Effects of Vagus Nerve Stimulation and Vagotomy on Systemic and Pulmonary Inflammation in a Two-Hit Model in Rats

Pulmonary inflammation contributes to ventilator-induced lung injury. Sepsis-induced pulmonary inflammation (first hit) may be potentiated by mechanical ventilation (MV, second hit). Electrical stimulation of the vagus nerve has been shown to attenuate inflammation in various animal models through the cholinergic anti-inflammatory pathway. We determined the effects of vagotomy (VGX) and vagus nerve stimulation (VNS) on systemic and pulmonary inflammation in a two-hit model. Male Sprague-Dawley rats were i.v. administered lipopolysaccharide (LPS) and subsequently underwent VGX, VNS or a sham operation. 1 hour following LPS, MV with low (8 mL/kg) or moderate (15 mL/kg) tidal volumes was initiated, or animals were left breathing spontaneously (SP). After 4 hours of MV or SP, rats were sacrificed. Cytokine and blood gas analysis was performed. MV with 15, but not 8 mL/kg, potentiated the LPS-induced pulmonary pro-inflammatory cytokine response (TNF-α, IL-6, KC: p<0.05 compared to LPS-SP), but did not affect systemic inflammation or impair oxygenation. VGX enhanced the LPS-induced pulmonary, but not systemic pro-inflammatory cytokine response in spontaneously breathing, but not in MV animals (TNF-α, IL-6, KC: p<0.05 compared to SHAM), and resulted in decreased pO2 (p<0.05 compared to sham-operated animals). VNS did not affect any of the studied parameters in both SP and MV animals. In conclusion, MV with moderate tidal volumes potentiates the pulmonary inflammatory response elicited by systemic LPS administration. No beneficial effects of vagus nerve stimulation performed following LPS administration were found. These results questions the clinical applicability of stimulation of the cholinergic anti-inflammatory pathway in systemically inflamed patients admitted to the ICU where MV is initiated

Ischemia of the lung causes extensive long-term pulmonary injury: an experimental study

Background: Lung ischemia-reperfusion injury (LIRI) is suggested to be a major risk factor for development of primary acute graft failure (PAGF) following lung transplantation, although other factors have been found to interplay with LIRI. The question whether LIRI exclusively results in PAGF seems difficult to answer, which is partly due to the lack of a long-term experimental LIRI model, in which PAGF changes can be studied. In addition, the long-term effects of LIRI are unclear and a detailed description of the immunological changes over time after LIRI is missing. Therefore our purpose was to establish a long-term experimental model of LIRI, and to study the impact of LIRI on the development of PAGF, using a broad spectrum of LIRI parameters including leukocyte kinetics.Methods: Male Sprague-Dawley rats (n = 135) were subjected to 120 minutes of left lung warm ischemia or were sham-operated. A third group served as healthy controls. Animals were sacrificed 1, 3, 7, 30 or 90 days after surgery. Blood gas values, lung compliance, surfactant conversion, capillary permeability, and the presence of MMP-2 and MMP-9 in broncho-alveolar-lavage flui

Boosting antenatal care attendance and number of hospital deliveries among pregnant women in rural communities: a community initiative in Ghana based on mobile phones applications and portable ultrasound scans

BACKGROUND: The World Health Organization has recommended at least four antenatal care (ANC) visits and skilled attendants at birth. Most pregnant women in rural communities in low-income countries do not achieve the minimum recommended visits and deliver without skilled attendants. With the aim of increasing number of ANC visits, reducing home deliveries, and supplementing care given by ANC clinics, a proposed system based on low-cost mobile phones and portable ultrasound scan machines was piloted. METHODS: A sample of 323 pregnant women from four rural communities in the Central Region of Ghana were followed within a 11-month project. In each community, at least one health worker was trained and equipped with a mobile phone to promote ANC and hospital deliveries in her own community. If women cannot attend ANC, technicians acquired scans by using portable ultrasound machines in her community directly and sent them almost in real time to be analyzed by a gynecologist in an urban hospital. A preliminary survey to assess ANC status preceding the pilot study was conducted. During this, one hundred women who had had pregnancies within five years prior to the study were interviewed. RESULTS: The preliminary survey showed that women who attended ANC were less likely to have a miscarriage and more likely to have delivery at hospital or clinic than those who did not, and women who attained at least four ANC visits were less likely to practice self-medication. Among the women involved in the project, 40 gave birth during the period of observation. The proposed prenatal care approach showed that 62.5 % of pregnant women who gave birth during the observation period included in the project (n=40) had their labor attended in clinics or hospitals as against 37.5 % among the cases reported in the pre-survey. One case of ectopic and two cases of breech pregnancies were detected during the pilot through the proposed approach, and appropriate medical interventions were sought. CONCLUSION: Our results show that the proposed prenatal care approach can make quality ANC accessible in rural communities where pregnant women have not been able to access proper ANC

