Search

Welcome to the first issue of the Future Hospital Journal of the Royal College of Physicians. It is both an honour and pleasure to introduce an initiative designed not only to promote and develop the contents of the RCP report Future hospital: caring for medical patients , published in September 2013, but also to publish original research, reviews, guidance and opinion concerning innovation in systems of clinical practice, administration and management, and the organisation and delivery of health care. In our three editions per year, we aim to promote balanced and responsible debate regarding these issues among the fellows and members of the RCP, and to communicate innovative ideas to clinicians, technical and administrative staff and managers, patients and carers, and those engaged politically in providing and developing current and future healthcare systems. Above all, the editorial board hopes to carry out its mission in a manner that informs, stimulates, and entertains its readers. The task we face in improving healthcare through this medium is significant. At its birth in July 1948 the NHS assumed control of around 480,000 hospital beds, employed 5,000 consultants and in its first 12 months cost the nation £248 million to provide comprehensive healthcare free at the point of access to around 50 million people. Even from the perspective lent by 66 years, radical changes have occurred since this modest nativity. Indeed, Westminster no longer even presides over a truly national health service, responsibility for which has been devolved to Wales, Scotland and Northern Ireland; and in England to Foundation Trusts, or the Trust Development Agency. Indeed, the powers of the current secretary of state to close even a single accident and emergency department appear to be curtailed by legislation designed to free the modern NHS from central control.1 Second, in England alone a consultant …

Your editor is often struck by the number of individuals whom he encounters in various healthcare-related settings who, through their keenness to improve services to the patients they serve identify a perceived or real deficiency in care and assert ‘they should do something about it’. He often muses as to whom ‘they’ actually are? Sometimes this is self-evident. Individuals encountering the day-to-day frustrations associated with providing a clinical service either should be able to overcome these through their own initiative, or turn to line managers or systems of governance for assistance. Indeed, annual appraisal is supposed to bring together the lessons learnt in clinical practice to develop ourselves and improve our performance. However, sometimes ‘they’ are less easy to identify. Do we mean others within the provider arm of the NHS, who may be employed by the public or (increasingly) the private sectors? Do we mean commissioners, who may be difficult to identify or to interact with directly for those working at the coal face, but who seem to place increasing demands upon those that supply services, thereby applying the principles of Outcomes Based Incentivised Commissioning (sic)? Or do we mean ‘the government’? Since the Health and Social Care Act of 2013 arrived to brighten our professional lives, your editor perceives an increasing distance being created between elected politicians taking responsibility for deficiencies (but rather less so for any successes) in healthcare provision and those tasked with overseeing its provision. In an effort to address this question, I have in this column selected three pieces of evidence that have emerged since last I wrote, each of which cast some light upon this issue. The first is the NHS Five Year Forward View (‘5YFV’) published in October 2014 by NHS England, which sets a positive spin on the future, based around …

An aspect of the report of the Future Hospital Commission (FHC) that was considered controversial when it was published 2 years ago was the perception that medical generalism was favoured over the trend towards increased specialisation. This notion was an oversimplification of a complex problem. A compelling component of the evidence gathered by the FHC came from patients and carers, who were engaged at all levels of the exercise. It became clear that they found the tendency for multiple specialists, often with extremely focused areas of expertise limited to a single organ (or indeed a part of that organ), to come to their bedside, pronounce on that specific aspect of their care and then depart to be frustrating, notwithstanding the undoubted improvements in clinical outcomes such specialisation has achieved. In response, a central recommendation of the FHC was that a trained clinician would assume overall responsibility for managing and coordinating each patient's care. This role could be fulfilled by generalists, or delivered by specialists for part of their job plan. All those involved in producing the FHC report were adamant that maintaining and augmenting the access of patients to specialist care could not be compromised in the future hospital; the issue was merely that the coordination of these efforts and their delivery as part of a comprehensive care plan was often lacking. Robert Francis also emphasised this point in his report into the Mid-Staffordshire case, asserting that the responsibility for the delivery of a basic level of care to all patients needed to be …

Aim: We investigated whether plasma levels of the inflammation marker S100A8/A9, could predict acute kidney injury (AKI) onset in patients undergoing cardiac surgery necessitating cardiopulmonary bypass (CPB). Patients & methods: Plasma levels of S100A8/A9 and other neutrophil cytosolic proteins were measured in 39 patients pre- and immediately post-CPB. Results: All markers increased significantly post-CPB with S100A8/A9, S100A12 and myeloperoxidase levels significantly higher in patients who developed AKI within 7 days. S100A8/A9 had good prognostic utility for AKI, with an area under the receiver operating characteristic curve of 0.81 (95% CI: 0.676–0.949) and a cut-off value of 10.6 μg/ml (85.7% sensitivity and 75% specificity) irrespective of age. Conclusion: Plasma S100A8/A9 levels immediately after cardiac surgery, can predict onset of AKI, irrespective of age.

Diffuse alveolar hemorrhage is characterized by the presence of red blood cells and free hemoglobin in the alveoli and complicates a number of serious medical and surgical lung conditions including the pulmonary vasculitides and acute respiratory distress syndrome. In this study we investigated the hypothesis that exposure of human alveolar epithelial cells to hemoglobin and its breakdown products regulates chemokine release via iron- and oxidant-mediated activation of the transcription factor NF-κB. Methemoglobin alone stimulated the release of IL-8 and MCP-1 from A549 cells via activation of the NF-κB pathway; additionally, IL-8 required ERK activation and MCP-1 required JNK activation. Neither antioxidants nor iron chelators and knockdown of ferritin heavy and light chains affected these responses, indicating that iron and reactive oxygen species are not involved in the response of alveolar epithelial cells to methemoglobin. Incubation of primary cultures of human alveolar type 2 cells with methemoglobin resulted in a similar pattern of chemokine release and signaling pathway activation. In summary, we have shown for the first time that methemoglobin induced chemokine release from human lung epithelial cells independent of iron- and redox-mediated signaling involving the activation of the NF-κB and MAPK pathways. Decompartmentalization of hemoglobin may be a significant proinflammatory stimulus in a variety of lung diseases.

