆₅and VEGF₁₈₉isoform mRNA expression increased in later ARDS (p < 0.05). The ratio of soluble to cell-associated isoforms was lower in early ARDS than normal subjects and later ARDS and also in murine lung injury. ATII cells constitutionally produced VEGF₁₆₅and VEGF₁₂₁protein which was increased by LPS (p < 0.05). VEGF₁₆₅upregulated ATII cell proliferation (p < 0.001) that was inhibited by soluble VEGF receptor 1 (<it>sflt</it>) (p < 0.05).</p> <p>Conclusion</p> <p>These data demonstrate that changes in VEGF isoform expression occur in ARDS which may be related to their production by and mitogenic effect on ATII cells; with potentially significant clinical consequences.</p

Admission of advanced lung cancer patients to intensive care unit: A retrospective study of 76 patients

<p>Abstract</p> <p>Background</p> <p>Criteria for admitting patients with incurable diseases to the medical intensive care unit (MICU) remain unclear and have ethical implications.</p> <p>Methods</p> <p>We retrospectively evaluated MICU outcomes and identified risk factors for MICU mortality in consecutive patients with advanced lung cancer admitted to two university-hospital MICUs in France between 1996 and 2006.</p> <p>Results</p> <p>Of 76 included patients, 49 had non-small cell lung cancer (stage IIIB n = 20; stage IV n = 29). In 60 patients, MICU admission was directly related to the lung cancer (complication of cancer management, n = 30; cancer progression, n = 14; and lung-cancer-induced diseases, n = 17). Mechanical ventilation was required during the MICU stay in 57 patients. Thirty-six (47.4%) patients died in the MICU. Three factors were independently associated with MICU mortality: use of vasoactive agents (odds ratio [OR] 6.81 95% confidence interval [95%CI] [1.77-26.26], p = 0.005), mechanical ventilation (OR 6.61 95%CI [1.44-30.5], p = 0.015) and thrombocytopenia (OR 5.13; 95%CI [1.17-22.5], p = 0.030). In contrast, mortality was lower in patients admitted for a complication of cancer management (OR 0.206; 95%CI [0.058-0.738], p = 0.015). Of the 27 patients who returned home, four received specific lung cancer treatment after the MICU stay.</p> <p>Conclusions</p> <p>Patients with acute complications of treatment for advanced lung cancer may benefit from MCIU admission. Further studies are necessary to assess outcomes such as quality of life after MICU discharge.</p

Conditional deletion of epithelial IKKβ impairs alveolar formation through apoptosis and decreased VEGF expression during early mouse lung morphogenesis

<p>Abstract</p> <p>Background</p> <p>Alveolar septation marks the beginning of the transition from the saccular to alveolar stage of lung development. Inflammation can disrupt this process and permanently impair alveolar formation resulting in alveolar hypoplasia as seen in bronchopulmonary dysplasia in preterm newborns. NF-κB is a transcription factor central to multiple inflammatory and developmental pathways including dorsal-ventral patterning in fruit flies; limb, mammary and submandibular gland development in mice; and branching morphogenesis in chick lungs. We have previously shown that epithelial overexpression of NF-κB accelerates lung maturity using transgenic mice. The purpose of this study was to test our hypothesis that targeted deletion of NF-κB signaling in lung epithelium would impair alveolar formation.</p> <p>Methods</p> <p>We generated double transgenic mice with lung epithelium-specific deletion of IKKβ, a known activating kinase upstream of NF-κB, using a cre-<it>loxP </it>transgenic recombination strategy. Lungs of resulting progeny were analyzed at embryonic and early postnatal stages to determine specific effects on lung histology, and mRNA and protein expression of relevant lung morphoreulatory genes. Lastly, results measuring expression of the angiogenic factor, VEGF, were confirmed <it>in vitro </it>using a siRNA-knockdown strategy in cultured mouse lung epithelial cells.</p> <p>Results</p> <p>Our results showed that IKKβ deletion in the lung epithelium transiently decreased alveolar type I and type II cells and myofibroblasts and delayed alveolar formation. These effects were mediated through increased alveolar type II cell apoptosis and decreased epithelial VEGF expression.</p> <p>Conclusions</p> <p>These results suggest that epithelial NF-κB plays a critical role in early alveolar development possibly through regulation of VEGF.</p

Central venous catheter use in severe malaria: time to reconsider the World Health Organization guidelines?