Ischaemic conditioning and targeting reperfusion injury: a 30 year voyage of discovery

To commemorate the auspicious occasion of the 30th anniversary of IPC, leading pioneers in the field of cardioprotection gathered in Barcelona in May 2016 to review and discuss the history of IPC, its evolution to IPost and RIC, myocardial reperfusion injury as a therapeutic target, and future targets and strategies for cardioprotection. This article provides an overview of the major topics discussed at this special meeting and underscores the huge importance and impact, the discovery of IPC has made in the field of cardiovascular research

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Ischaemic conditioning and reperfusion injury

The 30-year anniversary of the discovery of 'ischaemic preconditioning' is in 2016. This endogenous phenomenon can paradoxically protect the heart from acute myocardial infarction by subjecting it to one or more brief cycles of ischaemia and reperfusion. Apart from complete reperfusion, this method is the most powerful intervention known for reducing infarct size. The concept of ischaemic preconditioning has evolved into 'ischaemic conditioning', a term that encompasses a number of related endogenous cardioprotective strategies, applied either directly to the heart (ischaemic preconditioning or postconditioning) or from afar, for example a limb (remote ischaemic preconditioning, perconditioning, or postconditioning). Investigations of signalling pathways underlying ischaemic conditioning have identified a number of therapeutic targets for pharmacological manipulation. Over the past 3 decades, a number of ischaemic and pharmacological cardioprotection strategies, discovered in experimental studies, have been examined in the clinical setting of acute myocardial infarction and CABG surgery. The results from many of the studies have been disappointing, and no effective cardioprotective therapy is currently used in clinical practice. Several large, multicentre, randomized, controlled clinical trials on cardioprotection have highlighted the challenges of translating ischaemic conditioning and pharmacological cardioprotection strategies into patient benefit. However, a number of cardioprotective therapies have shown promising results in reducing infarct size and improving clinical outcomes in patients with ischaemic heart disease

Role of tachykinins in bronchial hyper-responsiveness.

1. Sensory afferent fibres mediate important protective reflexes in the lung. Small, unmyelinated C-fibre nerves have both sensory afferent and effector functions. C-fibres contain a number of neuropeptides, including the tachykinins, which have pro-inflammatory effects in the airways. Following stimulation with capsaicin and other stimuli, neuropeptides are released from the nerve endings, either directly or by axonal reflexes. 2. Important tachykinin effects include smooth muscle contraction, vasodilatation and oedema, mucus secretion and inflammatory cell activation. There are also trophic effects, including proliferation of fibroblasts, smooth muscle and epithelial cells. 3. Tachykinins mediate their effects by binding to G-proteinlinked receptors. Receptor-specific agonists and antagonists are available, which have helped clarify the effects of tachykinins. These agents may have therapeutic potential. 4. Tachykinins are degraded by the enzyme neutral endo-peptidase. 5. Studies in humans in vivo show an increase in airways resistance following challenge with tachykinins. There is some evidence for an increase in tachykinins and their receptors in airway inflammation, but this has not been found in all studies. A reduction in neutral endopeptidase has been seen in some animal models of airway inflammation, but this has not been shown in human disease. 6. Trials of tachykinin receptor antagonists in human asthma have begun, but it is too early to say what their therapeutic impact will be