Background and objective: ARDS is characterized by bilateral pulmonary infiltrates and refractory hypoxemia attributed to V/Q mismatch. We used dynamic CT to characterize changes in lung composition, regional perfusion and tissue distribution in patients with ARDS in comparison with healthy subjects. Methods: The Fick principle was applied to serial attenuation measurements constructed from sequential CT images acquired during the passage of a bolus of iodinated contrast medium in healthy subjects (n = 3) and patients with ARDS (n = 11). Perfusion was calculated by the Mullani-Gould method and mapped throughout both lungs. Gradients of perfusion and tissue density against vertical height were constructed. Results: In comparison with normal individuals, the tissue component of lungs from patients with ARDS was significantly increased (P

Purpose To establish the relationship between plasma levels of thioredoxin (Trx) and macrophage migration inhibitory factor (MIF) in systemic inflammatory stress syndrome (SIRS)/sepsis. Methods Enzyme-linked immunosorbent assay measurements of Trx, MIF, IL-6, -8, and -10 and enzyme-linked fluorescent assay determination of procalcitonin (PCT) in plasma from patients with SIRS/sepsis, neutropenic sepsis, healthy volunteers and pre-oesophagectomy patients. Results Thioredoxin was significantly higher in SIRS/sepsis patients [101.3 ng ml−1, interquartile range (IQR) 68.7–155.6, n = 32] compared with that in healthy controls (49.5 ng ml−1, IQR 31.4–71.1, P

08.04.15 KB. Ok to add published paper to spiral, OA paper originally published by Macmillan (now under Wiley)

Rationale and Objectives Pulmonary vascular control mechanisms are complex and likely to differ between species. We wish to quantify regional perfusion and the effects of gravity using computed tomography. Materials and Methods Sequential density measurements following the administration of a bolus of iodinated contrast medium were acquired from four healthy human subjects and four dogs. Results In humans, perfusion (Q) was linear throughout most of the range of vertical height, with an overall gradient of −2.6% cm−1. However, when perfusion was normalized to “tissue” density (blood plus tissue: sQt), maximum perfusion occurred around the mid-range of vertical height, being 9% (range 1–22%) greater than either the dorsal or ventral extreme. Within discrete transverse axial sections, concentric zones of perfusion centered on blood vessels were demonstrated. The relationship between sQt and vertical height in dogs was distinctly linear, with a gradient of −7.2% cm−1. In dogs, the median gradient of Q was −13.6% cm−1 (range −9.7 to −17.1%). Conclusions Differences in regional pulmonary perfusion, particularly the vertical gradient observed in humans and dogs, may in part reflect anatomic differences between the symmetric dichotomous branching structure of the human pulmonary vasculature and the more asymmetrical structure found in dogs.

Changes in iron homeostatic responses routinely accompany infectious or proinflammatory insults. The systemic inflammatory response syndrome (SIRS) and the development of acute lung injury (ALI) feature pronounced systemic and lung-specific alterations in iron/heme mobilization and decompartmentalization; such responses may be of pathological significance for both the onset and progression of acute inflammation. The potential for excessive iron-catalyzed oxidative stress, altered proinflammatory redox signaling, and provision of iron as a microbial growth factor represent obvious adverse aspects of altered in vivo iron handling. The release of hemoglobin during hemolytic disease or surgical procedures such as those utilizing cardiopulmonary bypass procedures further impacts on iron mobilization, turnover, and storage with associated implications. Genetic predisposition may ultimately determine the extent to which SIRS and related syndromes develop in response to such changes. The design of specific therapeutic interventions based on endogenous stratagems to limit adverse aspects of altered iron handling may prove of therapeutic benefit for the treatment of SIRS and ALI.

Pathogens contain specific pathogen-associated molecular patterns, which activate pattern recognition receptors of the innate immune system such as Toll-like receptors (TLRs). Although there is a clear evidence of how macrophages sense pathogens, we know less about such processes in vessels. This is critical to understand because activation of vascular cells and the subsequent induction of inflammatory genes by bacteria are crucial events in the development of septic shock. In the current study we have used genetically modified mice to investigate the role of TLRs, adapter proteins, tumor necrosis factor alpha (TNFalpha), and nitric oxide synthase II (NOSII) in vascular dysfunction induced by Gram-positive (Staphylococcus aureus) or Gram-negative (Escherichia coli) bacteria. Our data show that Gram-positive S. aureus or Gram-negative E. coli causes vascular dysfunction via the induction of NOSII. For S. aureus, this process requires TLR2, TLR6, myeloid differentiation factor 88 (MyD88) adapter-like, MyD88, and TNF, but not TLR4 or TLR1. Vascular dysfunction induced by E. coli requires TLR4 but has no requirement for TLR2, TLR1, TLR6, or TNF, and a partial but incomplete requirement of MyD88 and TIR domain-containing adapter inducing interferon-beta. Staphylococcus aureus induced NOSII protein expression in vascular smooth muscle cells but not in macrophages, whereas E. coli induced NOSII in both cell types. Our data are the first to establish the definitive roles of specific TLRs in the sensing of Gram-positive and Gram-negative bacteria by vessels and demonstrate that macrophages and blood vessels may differ in their response to pathogens.

Leadership: a process of social influence in which a person can enlist the aid and support of others in the accomplishment of a common task – Martin Chemers1 Make a decision. Make a DECISION. Make ANY decision. Make it NOW! – staff sergeant to officer cadet, Royal Military Academy Sandhurst (2012). The above definition and quotation respectively provide your editor with food for thought concerning the concept of leadership, which is the special focus of this issue of Future Hospital Journal . On the one hand this appears to be a collaborative and persuasive skill exercised in measured and controlled circumstances; while on the other it involves taking immediate responsibility for executing a task with potentially profound consequences for all involved, and moreover doing so when tired, hungry and challenged by imperfect knowledge and understanding of the situation in which the leader finds themselves. Parallels between this military approach, in which the challenge of leading more experienced operatives through complex manoeuvres is imposed on the successful trainee immediately after qualification, with that applied to pre-registration house officers in 1979 (the year of your editor's graduation) seem superficially to be numerous, excepting the element of physical danger. Thus, a one-in-two rota leading to progressive exhaustion, insertion into the ‘frontline’ with minimal experience immediately post medical school, and the need to convey authority to nursing and allied health professionals with immensely more experience and ability than oneself when fearful of the consequences of ‘getting it wrong’ are strangely familiar concepts. So if this is how leadership is exerted, how can we know if we are ever going to be up to the task? Maybe the armed forces again show the way. The systems employed by Admiralty Interview or Army Officer Selection Boards have been developed over decades and are designed to …

Aim The treatment of patients with pulmonary arterial hypertension remains a challenge. We set out to investigate the use of sildenafil, a selective inhibitor of phosphodiesterase type 5, in patients with this disease. Methods and results Ten patients (8 females, mean age 34.5±3.3 years) with pulmonary hypertension underwent right heart catheterisation with vasodilator testing using incremental doses of intravenous sildenafil without adverse events. All patients were subsequently commenced on oral sildenafil 50 mg t.d.s. Nine patients had repeat right heart catheterisation 3 months after the commencement of oral therapy. There was a significant reduction in mean pulmonary artery pressure (from 55.8±5.9 to 50.4±6.1 mmHg, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.038\) \end{document}) and pulmonary vascular resistance (from 10.1±1.7 to 8.6±1.5 Wood units, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.009\) \end{document}), and an increase in cardiac output (from 4.7±0.3 to 5.0±0.4 l/min, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(p=0.15\) \end{document}). Furthermore, there was a significant increase in the 6-minute walk test, a mean of 112 m. In response to a quality-of-life questionnaire, patients indicated marked clinical improvement on sildenafil. Sildenafil was discontinued in 1 patient due to a transient visual disturbance. The only patient previously awaiting transplantation was removed from the active transplantation list. Conclusions Sildenafil is well tolerated in its intravenous and oral forms and appears to improve both pulmonary haemodynamics and the clinical status of patients with pulmonary hypertension after 3 months of oral therapy.