<p>Abstract</p> <p>Background</p> <p>To optimize the fluid status of adult patients with severe malaria, World Health Organization (WHO) guidelines recommend the insertion of a central venous catheter (CVC) and a target central venous pressure (CVP) of 0-5 cmH₂O. However there are few data from clinical trials to support this recommendation.</p> <p>Methods</p> <p>Twenty-eight adult Indian and Bangladeshi patients admitted to the intensive care unit with severe <it>falciparum </it>malaria were enrolled in the study. All patients had a CVC inserted and had regular CVP measurements recorded. The CVP measurements were compared with markers of disease severity, clinical endpoints and volumetric measures derived from transpulmonary thermodilution.</p> <p>Results</p> <p>There was no correlation between the admission CVP and patient outcome (p = 0.67) or disease severity (p = 0.33). There was no correlation between the baseline CVP and the concomitant extravascular lung water (p = 0.62), global end diastolic volume (p = 0.88) or cardiac index (p = 0.44). There was no correlation between the baseline CVP and the likelihood of a patient being fluid responsive (p = 0.37). On the occasions when the CVP was in the WHO target range patients were usually hypovolaemic and often had pulmonary oedema by volumetric measures. Seven of 28 patients suffered a complication of the CVC insertion, although none were fatal.</p> <p>Conclusion</p> <p>The WHO recommendation for the routine insertion of a CVC, and the maintenance of a CVP of 0-5 cmH₂O in adults with severe malaria, should be reconsidered.</p

COL04-05 Retour sur l’utilisation pratique de l’outil ConsoRes – un plébiscite à 3 ans du début d’un déploiement progressif

International audienceIntroduction – objectifsConsores, e-outil de suivi automatisé des consommations d’antibiotiques (ATB) et des résistances bactériennes, a été progressivement déployé dans les établissements de santé (ES) depuis 2012. Nous présentons ici les résultats d’une seconde enquête de satisfaction adressée à l’ensemble des inscrits à ConsoRes (320 ES).Matériels et méthodesEnquête en ligne (via Sphinx Online®) du 28 janvier au 11 février 2014 proposée à 551 contacts (pharmaciens, bactériologistes, cliniciens, référents…).Résultats169 questionnaires (31 %) ont été retournés. 55 % répondants ne se sont inscrits à ConsoRes qu’en 2013. La périodicité de surveillance est majoritairement trimestrielle. Les répondants exercent principalement en CH (36,7 %), MCO (20 %) ou CHU (15 %). Pour 88 %, l’outil répond à leurs attentes pour piloter plus efficacement les consommations d’ATB au sein de leur ES, 90 % pensent continuer à l’utiliser régulièrement et 83 % des répondants recommanderaient ConsoRes à des collègues d’autres ES. En pratique, 62 % font suivre des informations ciblées aux cliniciens, dont 43 % régulièrement et 22 % dès qu’une information leur apparait pertinente. Parmi les inscrits en 2013, 57 % ont pu identifier et mettre en œuvre des actions pour améliorer l’usage des ATB grâce aux données fournies par ConsoRes. Parmi les utilisateurs inscrits depuis 2012, 70 % (21/30) ont mis en place des actions au sein de leur ES. Près d’un tiers des répondants estime avoir besoin d’un accompagnement complémentaire dans l’analyse et l’interprétation des données issues de ConsoRes.ConclusionConsoRes bénéficie d’un fort taux de recommandation. L’accompagnement dans l’analyse et dans l’interprétation des données reste une demande forte. Ainsi, ConsoRes doit devenir un outil de pilotage utile aux référents ATB locaux ou régionaux pour guider les ES dans le choix des actions d’amélioration

Looking at hospitalized persons throughout the prism of the handicap

International audienceOBJECTIVE:To describe the disability status of non-selected hospitalized persons.METHODS AND FINDINGS:We conducted a cross-sectional survey to assess activity limitations of every person older than 18 years hospitalized in a regional university hospital covering all medical fields. Evaluators rated, on a scale from 0 to 4, 22 selected items of the International Classification of Functioning (ICF), covering the 6 following domains: learning and applying knowledge, general tasks and demands, communication, mobility, self-care, and interpersonal interactions and relationships. Univariate and multivariate analyses were performed to analyze the prevalence, severity and profile of the handicap in terms of sociodemographic characteristics and care pathways.RESULTS:Among 1572 eligible persons, 1267 (81%) were surveyed (mean age 62.7±20.4years; 655 males [51.7%]). Overall, 82% showed at least one activity limitation. For 52%, disability was severe or total for at least one ICF item. Prevalence of disabilities was higher for mobility (75%) and self-care domains (63%). Disability was strongly related to age: age older than 80years versus 18 to 44years (OR=12.8 95% CI 6.4-27.9]; P<0.01). Disability was associated with hospitalization in rehabilitation units (96%; OR=4.3 [95% CI 2.2-5.3]; P<0.01). Severe disability was associated with hospitalization in critical care units (OR=6.7 [CI 3.2-15.1]; P<0.001) and psychiatry units (OR=5.3 [CI 2.7-11.4]; P<0.001).CONCLUSION:Handicap was common in hospitalized persons, involving all 6 tested ICF activity domains, particularly mobility and self-care. This study alerts care givers, hospital administrators, and in general, people influencing health policies about the need to plan actions to reduce activity limitations of hospitalized persons, whatever the cause of the hospitalization