Enhanced monocyte recruitment and delayed alternative macrophage polarization accompanies impaired repair following myocardial infarction in C57BL/6 compared to BALB/c mice.

Activation of the innate immune response following myocardial infarction (MI) is essential for infarct repair. Preclinical models of MI commonly use C57BL/6 mice, which have a type 1-dominant immune response, whereas other mouse strains such as BALB/c mice have a type 2-dominant immune response. We compared C57BL/6 and BALB/c mice to investigate whether predisposition towards a proinflammatory phenotype influences the dynamics of the innate immune response to MI and associated infarct healing and the risk of cardiac rupture. MI was induced by permanent coronary artery ligation in 12-15-week-old male wild-type BALB/c and C57BL/6 mice. Prior to MI, C57BL/6 mice had a lower proportion of CD206+ anti-inflammatory macrophages in the heart and an expanded blood pool of proinflammatory Ly6Chigh monocytes in comparison to BALB/c mice. The systemic inflammatory response in C57BL/6 mice following MI was more pronounced, with greater peripheral blood Ly6Chigh monocytosis, splenic Ly6Chigh monocyte mobilization and myeloid cell infiltration of pericardial adipose tissue. This led to an increased and prolonged macrophage accumulation, as well as delayed transition towards anti-inflammatory macrophage polarization in the infarct zone and surrounding tissues of C57BL/6 mice. These findings accompanied a higher rate of mortality due to cardiac rupture in C57BL/6 mice compared with BALB/c mice. We conclude that lower post-MI survival of C57BL/6 mice over BALB/c mice is mediated in part by a more pronounced and prolonged inflammatory response. Outcomes in BALB/c mice highlight the therapeutic potential of modulating resolution of the innate immune response following MI for the benefit of successful infarct healing.

Immune cell and transcriptomic analysis of the human decidua in term and preterm parturition.

STUDY QUESTION: Is labour, both at term and preterm, associated with alterations in decidual lymphocyte densities and widespread changes to the decidual transcriptome? SUMMARY ANSWER: The onset of parturition, both at term and preterm, is associated with widespread gene expression changes in the decidua, many of which are related to inflammatory signalling, but is not associated with changes in the number of any of the decidual lymphocyte populations examined. WHAT IS KNOWN ALREADY: Given its location, directly at the maternal-foetal interface, the decidua is likely to play a pivotal role in the onset of parturition, however, the molecular events occurring in the decidua in association with the onset of labour, both at term and preterm, remain relatively poorly defined. Using flow cytometry and microarray analysis, the present study aimed to investigate changes to the immune cell milieu of the decidua in association with the onset of parturition and define the decidual gene signature associated with term and preterm labour (PTL). STUDY DESIGN, SIZE, DURATION: This study used decidual samples collected from 36 women across four clinical groups: term (38-42 weeks of gestation) not in labour, TNL; term in labour, TL; preterm (<35 weeks of gestation)not in labour, PTNL; and preterm in labour, PTL. PARTICIPANTS/MATERIALS, SETTING, METHODS: Decidual lymphocytes were isolated from fresh decidual tissue collected from women in each of our four patient groups and stained with a panel of antibodies (CD45, CD3, CD19, CD56, CD4, CD8 and TCRVα24-Jα18) to investigate lymphocyte populations present in the decidua (TNL, n = 8; TL, n = 7; PTNL, n = 5; PTL, n = 5). RNA was extracted from decidual tissue and subjected to Illumina HT-12v4.0 BeadChip expression microarrays (TNL, n = 11; TL, n = 8; PTNL, n = 7; PTL, n = 10). Quantitative real-time PCR (qRT-PCR) was used to validate the microarray results. MAIN RESULTS AND THE ROLE OF CHANCE: The relative proportions of decidual lymphocytes (T cells, NK cells, B cells and invariant natural killer (iNKT) cells) were unaffected by either gestation or labour status. However, we found elevated expression of the non-classical MHC-protein, CD1D, in PTL decidua samples (P < 0.05), suggesting the potential for increased activation of decidual invariant NKT (iNKT) cells in PTL. Both term and PTL were associated with widespread gene expression changes, particularly related to inflammatory signalling. Up-regulation of candidate genes in TL (IL-6, PTGS2, ATF3, IER3 and TNFAIP3) and PTL (CXCL8, MARCO, LILRA3 and PLAU) were confirmed by qRT-PCR analysis. LARGE SCALE DATA: Microarray data are available at www.ebi.ac.uk/arrayexpress under accession number E-MTAB-5353. LIMITATIONS REASONS FOR CAUTION: Whilst no changes in lymphocyte number were observed across our patient samples, we did not investigate the activation state of any of the immune cell sub-populations examined, therefore, it is possible that the function of these cells may be altered in association with labour onset. Additionally, the results of our transcriptomic analyses are descriptive and at this stage, we cannot prove direct causal link with the up-regulation of any of the genes examined and the onset of either term or PTL. WIDER IMPLICATIONS OF THE FINDINGS: Our findings demonstrate that the onset of parturition is associated with widespread changes to the decidual transcriptome, and there are distinct gene expression changes associated with term and PTL. We confirmed that an inflammatory signature is present within the decidua, and we also report the up-regulation of several genes involved in regulating the inflammatory response. The identification of genes involved in regulating the inflammatory response may provide novel molecular targets for the development of new, more effective therapies for the prevention of preterm birth (PTB). Such targets are urgently required. STUDY FUNDING AND COMPETING INTEREST(S): This work was supported by Medical Research Council (grant number MR/L002657/1) and Tommy's, the baby charity. Jane Norman has had research grants from the charity Tommy's and from the National Institute for Health Research on PTB during the lifetime of this project. Jane Norman also sits on a data monitoring committee for GSK for a study on PTB prevention and her institution receives financial recompense for this. The other authors do not have any conflicts of interest to declare.