Acute exacerbations of idiopathic pulmonary fibrosis/cryptogenic fibrosing alveolitis (IPF/CFA) are rare and typically terminal events, but their relationship to underlying patterns of idiopathic interstitial pneumonias is unknown. We reviewed autopsy material from patients who died of diffuse alveolar damage in the clinical setting of pulmonary fibrosis, both idiopathic and with background fibrosing alveolitis with connective tissue disorders (FA-CTDs), and compared them with cases of acute interstitial pneumonia. Of 15 patients with acute exacerbations of IPF/CFA (n = 12) or FA-CTD (n = 3), 12 had a background pattern of usual interstitial pneumonia and 3 had fibrotic nonspecific interstitial pneumonia. All cases of fibrotic nonspecific interstitial pneumonia were seen in association with FA-CTD. The cause of acute exacerbations is unknown, but our data suggest that toxic effects of oxygen and triggering infection are unlikely causes. In patients with CTDs, it remains uncertain whether the acute exacerbation is related to the fibrosis, the associated CTD, or a combination of these factors. Acute exacerbations of IPF/CFA may be a more common terminal event than previously thought.

During his ride to work on the London underground earlier this summer, your correspondent was interested to spot a sentence in the editorial columns of a leading newspaper, which read ‘.… it is shocking that it took the inspectors so long to identify and document the problem …’ This sentiment had particular resonance for him in the context of the Future Hospital Journal ( FHJ ), in that a principal driver for the work of the Future Hospital Commission (FHC) emerged from the review of the Mid Staffordshire NHS Foundation Trust by Sir Robert Francis QC. There, the failure not only of inspectors and regulators, but also of clinicians (in the widest sense) and their leaders, managers and inspectors, to identify problems in that Trust, resulted in shocking patient neglect, and saw the NHS at its lowest ebb for decades. However, the sentence did not refer to Mid Staffordshire, but rather to the recent ‘Trojan horse’ episode in Birmingham: the allegations of infiltration of school governing bodies by those seeking to advance specific political and/or religious agendas. The immediate reaction of politicians was to propose that state schools should face unannounced spot inspections. Whether the threat of an inspection, announced or not, improves any public service in many ways underpins the special focus of this issue: regulation and the regulators. The inspection mantra has been applied to other public services, many of which seem to be increasingly under the cosh. Your editor had time to recall without difficulty …

We tested the effects of 11 commercially-available isoprostanes on platelet aggregation directly or when triggered by the thromboxane receptor agonist U46619 or collagen in healthy human citrated blood using a whole blood aggregometer. None of the isoprostanes tested triggered aggregation alone, nor facilitated aggregation by a sub-threshold dose of U46619 or collagen. Five isoprostanes inhibited aggregation (rank order of potency 8-iso PGE1>8-iso PGE2>8-iso PGF2α>8-iso PGF3α>8-iso-13,14-dihydro-15-keto PGF2α). Blood incubated with LPS to induce a gross inflammatory response exhibited a time dependent (2 – 12 h) reduction in aggregation to U46619 but maintained a consistent response to collagen. Under these conditions, as in control blood, none of the isoprostanes tested induced aggregation. In fact, the inhibitory actions of isoprostanes on U46619-induced aggregation were enhanced in blood treated with LPS. L-NAME inhibited aggregation induced by U46619 in fresh blood and in blood treated with LPS. In the presence of L-NAME, (with or without LPS) none of the isoprostanes tested induced aggregation but retained their inhibitory action. Thus, in human whole blood the action of 8-iso PGE1, 8-iso PGE2, 8-iso PGF2α, 8-iso PGF3α, and 8-iso-13,14-dihydro-15-keto PGF2α is antiaggregatory. Moreover, this inhibitory capacity is still apparent and may be enhanced in blood subjected to inflammatory stimulation. Keywords: Isoprostanes, whole blood aggregometry, lipopolysaccharide Introduction Isoprostanes are a family of prostaglandin (PG) isomers generated by free radical-catalysed peroxidation and then rearrangement of arachidonic acid (Morrow et al., 1990; 1992). In addition, isoprostanes can be produced by cyclo-oxygenase (COX) dependent pathways (Pratico et al., 1995; Klein et al., 1997; Jourdan et al., 1997a; 1999). Several cell types have been shown to release increased levels of the F2 isoprostane, 8-iso PGF2α, when stimulated with inflammatory mediators or subjected to oxidative stress in vitro (Patrignani et al., 1996; Vacchiano et al., 1998; Jourdan et al., 1999). Furthermore, 8-iso PGF2α levels are elevated in rats in vivo when prooxidant conditions are induced experimentally (Morrow et al., 1992b; Dabbagh et al., 1994; Awad et al., 1994; Lynch et al., 1996). Similarly, elevated isoprostane production has been demonstrated in clinical conditions characterized by oxidant stress including diabetes (Davi et al., 1999), alcoholism (Alehnik et al., 1998), paraquat poisoning (Delanty et al., 1996), myocardial reperfusion (Reilly et al., 1997), critical illness (Carpenter et al., 1998), pre-eclampsia (Walsh et al., 2000) and smoking (Morrow et al., 1995). Consequently, the measurement of 8-iso PGF2α in plasma and urine has been proposed as a relevant and convenient method to monitor oxidant stress in man (Roberts & Morrow, 2000). However, beyond their role as oxidant markers, isoprostanes have demonstrable biological actions in some tissues. 8-iso PGF2α causes contraction of isolated blood vessels, (Kromer & Tippins, 1996; Jourdan et al., 1997b; Gardan et al., 2000; Oliviera et al., 2000), lymphatics, (Sinzinger et al., 1997) and airway (Kawikova et al., 1996) and myometrial smooth muscle (Crankshaw, 1995). Where studied, smooth muscle contraction appears to be mediated in part via thromboxane TP receptors (Fukunaga et al., 1993; Kromer & Tippins, 1996; Jourdan et al., 1997b; Gardan et al., 2000; Oliviera et al., 2000). However, the effects of 8-iso PGF2α on smooth muscle function may be altered in pathophysiological settings. Thus, its vasoconstrictor effect is increased after ischaemia (Kromer & Tippins, 1996; 1999), endothelial damage and nitric oxide synthase (NOS) inhibition (Jourdan et al., 1997b; Sametz et al., 1999). 8-iso PGF2α also has actions on isolated platelets where, in contrast to smooth muscle preparations, it may not apparently fully activate platelet TP receptors to cause aggregation (Pratico et al., 1996; Habib et al., 1999) and instead inhibits the proaggregatory effects of the TP ligand U46619 (Morrow et al., 1992c; Yin et al., 1994). In addition, although the E2 isoprostane, 8-iso PGE2, causes aggregation of platelets in a sub-population of human volunteers, it also inhibits U46619-induced aggregation (Longmire et al., 1994). Whether or not pathophysiological events alter platelet responses to isoprostanes is not known. In addition to 8-iso PGF2α and 8-iso PGE2, a range of synthetic isoprostanes is now available, the majority of which have not been tested in either smooth muscle or platelet preparations. The aims of this study were therefore firstly, to investigate the effects of a range of isoprostanes on aggregation of human whole blood and secondly, to assess the effects of a gross inflammatory stimulus induced by bacterial lipopolysaccharide (LPS), on the response of whole blood to isoprostanes.

Postpneumonectomy pulmonary oedema (PPO) develops in approximately 5% of patients undergoing pneumonectomy or lobectomy, and has a high associated mortality (>50%). In its extreme form, PPO follows a clinical and histopathological course indistinguishable from acute respiratory distress syndrome. Perioperative fluid overload, impaired lymphatic drainage following node dissection and trauma caused by surgical manipulation have been implicated in the pathogenesis of PPO. However, PPO more probably represents the pulmonary manifestation of a panendothelial injury consequent upon inflammatory processes induced by the surgical procedure, which involves collapse and re-expansion of the operative lung to permit hilar dissection and pulmonary resection. High inspired oxygen concentrations are required to overcome the effects of shunt. Animal studies have shown that pulmonary ischaemia/reperfusion can result in oedema formation, possibly due to the generation of pro-oxidant forces. Moreover, plasma taken from patients undergoing lobectomy or pneumonectomy (but not lesser resections) shows evidence of oxidative damage. Such evidence suggests either that the high inspired oxygen concentrations associated with one-lung ventilation, or ischaemia/reperfusion injury, may modulate post-pneumonectomy pulmonary oedema. Mechanisms by which redox imbalance may result in tissue damage and postpneumonectomy pulmonary oedema are discussed.

There is increasing evidence supporting a role for endothelin-1 (ET-1) in human pulmonary hypertension. The aim of this study was to determine the relative roles of human pulmonary microvascular endothelial cells (HPMVE) and human pulmonary artery smooth muscle (HPASM) cells to produce ET-1 under inflammatory conditions and to investigate further possible control mechanisms of ET-1 production by HPASM. Although HPMVE cells produced more ET-1 than HPASM when cultured with fetal calf serum (FCS) alone and after treatment with cytokines; HPASM produced significant amounts of ET-1 after stimulation with cytokines. Cytokine-stimulated increase in ET-1 production by HPASM was inhibited by cicaprost, a prostacyclin analogue, and other agents that are known to increase intracellular cyclic AMP. Cicaprost also inhibited proliferation of HPASM in response to FCS lending support to the theory that part of the clinical benefit seen in long-term treatment with prostacyclin in pulmonary hypertension may be a result of inhibition of ET-1 production in these cells.

Haem oxygenase-1 (HO-1) is a highly inducible stress protein that removes haem from cells with the release of biliverdin, carbon monoxide and low-molecular-mass iron (LMrFe). Several antioxidant functions have been ascribed to HO; its induction is considered to be a protective event. However, LMrFe produced during haem catabolism might elicit a pro-oxidant response, with deleterious consequences. We therefore investigated the delicate balance between pro-oxidant and antioxidant events with the use of a microsomal lipid peroxidation (LPO) system. By using microsomal-bound HO in an NADPH-dependent LPO system, we assessed the pro-oxidant nature of the released LMrFe and the antioxidant effect of the released bilirubin. Hb, a biologically relevant substrate for HO, was included with the microsomes to supplement the source of haem iron and to promote LPO. We found significant increases in microsomal LPO, by using the thiobarbituric acid (TBA) test, after incubation with Hb. This Hb-stimulated peroxidation was inhibited by HO inhibitors and by iron chelators, suggesting a HO-driven, iron-dependent mechanism. GLC-MS was employed to measure the specific LPO product 4-hydroxy-2-nonenal and to confirm our TBA test results. A HO inhibitor attenuated an increase in intracellular LMrFe that occurred after treatment of rat pulmonary artery smooth-muscle cells with Hb. Additionally, exogenously added bilirubin at an equimolar concentration to the LMrFe present in both microsomal and liposomal systems was unable to prevent the pro-oxidant effect of the iron. Under certain circumstances HO can act as a pro-oxidant and seems to have a role in stimulating microsomal LPO.

Inhaled nitric oxide (.NO) is used to improve gas exchange and reduce pulmonary vascular resistance (PVR) in patients with the acute respiratory distress syndrome (ARDS). Although controlled studies have shown no survival benefit, some investigators have suggested that inhaled.NO may have antiinflammatory properties under these circumstances. In contrast, others have speculated that.NO given by inhalation could be cytotoxic, as it combines with superoxide at near diffusion-limited rates to produce the highly reactive oxidant peroxynitrite (ONOO(-)). We therefore quantified levels of 3-nitrotyrosine, a marker for ONOO(-) formation, in bronchoalveolar lavage fluid (BAL) from patients with ARDS receiving inhaled.NO, and from patients with comparable lung injury who were not so treated. We also measured levels of 3-chlorotyrosine as an index of neutrophil activation to assess indirectly the effects of inhaled.NO on lung inflammation. Patients receiving .NO had increased levels of 3-nitrotyrosine (6.76 +/- 2.79 versus 0.4 +/- 0.15 nmol/mg of protein, p < 0.05) and 3-chlorotyrosine (7.97 +/- 2.74 versus 1. 53 +/- 1.09 nmol/mg of protein, p < 0.05) in BAL protein compared with controls. In patients with ARDS, inhaled.NO increases the formation of 3-nitrotyrosine and is accompanied by an increase in levels of 3-chlorotyrosine (a marker of neutrophil activation). The possible long-term consequences of these observations remain to be evaluated.

Pulmonary hypertension is characterized by hypertrophy and hyperplasia of vascular smooth muscle occurring via an unknown mechanism. Cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) are expressed under inflammatory conditions and produce mediators that regulate growth in some tissues. We have therefore addressed the question of COX-2 and iNOS involvement in proliferation of human and rat pulmonary artery (PA) smooth-muscle cells (SMC). Interleukin (IL)-1beta suppressed proliferation of both human and rat PA SMC. Moreover, IL-1beta induced COX-2 expression in both cell types. By contrast, IL-1beta stimulated the expression of iNOS protein in rat cells only. COX-2 induced in human cells inhibited proliferation, whereas COX-2 products in rat cells were without affect. However, iNOS activity in rat cells suppressed their proliferation. We conclude that human and rat evolution has diverged such that COX-2 and iNOS, although induced by the same mediator, have different levels of activity and functions in the two species. In humans, induction of COX-2 during pulmonary hypertension may be beneficial for long-term treatment of this disease.

Timothy W Evans is professor of intensive care medicine, Imperial College School of Medicine, Royal Brompton Hospital, London and Mark Smithies is director of intensive care, University Hospital of Wales, Cardiff.