Low-pathogenicity Mycoplasma spp. alter human monocyte and macrophage function and are highly prevalent among patients with ventilator-acquired pneumonia.

BACKGROUND: Ventilator-acquired pneumonia (VAP) remains a significant problem within intensive care units (ICUs). There is a growing recognition of the impact of critical-illness-induced immunoparesis on the pathogenesis of VAP, but the mechanisms remain incompletely understood. We hypothesised that, because of limitations in their routine detection, Mycoplasmataceae are more prevalent among patients with VAP than previously recognised, and that these organisms potentially impair immune cell function. METHODS AND SETTING: 159 patients were recruited from 12 UK ICUs. All patients had suspected VAP and underwent bronchoscopy and bronchoalveolar lavage (BAL). VAP was defined as growth of organisms at >10(4) colony forming units per ml of BAL fluid on conventional culture. Samples were tested for Mycoplasmataceae (Mycoplasma and Ureaplasma spp.) by PCR, and positive samples underwent sequencing for speciation. 36 healthy donors underwent BAL for comparison. Additionally, healthy donor monocytes and macrophages were exposed to Mycoplasma salivarium and their ability to respond to lipopolysaccharide and undertake phagocytosis was assessed. RESULTS: Mycoplasmataceae were found in 49% (95% CI 33% to 65%) of patients with VAP, compared with 14% (95% CI 9% to 25%) of patients without VAP. Patients with sterile BAL fluid had a similar prevalence to healthy donor BAL fluid (10% (95% CI 4% to 20%) vs 8% (95% CI 2% to 22%)). The most common organism identified was M. salivarium. Blood monocytes from healthy volunteers incubated with M. salivarium displayed an impaired TNF-α response to lipopolysaccharide (p=0.0003), as did monocyte-derived macrophages (MDMs) (p=0.024). MDM exposed to M. salivarium demonstrated impaired phagocytosis (p=0.005). DISCUSSION AND CONCLUSIONS: This study demonstrates a high prevalence of Mycoplasmataceae among patients with VAP, with a markedly lower prevalence among patients with suspected VAP in whom subsequent cultures refuted the diagnosis. The most common organism found, M. salivarium, is able to alter the functions of key immune cells. Mycoplasmataceae may contribute to VAP pathogenesis.

Optical projection tomography permits efficient assessment of infarct volume in the murine heart postmyocardial infarction.