Experimental sepsis induces disturbances in microcirculatory flow and nutrient exchange that may result in impaired tissue oxygenation. Volume resuscitation is a principal clinical intervention in patients with sepsis. Nitric oxide (NO) has been implicated in the pathophysiology of endotoxemia, but few data exist concerning the effects of either NO synthase inhibition (NOSi) or volume resuscitation on microvascular regulation and tissue oxygenation. Amperometric measurements were made of skeletal muscle (tissue) oxygen tension (PtO2) and its response to changes in fraction of inspired oxygen (FIO2) in rats rendered endotoxemic. Simultaneous measurements were made of systemic hemodynamic indices and arterial blood gas tensions. At normal PaO2, PtO2 in endotoxemic animals was significantly lower than in control animals, with marked attenuation of the response to increasing FIO2. These changes were associated with significant metabolic acidemia. In volume-resuscitated endotoxemic rats, PtO2 and blood pH were unchanged. A significant reduction in the PtO2 response to hyperoxia was observed in animals treated with the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME), an effect not reversed by fluid resuscitation. These data suggest that significant tissue hypoxia and abnormal microvascular control occur in endotoxemia. Volume resuscitation can reverse the changes in PtO2, whereas nitric oxide synthase (NOS) inhibition has deleterious effects on muscle PtO2 in both control and endotoxemic animals.

Sepsis and its related syndromes represent potentially devastating illnesses, estimated to account for 1% of all hospital admissions and for 100 000 deaths per annum in the U.S.A. alone. Although sepsis is defined as the systemic response to infection, an infective organism is found in fewer than 50% of cases. It is therefore increasingly recognised that sepsis represents only one example of a systemic inflammatory response that can be triggered not only by infection, but also by noninfectious disorders such as trauma and pancreatitis. The clinical features of these conditions are thought to be attributable to the triggering of a cascade of inflammatory mediators, the overproduction of which result in organ dysfunction. This spectrum of diseases shares a common, overlapping clinical end-point, termed the systemic inflammatory response syndrome. The definitions of sepsis, the systemic inflammatory response syndrome and related syndromes are shown in Table 1. The systemic inflammatory response syndrome is associated with considerable morbidity and is the leading cause of death in the intensive care unit, attributable to refractory hypotension, cardiac dysfunction and multi-organ failure. In the 40% of patients with sepsis who develop cardiovascular impairment, mortality rises from 20% to 70–90%, a figure that has changed little in recent years, despite considerable advances in supportive techniques. This review describes the changes in cardiac function in sepsis, outlines the underlying mechanisms by which they are thought to occur, and discusses the current

Waxing lyrical at the end of my last editorial about the challenges to the profession afforded by increased regulation, I referred to the ‘…distinguished histories and attractive premises…’ of medical royal colleges. As it turns out, this was an unwittingly apposite allusion, given that 2014 is the 50th anniversary of the current premises of the Royal College of Physicians (RCP) in London's Regent's Park. Some readers may know that the RCP was originally based at three sites in the City of London, all near St Paul's Cathedral, before moving to Pall Mall East overlooking Trafalgar Square, and finally on to its current location. Architectural commentators regard our current building as a masterpiece, containing ‘exceptional complexity within its confident form’ as well as being ‘well considered and well made’.1 Given the RCP's somewhat staid reputation, I was interested to read that when interviewing a young Denys Lasdun2 as the potential architect for the new building, our forefathers pointed out of the window, at South Africa House opposite, and asked if he would design something along those lines; in other words a classical, porticoed edifice. The short answer seems to have been ‘no’, and the end product reinforces that view, being described by influential commentators as ‘Oa subtle and beautiful exploration in three dimensions of the old and new…’ Importantly for the theme of this edition of the FHJ , the RCP was at the time embarking upon a sustained engagement with the public on smoking cessation, the dangers of which were only becoming apparent at that time (the late 1950s). The proposal that the design and subsequent appearance of the …

Postpneumonectomy pulmonary oedema (PPO) complicates a significant number of thoracic surgical procedures involving lung resection and in its extreme form is indistinguishable from the acute respiratory distress syndrome. This study investigated the possibility that ischaemia-reperfusion (I-R) injury contributes to PPO via the production of damaging reactive oxygen species. In a prospective, observational, comparative study, patients undergoing pneumonectomy, lobectomy, or wedge resection or open lung biopsy were investigated for perioperative changes in lung function indicative of lung injury and changes in plasma indices of oxidative damage. Significant percentage perioperative falls in plasma protein thiol levels (-17.9+/-7.0% for pneumonectomy, -24.3+/-5.5% for two-lobe lobectomy and -10.2+/-2.2% for one-lobe lobectomy, p

Elevated levels of nitric oxide (NO) are detectable in the exhaled breath of patients suffering from a number of inflammatory lung diseases. We hypothesized that NO would be detectable in the exhaled air of patients with the acute respiratory distress syndrome (ARDS) undergoing mechanical ventilation and that the concentration would be greater than that from a control group of ventilated subjects. The concentration of NO in the lower airways of 13 patients with ARDS and 18 patients anesthetized and ventilated prior to cardiac surgery was measured by chemiluminescence. The NO concentration was 1.13 +/- 0.36 (mean +/- SEM) parts per billion (ppb) in the ARDS group and 5.5 +/- 0.8 ppb in the control group (2 p0.0001). NO is detectable in the exhaled air of patients with ARDS and is at a lower concentration than in control subjects.

Ischemia-reperfusion (IR) lung injury occurs after various clinical procedures, including cardiopulmonary bypass. It is not clear whether endogenous nitric oxide (NO) is protective or injurious in lungs subjected to IR. Thus, in this study we examined the contribution of endogenous NO to IR injury in isolated, blood-perfused rat lungs. Lungs of male Wistar rats (300 g) were subjected to 30 min ischemia and 180 min reperfusion (I30R180). Lungs were sampled for inducible nitric oxide synthase (i-NOS) mRNA expression (each n = 3) and NOS enzyme activity (each n = 4) at different time points. NOS inhibitors NG-nitro-L-arginine-methyl ester (10[-4] M) and aminoguanidine (10[-4] M) were used to study the contribution of NO to IR injury in lungs subjected to I30R30 and I30R180. The contribution of i-NOS to IR lung injury was studied by inducing i-NOS enzyme with Salmonella lipopolysaccharide, followed by I30R30. We found that ischemia-reperfusion alone can upregulate i-NOS mRNA and i-NOS enzyme activity (p0.05, ANOVA), but downregulate constitutive NOS enzyme activity over 180 min reperfusion. Endogenously produced NO is protective against lung injury in I30R180 in normal rats and lung injury in I30R30 in septic rats. NO is also pivotal in maintaining pulmonary vascular homeostasis in septic rat lungs undergoing IR.

Abdominal compartment syndrome is an increasingly recognized phenomenon. We report the case of an otherwise fit and healthy 42-year-old man who underwent plication of the right hemidiaphragm for idiopathic phrenic paresis. His postoperative recovery was complicated by abdominal compartment syndrome, which was managed conservatively. We believe this is the only report of this complication after diaphragmatic plication and one of very few reported thoracic causes of abdominal compartment syndrome.

Cardiopulmonary bypass surgery (CPB) causes lung injury and at least 2% of adult patients and more children develop the most severe from acute respiratory distress syndrome (ARDS). Pulmonary surfactant deficiency contributes to the pathogenesis of ARDS. It has been proposed that surfactant therapy immediately after CPB might arrest progression to ARDS. However, many patients develop only mild lung injury after CPB. Thus early markers are needed to identify those patients at highest risk to guide selection for treatment. The aim of this study was to determine whether changes in surfactant phospholipids occur, and reflect severity of lung injury within the first few hours after bypass. Because of the relatively low incidence of ARDS in adult patients, this study was conducted using young pigs highly susceptible to bypass-induced lung injury. Eight pigs were given 2 hours bypass. Six controls underwent 'sham' bypass. At 3 h after bypass pulmonary vascular endothelial permeability was assessed by transcapillary leakage of radiolabelled transferrin. A 4 hour broncho-alveolar lavage (BAL) was used to assess intra-alveolar levels of surfactant, inflammatory cells and oedema protein. Bypass caused falls in arterial oxygenation and lung compliance (P < 0.01), but at this early stage in progression of lung injury BAL surfactant phospholipid and albumin levels were within the control range indicating that the alveolar epithelium had not yet suffered major damage. The main abnormalities were increases in vascular endothelial permeability (P < 0.01), BAL neutrophils (P < 0.01), total protein and sphingomyelin (SM) (P < 0.05). Lung histology showed that the main damage was interstitial oedema located around the bronchioles and their associated vessels. A single instilled dose of surfactant phospholipids in 5 animals caused excess in vivo supplementation and did not reduce the early pathophysiologic changes. Our findings suggest that surfactant phospholipid deficiency does not make a major contribution in the initial stages of lung injury after CPB, and that excessive phospholipid supplementation at this stage can be deleterious.

1. The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful, oxidant, peroxynitrite (ONOO-). When formed in large amounts, ONOO- is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO- can cause vasodilatation and at higher concentrations can activate poly (adenosine 5'-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5'-triphosphate (ATP). As the lung represents a prime site for ONOO- formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO- on pulmonary artery rings. 2. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO- (10 nM-100 microM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO-, tissues were pre-contracted with the thromboxane mimetic U46619 (1 microM). Once a stable base-line was achieved, ONOO- was added in a cumulative fashion. ONOO- had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 microM to 100 microM. In some experiments the effects of freshly prepared ONOO- solutions were compared with those allowed to decay at 4 degrees C for 2 days. 3. In some experiments either vehicle or ONOO- (1, 10 or 100 microM) was added for 15 min before U46619 (1 microM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM-100 microM) were then constructed. In these experiments, ONOO- (1 microM or 10 microM) had no effect on the actions of acetylcholine. However, at the highest concentration tested (100 microM), ONOO- increased acetylcholine-induced relaxations. 4. The vasodilator actions of ONOO- were unaffected by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) or by removal of superoxide anions with superoxide dismutase (SOD) (30 units ml-1). However, the relaxations induced by ONOO- were significantly inhibited by the PARS inhibitor, 3-aminobenzamide (10 microM). In contrast to its effects on ONOO-, 3-aminobenzamide had no effect on the relaxation caused by acetylcholine or sodium nitrite, but actually increased that induced by sodium nitroprusside. 5. These data show that ONOO- causes vasodilatation of rat pulmonary arteries, probably via activation of PARS. Moreover, at concentrations where relaxation was achieved, ONOO- did not affect the ability of pulmonary artery rings to relax to acetylcholine. We propose that ONOO-, but not endothelially derived NO, activates PARS resulting in the rapid depletion of ATP and a consequent reduction in contraction as well as other active processes of vascular smooth muscle. The finding that 3-aminobenzamide inhibited the actions of ONOO- but not acetylcholine, suggests that NO and ONOO- cause relaxation by independent mechanisms. It has been suggested that ONOO- is responsible for the vascular hyporesponsiveness to constrictor agents seen in experimental sepsis. This observation together with our current finding, that 3-aminobenzamide inhibits the relaxation induced by ONOO- but not by acetylcholine, suggests that inhibitors of PARS may reduce the persistent hypotension seen in sepsis without affecting the actions of endothelium-derived NO. Thus, the use of PARS inhibitors may represent a novel therapeutic approach to the treatment of septic shock.

1. 8-Iso prostaglandin F2 alpha (8-iso PGF2 alpha) is one of a series of prostanoids formed independently of the cyclo-oxygenase pathway. It has been shown to be upregulated in many conditions of oxidant stress where its formation is induced by free radical-catalysed actions on arachidonic acid. As 8-iso PGF2 alpha is formed in vivo in diseases in which oxidant stress is high such as septic shock, we have assessed the relative potency and efficacy of this compound in pulmonary arteries from control and lipopolysaccharide (LPS)-treated rats. 2. Several studies have characterized the contractile actions of 8-iso PGF2 alpha on various smooth muscle preparations, but its potential dilator actions have not been addressed. Thus these studies examined both the contractile and dilator actions of 8-iso PGF2 alpha in rat pulmonary artery rings. The thromboxane mimetic U46619, PGE2 sodium nitroprusside (SNP) and acetyl choline (ACh) were used for comparison. Each prostanoid had to be dissolved in ethanol to a maximum concentration of 1 x 10-2 M. At high concentrations, ethanol directly contracted pulmonary vessels. We were therefore limited by the actions of the vehicle such that we were unable to add prostanoids at concentrations higher than 1 x 10-4 M. In some cases this meant that maximum responses were not achieved and in these cases the Emax and pD2 values are apparent estimates. 3. The following rank order of potency was obtained from contractile studies; U46619 > 8-iso PGF2 alpha > PGE2, each prostanoid producing concentration-dependent contractions (10(-10)-3 x 10(-4) M, 10(-9)-10(-4) M, 10(-8)-10(-4) M, respectively). As has been shown previously for other smooth muscle preparations, the thromboxane receptor (TP) antagonist ICI 192605, (1 x 10(-6), 1 x 10(-5) and 1 x 10(-4) M), inhibited the contractions of 8-iso PGF2 alpha in a concentration-dependent fashion. 4. The nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 1 x 10(-4) M), enhanced the contractile function of both 8-iso PGF2 alpha and PGE2, but had no effect on that caused by U46619. Similarly, L-NAME inhibited the dilator function of all agents tested except the exogenous nitric oxide (NO) donor SNP indicating that PGE2 and 8-iso PGF2 alpha like ACh, act through the release of NO. The specificity of the effects of L-NAME were confirmed in studies with the inactive enantiomer D-NAME (1 x 10(-4) M), which did not affect the contractile or the dilator actions of 8-iso PGF2 alpha. Furthermore, ICI 192605 enhanced the dilator actions of 8-iso PGF2 alpha, suggesting that the dilator component of 8-iso PGF2 alpha was achieved via activation of a non-TP receptor. 5. Isoprostanes may modulate vascular tone by a direct action on TP receptors to cause contraction and via a distinct receptor leading to the release of NO to cause dilation.