The extent of infarct injury is a key determinant of structural and functional remodeling following myocardial infarction (MI). Infarct volume in experimental models of MI can be determined accurately by in vivo magnetic resonance imaging (MRI), but this is costly and not widely available. Experimental studies therefore commonly assess injury by histological analysis of sections sampled from the infarcted heart, an approach that is labor intensive, can be subjective, and does not fully assess the extent of injury. The present study aimed to assess the suitability of optical projection tomography (OPT) for identification of injured myocardium and for accurate and efficient assessment of infarct volume. Intact, perfusion-fixed, optically cleared hearts, collected from mice 7 days after induction of MI by coronary artery occlusion, were scanned by a tomograph for autofluorescence emission after UV excitation, generating >400 transaxial sections for reconstruction. Differential autofluorescence permitted discrimination between viable and injured myocardium and highlighted the heterogeneity within the infarct zone. Two-dimensional infarct areas derived from OPT imaging and Masson's trichrome staining of slices from the same heart were highly correlated (r(2) = 0.99, P < 0.0001). Infarct volume derived from reconstructed OPT sections correlated with volume derived from in vivo late gadolinium enhancement MRI (r(2) = 0.7608, P < 0.005). Tissue processing for OPT did not compromise subsequent immunohistochemical detection of endothelial cell and inflammatory cell markers. OPT is thus a nondestructive, efficient, and accurate approach for routine in vitro assessment of murine myocardial infarct volume.

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

Both term and preterm parturition are characterized by an influx of macrophages and neutrophils into the myometrium and cervix, with co-incident increased peripheral blood monocyte activation. Infection and inflammation are strongly implicated in the pathology of preterm labour (PTL), with progesterone considered a promising candidate for its prevention or treatment. In this study, we investigated the effect of monocytes on myometrial smooth muscle cell inflammatory cytokine production both alone and in response to LPS, a TLR4 agonist used to trigger PTL in vivo. We also investigated the effect of monocytes on myocyte contraction. Monocytes, isolated from peripheral blood samples from term pregnant women, were cultured alone, or co-cultured with PHM1-41 myometrial smooth muscle cells, for 24 h. In a third set of experiments, PHM1-41 myocytes were cultured for 24 h in isolation. Cytokine secretion was determined by ELISA or multiplex assays. Co-culture of monocytes and myocytes led to synergistic secretion of pro-inflammatory cytokines and chemokines including IL-6, IL-8 and MCP-1, with the secretion being further enhanced by LPS (100 ng/ml). The synergistic secretion of IL-6 and IL-8 from co-cultures was mediated in part by direct cell-cell contact, and by TNF. Conditioned media from co-cultures stimulated contraction of PHM1-41 myocytes, and the effect was inhibited by progesterone. Both progesterone and IL-10 inhibited LPS-stimulated IL-6 and IL-8 secretion from co-cultures, while progesterone also inhibited chemokine secretion. These data suggest that monocytes infiltrating the myometrium at labour participate in crosstalk that potentiates pro-inflammatory cytokine secretion, an effect that is enhanced by LPS, and can augment myocyte contraction. These effects are all partially inhibited by progesterone.

15-epi-lipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth.

Preterm birth remains the leading cause of neonatal mortality and morbidity worldwide. There are currently few effective therapies and therefore an urgent need for novel treatments. Although there is much focus on trying to alter gestation of delivery, the primary aim of preterm birth prevention therapies should be to reduce prematurity related mortality and morbidity. Given the link between intrauterine infection and inflammation and preterm labour (PTL), we hypothesized that administration of lipoxins, key anti-inflammatory and pro-resolution mediators, could be a useful novel treatment for PTL. Using a mouse model of infection-induced PTL, we investigated whether 15-epi-lipoxin A4 could delay lipopolysaccharide (LPS)-induced PTL and reduce pup mortality. On D17 of gestation mice (n = 9-12) were pretreated with vehicle or 15-epi-lipoxin A4 prior to intrauterine administration of LPS or PBS. Although pretreatment with 15-epi-lipoxin A4 did not delay LPS-induced PTL, there was a significant reduction in the mortality amongst prematurely delivered pups (defined as delivery within 36 h of surgery) in mice treated with 15-epi-lipoxin A4 prior to LPS treatment, compared with those receiving LPS alone (P < 0.05). Quantitative real-time (QRT)-PCR analysis of utero-placental tissues harvested 6 h post-treatment demonstrated that 15-epi-lipoxin A4 treatment increased Ptgs2 expression in the uterus, placenta and fetal membranes (P < 0.05) and decreased 15-Hpgd expression (P < 0.05) in the placenta and uterus, suggesting that 15-epi-lipoxin A4 may regulate the local production and activity of prostaglandins. These data suggest that augmenting lipoxin levels could be a useful novel therapeutic option in the treatment of PTL, protecting the fetus from the adverse effects of infection-induced preterm birth.

Soluble tumour necrosis factor receptor-1 (sTNFR1) levels are positively associated with exercise intensity in athletes after strenuous off-road cycling.

AIM: Strenuous exercise can enhance plasma levels of pro- and anti-inflammatory cytokines. Increases in plasma tumor necrosis factor-alpha (TNF-α) are followed rapidly by a rise in its natural inhibitors, soluble TNF receptors (sTNFRs). These inhibitors likely prevent an over-response to the cytokine. Aims of the present study were: 1) analyze plasma sTNFR1 at different time-points in response to a strenuous off-road cycling competition; 2) evaluate whether plasma levels of sTNFR1 correlate to increased blood lactate levels on completion of the exercise. METHODS: Eight trained off-road cyclists took part in this study and the data collection occurred during an official off-road race. Blood samples were collected pre-race, immediately post-race, and 1 h, 2 h and 24 h during the recovery period, for plasma sTNFR1 and blood lactate determination. RESULTS: Increase in sTNFR1 plasma levels were observed immediately post-race, 1 h and 2 h post-race (P<0.01), returning to baseline levels at the end of the recovery period (24 h). Significant correlation between plasma levels of sTNFR1 and blood lactate concentration were observed at the end of the race (r=0.925; P<0.001). CONCLUSION: An off-road cycling race stimulated an increase in plasma sTNFR1 and this anti-inflammatory molecule was positively correlated to blood lactate concentration. This result reinforces the view that exercise intensity influences the increase in plasma anti-inflammatory molecules.

Combined dysfunctions of immune cells predict nosocomial infection in critically ill patients.

BACKGROUND: Nosocomial infection occurs commonly in intensive care units (ICUs). Although critical illness is associated with immune activation, the prevalence of nosocomial infections suggests concomitant immune suppression. This study examined the temporal occurrence of immune dysfunction across three immune cell types, and their relationship with the development of nosocomial infection. METHODS: A prospective observational cohort study was undertaken in a teaching hospital general ICU. Critically ill patients were recruited and underwent serial examination of immune status, namely percentage regulatory T-cells (Tregs), monocyte deactivation (by expression) and neutrophil dysfunction (by CD88 expression). The occurrence of nosocomial infection was determined using pre-defined, objective criteria. RESULTS: Ninety-six patients were recruited, of whom 95 had data available for analysis. Relative to healthy controls, percentage Tregs were elevated 6-10 days after admission, while monocyte HLA-DR and neutrophil CD88 showed broader depression across time points measured. Thirty-three patients (35%) developed nosocomial infection, and patients developing nosocomial infection showed significantly greater immune dysfunction by the measures used. Tregs and neutrophil dysfunction remained significantly predictive of infection in a Cox hazards model correcting for time effects and clinical confounders {hazard ratio (HR) 2.4 [95% confidence interval (CI) 1.1-5.4] and 6.9 (95% CI 1.6-30), respectively, P=0.001}. Cumulative immune dysfunction resulted in a progressive risk of infection, rising from no cases in patients with no dysfunction to 75% of patients with dysfunction of all three cell types (P=0.0004). CONCLUSIONS: Dysfunctions of T-cells, monocytes, and neutrophils predict acquisition of nosocomial infection, and combine additively to stratify risk of nosocomial infection in the critically ill.

Moving into the red - a near infra-red optical probe for analysis of human neutrophil elastase in activated neutrophils and neutrophil extracellular traps.

Neutrophils are the first immune cells recruited for defence against invading pathogens; however, their dysregulated activation and subsequent release of the enzyme human neutrophil elastase is associated with several, inflammation-based, diseases. Herein, we describe a FRET-based, tri-branched (one quencher, three fluorophores) near infrared probe that provides an intense OFF/ON amplified fluorescence signal for specific detection of human neutrophil elastase. The probe allowed selective detection of activated neutrophils and labelling of neutrophil extracellular traps.

Minimally invasive mastectomy: minimal incisions for better aesthetic quality of breast reconstruction.