Background. The receptor for advanced glycation end products (RAGE) is an inflammation-perpetuating receptor, and soluble RAGE (sRAGE) is a marker of cellular RAGE expression. This study investigated whether raised plasma levels prior to surgery of sRAGE or S100A8/A9 (a RAGE ligand) were associated with longer duration of hospital care in patients undergoing cardiac surgery necessitating cardiopulmonary bypass.Methods. Patients (n=130) undergoing elective cardiac surgery were enrolled prospectively. Plasma sRAGE and S100A8/A9 concentrations were measured before and 2 h after surgery.Results. Preoperative plasma sRAGE increased significantly (P<0.0001) from 1.06 ng/mL (IQR, 0.72–1.76) to 1.93 ng/mL (IQR, 1.14–2.63) 2 h postoperatively. Plasma S100A8/9 was also significantly (P<0.0001) higher 2 h postoperatively (2.37 μg/mL, IQR, 1.81–3.05) compared to pre-operative levels (0.41 μg/mL, IQR, 0.2–0.65). Preoperative sRAGE, but not S100A8/A9, was positively and significantly correlated with duration of critical illness (r=0.3,P=0.0007) and length of hospital stay (LOS;r=0.31,P<0.0005). Multivariate binary logistic regression showed preoperative sRAGE to be, statistically, an independent predictor of greater than median duration of critical illness (odds ratio 16.6,P=0.014) and to be, statistically, the strongest independent predictor of hospital LOS.Conclusion. Higher preoperative plasma sRAGE levels were associated with prolonged duration of care in adults undergoing cardiac surgery requiring cardiopulmonary bypass.

The inflammatory response to cardiopulmonary bypass includes activation of complement and induction of several neutrophil activation pathways. A recombinant soluble form of complement receptor 1 was used as a specific inhibitor of complement activation in simulated cardiopulmonary bypass circuits. Substantial complement activation was observed in these circuits with progressive accumulation of both plasma C3a and terminal complement complex. Soluble complement receptor 1 resulted in a significant reduction in C3a levels ( p < 0.01) but did not inhibit terminal complement complex generation. A marked rise in neutrophil CD11b/CD18 expression, simultaneous loss of L-selectin expression, and a progressive accumulation of plasma elastase–α1 -antitrypsin occurred and were not affected by soluble complement receptor. However, generation of interleukin-8 in the circuits was inhibited ( p < 0.05) by pretreatment with soluble complement receptor. These data suggest that changes in neutrophil activation seen during cardiopulmonary bypass may not be induced directly by anaphylatoxin generation. (J T HORAC CARDIOVASC SURG 1996;111:451-9)

Purpose To investigate differences in cytokine/chemokine release in response to lipoteichoic acid (LTA) or lipopolysaccharide (LPS) and contributing cellular mechanisms, in order to improve understanding of the pathogenesis of sepsis. Methods Levels of cytokines/chemokines were measured in plasma and peritoneal lavage fluid of 10-week-old male mice (C57/B16) following intraperitoneal injection of LTA or LPS (250 µg), and in supernatants of murine J774.2 cells, immortalised blood monocytes, or isolated human monocytes treated with LTA or LPS (0–10 µg/ml). The role of cytokine/chemokine messenger RNA (mRNA) stability versus nuclear factor-kappaB (NF-κB) and activator protein-1 (AP-1) in mediating cytokine/chemokine release in J774 cells was also assessed. Results In mice, plasma levels of keratinocyte-derived chemokine (KC), macrophage inflammatory protein (MIP)-2, interleukin (IL)-10, interferon (IFN)-γ and tumour necrosis factor-alpha (TNF-α) and peritoneal lavage fluid levels of KC, MIP-2 and TNF-α increased significantly 1 h after LPS. Only KC and MIP-2 levels increased 1 h after LTA. LPS-treated (10 μg/ml) J774 cells released MIP-2, IL-10, IFN-γ and TNF-α but not KC (24 h), whereas cells treated with 10 μg/ml LTA released only MIP-2. LPS-stimulated human monocytes released IL-10 and IL-8 (24 h); by contrast, LTA-treated cells released only IL-8. LPS and LTA activated NF-κB and AP-1 in J774 cells. The protein synthesis inhibitor cycloheximide abolished LPS-induced IL-10 mRNA expression and increased LTA- and LPS-induced mRNA for MIP-2 in J774 cells. Conclusion LTA and LPS, at clinically relevant concentrations, induced differential cytokine/chemokine release in vitro and in vivo, via effects distal to activation of NF-κB/AP-1 that might include chromatin remodelling or mRNA stability. Electronic supplementary material The online version of this article (doi:10.1007/s00134-011-2444-5) contains supplementary material, which is available to authorized users.

Endothelial injury consequent upon widespread humoral and cellular activation is probably a major contributor to the phenomenon of cardiopulmonary bypass-induced organ dysfunction. This article reviews some of the mechanisms by which complement and neutrophil activation and interleukin-8 may be involved in this inflammatory response. In a model consisting of a simulated extracorporeal circulation we were able to demonstrate complement activation, profound and specific changes in neutrophil adhesion molecule expression, and interleukin-8 generation. The importance of these changes and their potential interactions are discussed.

1. Endotoxin induces nitric oxide synthase in vascular tissue, including rat main pulmonary artery. Currently available agents that cause inhibition of nitric oxide synthase are relatively non-selective between the constitutive and inducible forms of the enzyme. 2. Aminoguanidine caused a dose-dependent increase in phenylephrine-induced tension in intact and endothelium-denuded pulmonary artery rings from endotoxin-treated rats, but had no effect on sham-treated controls. 3. Contraction caused by aminoguanidine in endothelium-denuded vessels from endotoxin-treated rats was unaffected by indomethacin (10 microM), and by cimetidine and mepyramine (both 10 microM), excluding an effect of aminoguanidine mediated by arachidonic acid metabolites or histamine. 4. Contraction caused by aminoguanidine in endothelium-denuded vessels from endotoxin-treated rats was abolished by L-arginine (2 mM) and L-NG-monomethyl arginine (300 microM), but unaffected by D-arginine and D-NG-monomethyl arginine, suggesting that its action is mediated by the L-arginine/nitric oxide pathway. 5. Aminoguanidine had no effect on acetylcholine-induced relaxation of intact vessels from shamtreated rats. However, relaxation of artery rings from endotoxin-treated rats by L-arginine was competitively inhibited by aminoguanidine.6. These results in isolated main pulmonary arteries of the rat confirm previous reports that aminoguanidine is a selective inhibitor of inducible nitric oxide synthase.