BACKGROUND: Women with a family history of breast cancer who develop this disease are confronted with important situations regarding the increased risk for development of a second cancer in the contralateral breast. Prophylactic contralateral mastectomy (PCM) reduces by approximately 95% the risk for contralateral breast cancer. In spite of an increase in indications for PCM, the technical difficulties are many regarding the accomplishment of these procedures. The aim of this study is to describe the technique of mastectomy with preservation of the nipple-areola complex and a small incision, reducing surgical difficulties and complications attributed to this technique, thus allowing better aesthetic results in breast reconstruction. METHODS: Forty-six patients with indications for PCM (28 bilateral) were submitted to minimally invasive mastectomy from March 2005 to November 2007. A small incision in the superior pole of the areola, sufficient to pass a liposuction 4 mm cannula is made. With the help of this cannula, detachment of the skin from the gland tissue is performed. Then a 3.5 to 4.5-cm long incision in the inframammary fold is made. Glandular detachment is completed using cautery in the subglandular portion and scissors in the upper breast portion cutting the restraints left by the cannula. The mammary gland tissue is removed through this incision. RESULTS: Seventy-four breasts were operated on. The resected breast mass ranged from 285 g to 475 g. All 43 patients were reconstructed with prostheses. There was no necrosis of the nipple-areola complex or of the skin. CONCLUSIONS: This technique is an option for cases of patients with indications for PCM.

Isolated IgG2 deficiency is an independent risk factor for exacerbations in bronchiectasis.

BACKGROUND: Immunoglobulin G (IgG) subclass 2 deficiency is the most frequent IgG subclass deficiency identified in patients with bronchiectasis, but its clinical significance is not known. AIM: To analyse if bronchiectasis patients with isolated IgG2 deficiency at risk of recurrent exacerbations and/or hospitalization? Do patients with IgG2 deficiency have worse disease progression? DESIGN AND METHODS: This is a retrospective study (2015-20) exploring independent risk factors for recurrent exacerbations (3 or more per year) and/or hospitalization with bronchiectasis exacerbations using multivariable models using binary logistic regression. There was no patient with IgG deficiency, IgG 1, 3 or 4 deficiency, or IgA or IgM deficiency included. In this model, the authors included: serum IgG2 level; lung function; body mass index; MRC breathlessness scale; age; sex; number of bronchiectatic lobes; bacterial colonization; comorbidities; and the use of long-term immunosuppressant drugs or antibiotics for more than 28 days. Analysing 2-year longitudinal data, one-way ANOVA and Mann-Whitney U-test were used to compare bronchiectasis severity between patients with different IgG2 levels. RESULTS: Serum IgG2 levels (<2.68 g/l, 2.68-3.53 g/l and 3.54-4.45 g/l); hospital admission in the preceding 2 years; bacterial colonization with potentially pathogenic organisms and asthma were independent predictors for three or more bronchiectasis exacerbations. Those with low IgG2 levels (<2.68 g/l and 2.68-3.53 g/l), had worsening progression of their bronchiectasis, using the Bronchiectasis Severity Index, over 1 year compared with those who were IgG2 replete (>4.45 g/l) (P = 0.003, 0.013). CONCLUSION: Reduced IgG2 levels were an independent predictor for bronchiectasis exacerbations and have increased disease progression.

Female pelvic pain: a case report of mucocele of the appendix.

OBJECTIVE: To describe a rare case of mucocele of the appendix that simulated a cystic image by pelvic ultrasound (US). CASE: A patient with pelvic pain for two months and cystic image on the right ovary by US. After laparoscopy, the image showed a mucocele of the appendix. The patient underwent right colectomy. CONCLUSION: Mucocele may be a cause of pelvic pain and may simulate a cystic image on the right adnexa.

Sildenafil reduces alcohol-induced gastric damage: just say 'NO'.

Although sildenafil (Viagra) and other phosphodiesterase V (PDE V) inhibitors are increasingly recognized for their use in the treatment of male erectile dysfunction and perhaps more recently pulmonary artery hypertension, less is known of their potential beneficial effects in other situations. Medeiros et al., in the current issue of the British Journal of Pharmacology, report that sildenafil dramatically reduces alcohol-induced gastric damage in rats. The authors provide convincing evidence that such protection not only occurs via the nitric oxide (NO)/cGMP pathway, but also involves regulation of ATP-sensitive potassium channels. Therefore, in addition to exerting anti-impotence efficacy, PDE V inhibitors may provide significant beneficial effects from mucosal injury induced by alcohol.

MDR1 deficiency impairs mitochondrial homeostasis and promotes intestinal inflammation.