BACKGROUND--Endogenous vasodilators such as endothelially derived relaxant factor have been shown to modulate hypoxic pulmonary vasoconstriction. Sensory peptides such as substance P (SP) and calcitonin gene related peptide (CGRP) are also potent pulmonary vasodilators in both animals and humans. Their possible role in the modulation of the normal hypoxic pressor response has been examined in an isolated, ventilated, and blood perfused rat lung preparation. METHODS--Animals (n = 7) were pretreated with 50 mg/kg capsaicin administered subcutaneously to deplete nerve endings of sensory neuropeptides. A control group (n = 7) received a subcutaneous dose of capsaicin vehicle. One week later the rats were killed and the rise in pulmonary artery pressure was measured during four successive periods of hypoxic ventilation (FIO2 0.03), and after four injections of angiotensin II (1.0 microgram). RESULTS--A 60% depletion of SP levels was measured in the sciatic nerves of animals treated with capsaicin. The hypoxic pressor response was not significantly altered in capsaicin treated animals compared with controls, except during the fourth hypoxic episode when it was augmented. The angiotensin II pressor response was the same in both groups during each of the injections. CONCLUSION--The sensory neuropeptide SP (and possibly CGRP) does not have a major role in modulating the pulmonary vascular response to hypoxia.

1. Nonadrenergic, noncholinergic (NANC) nerves mediate vasodilatation in guinea-pig pulmonary artery (PA) by both endothelium-dependent and endothelium-independent mechanisms. The transmitter(s) involved in the endothelium-independent pathway have not yet been identified. We have therefore investigated the possibility that nitric oxide (NO) and guanosine 3',5'-cyclic monophosphate (cyclic GMP) may mediate this neural vasodilator response in guinea-pig branch PA rings denuded of endothelium. 2. Electric field stimulation (EFS, 50 V, 0.2 ms) induced a frequency-dependent (1-24 Hz), tetrodotoxin-sensitive relaxation of the U44069-precontracted PA rings in the presence of adrenergic and cholinergic blockade. 3. The NO synthase inhibitors NG-monomethyl L-arginine (L-NMMA, 100 microM) and NG-nitro L-arginine methyl ester (L-NAME, 30 microM), and the guanylyl cyclase inhibitor methylene blue (5 microM) inhibited the EFS (16 Hz)-induced relaxation by 53 +/- 5, 74 +/- 9 and 82 +/- 9% respectively (n = 5-7, P < 0.01, compared with control rings). 4. Excess concentrations of L-, but not D-arginine (300 microM) completely reversed the inhibitory effect of L-NMMA. 5. The EFS-elicited relaxation (4 Hz) was potentiated by 1 microM zaprinast, a type V phosphodiesterase inhibitor which inhibits guanosine 3':5'-cyclic monophosphate (cyclic GMP) degradation, but was unaffected by 0.1 microM zardaverine, a type III/IV phosphodiesterase inhibitor which inhibits cyclic AMP degradation. 6. EFS (50 V, 0.2 ms, 16 Hz) induced a 3 fold increase in tissue cyclic GMP content, an action which was inhibited by L-NMMA (100 microM). 7. Pyrogallol (100microM), a superoxide anion generator, also inhibited the EFS-induced relaxation by 53 +/- 9%, and this effect was prevented by superoxide dismutase.8. Chemical sympathetic denervation with 6-hydroxydopamine had no effect on the relaxant response to EFS in the endothelium-denuded PA rings.9. In endothelium-denuded branch PA rings at resting tone, L-NMMA (100 microM) significantly augmented the adrenergic contractile response, an effect which was completely reversed by L-arginine,but not by D-arginine. In the same groups of vessel rings, L-NMMA had no significant effect on the matched contractile response to exogenous noradrenaline.10. These results suggest that NO may be released from intramural nerve endings other than adrenergic nerves (probably NANC nerves), and this leads to vasodilatation via activation of guanylyl cyclase.

The case histories are presented of three adults who had severe hypercapnic acidosis despite mechanical ventilation with what were considered to be injurious tidal volumes and airway pressures. The use of a percutaneously inserted arteriovenous extracorporeal carbon dioxide removal (AV-ECCO(2)R) device facilitated a dramatic reduction in the amount of ventilatory support required, achieving a "lung-protective" level. Two patients survived to hospital discharge. One patient died after it became apparent that her late-stage interstitial lung disease was unresponsive to immunosuppression. AV-ECCO(2)R may be a useful strategy in facilitating lung-protective ventilation.

Endothelin-1 (ET-1) is a potent vasoconstrictor and co-mitogen for vascular smooth muscle and is implicated in pulmonary vascular remodeling and the development of pulmonary arterial hypertension. Vascular smooth muscle is an important source of ET-1. Here we demonstrate synergistic induction of preproET-1 message RNA and release of mature peptide by a combination of tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) in primary human pulmonary artery smooth muscle cells. This induction was prevented by pretreatment with the histone acetyltransferase inhibitor anacardic acid. TNFalpha induced a rapid and prolonged pattern of nuclear factor (NF)-kappaB p65 subunit activation and binding to the native preproET-1 promoter. In contrast, IFNgamma induced a delayed activation of interferon regulatory factor-1 without any effect on NF-kappaB p65 nuclear localization or consensus DNA binding. However, we found cooperative p65 binding and histone H4 acetylation at distinct kappaB sites in the preproET-1 promoter after stimulation with both TNFalpha and IFNgamma. This was associated with enhanced recruitment of RNA polymerase II to the ATG start site and read-through of the ET-1 coding region. Understanding such mechanisms is crucial in determining the key control points in ET-1 release. This has particular relevance to developing novel treatments targeted at the inflammatory component of pulmonary vascular remodeling.

Nitric oxide (NO) is an endogenous mediator of vascular tone and host defence. Inhaled nitric oxide (iNO) results in preferential pulmonary vasodilatation and lowers pulmonary vascular resistance. The route of administration delivers NO selectively to ventilated lung units so that its effect augments that of hypoxic pulmonary vasoconstriction and improves oxygenation. This 'Bench-to-bedside' review focuses on the mechanisms of action of iNO and its clinical applications, with emphasis on acute lung injury and the acute respiratory distress syndrome. Developments in our understanding of the cellular and molecular actions of NO may help to explain the hitherto disappointing results of randomised controlled trials of iNO.

BACKGROUND The acute administration of vasodilator drugs to patients with primary pulmonary hypertension has been advocated to identify those with reversible pulmonary vasoconstriction. Unfortunately, the usefulness of the drugs currently available is limited by accompanying systemic hypotension. A vasodilator with effects confined to the pulmonary circulation would therefore be advantageous in such patients. METHODS AND RESULTS The purine nucleoside adenosine was infused into the pulmonary artery in seven patients with primary pulmonary hypertension (baseline pulmonary vascular resistance [PVR], 442-1,295 dyne/cm/sec-5) to determine its effect on PVR. In all patients, there was a dose-dependent and significant reduction (mean maximal percent decrease from baseline, 38.9%; p less than 0.001) in PVR mediated through a decrease in pulmonary artery pressure and an increase in cardiac output. Systemic vascular resistance (SVR) also decreased, but the ratio of PVR to SVR decreased (maximal mean percent decrease from baseline) by 10.5% (p less than 0.025), indicating that adenosine has a preferential vasodilator effect on the pulmonary circulation when administered in this manner. CONCLUSIONS Because of its pharmacokinetic and vasodilator properties, adenosine may have a specific role in the investigation of primary pulmonary hypertension.