The multidrug resistance-1 (MDR1) gene encodes an ATP-dependent efflux transporter that is highly expressed in the colon. In mice, loss of MDR1 function results in colitis with similarities to human inflammatory bowel diseases (IBD). Here, we show that MDR1 has an unexpected protective role for the mitochondria where MDR1 deficiency results in mitochondrial dysfunction with increased mitochondrial reactive oxygen species (mROS) driving the development of colitis. Exogenous induction of mROS accelerates, while inhibition attenuates colitis in vivo; these effects are amplified in MDR1 deficiency. In human IBD, MDR1 is negatively correlated to SOD2 gene expression required for mROS detoxification. To provide direct evidential support, we deleted intestinal SOD2 gene in mice and showed an increased susceptibility to colitis. We exploited the genome-wide association data sets and found many (∼5%) of IBD susceptibility genes with direct roles in regulating mitochondria homeostasis. As MDR1 primarily protects against xenotoxins via its efflux function, our findings implicate a distinct mitochondrial toxin+genetic susceptibility interaction leading to mitochondrial dysfunction, a novel pathogenic mechanism that could offer many new therapeutic opportunities for IBD.

Human circulating eosinophils secrete macrophage migration inhibitory factor (MIF). Potential role in asthma.

Macrophage migration inhibitory factor (MIF) is a potent proinflammatory mediator that has been shown to potentiate lethal endotoxemia and to play a potentially important regulatory role in human acute respiratory distress syndrome (ARDS). We have investigated whether eosinophils are an important source of MIF and whether MIF may be involved in the pathophysiology of asthma. Unstimulated human circulating eosinophils were found to contain preformed MIF. Stimulation of human eosinophils with phorbol myristate acetate in vitro yielded significant release of MIF protein. For example, eosinophils stimulated with phorbol myristate acetate (100 nM, 8 h, 37 degreesC) released 1,539+/-435 pg/10(6) cells of MIF, whereas unstimulated cells released barely detectable levels (< 142 pg/10(6) cells, mean+/-SEM, n = 8). This stimulated release was shown to be (a) concentration- and time-dependent, (b) partially blocked by the protein synthesis inhibitor cycloheximide, and (c) significantly inhibited by the protein kinase C inhibitor Ro-31,8220. In addition, we show that the physiological stimuli C5a and IL-5 also cause significant MIF release. Furthermore, bronchoalveolar lavage fluid obtained from asthmatic patients contains significantly elevated levels of MIF as compared to nonatopic normal volunteers (asthmatic, 797.5+/-92 pg/ml; controls, 274+/-91 pg/ml). These results highlight the potential importance of MIF in asthma and other eosinophil-dependent inflammatory disorders.

Gut mucosal DAMPs in IBD: from mechanisms to therapeutic implications.

Endogenous damage-associated molecular patterns (DAMPs) are released during tissue damage and have increasingly recognized roles in the etiology of many human diseases. The inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn's disease (CD), are immune-mediated conditions where high levels of DAMPs are observed. DAMPs such as calprotectin (S100A8/9) have an established clinical role as a biomarker in IBD. In this review, we use IBD as an archetypal common chronic inflammatory disease to focus on the conceptual and evidential importance of DAMPs in pathogenesis and why DAMPs represent an entirely new class of targets for clinical translation.

Key mechanisms governing resolution of lung inflammation.

Innate immunity normally provides excellent defence against invading microorganisms. Acute inflammation is a form of innate immune defence and represents one of the primary responses to injury, infection and irritation, largely mediated by granulocyte effector cells such as neutrophils and eosinophils. Failure to remove an inflammatory stimulus (often resulting in failed resolution of inflammation) can lead to chronic inflammation resulting in tissue injury caused by high numbers of infiltrating activated granulocytes. Successful resolution of inflammation is dependent upon the removal of these cells. Under normal physiological conditions, apoptosis (programmed cell death) precedes phagocytic recognition and clearance of these cells by, for example, macrophages, dendritic and epithelial cells (a process known as efferocytosis). Inflammation contributes to immune defence within the respiratory mucosa (responsible for gas exchange) because lung epithelia are continuously exposed to a multiplicity of airborne pathogens, allergens and foreign particles. Failure to resolve inflammation within the respiratory mucosa is a major contributor of numerous lung diseases. This review will summarise the major mechanisms regulating lung inflammation, including key cellular interplays such as apoptotic cell clearance by alveolar macrophages and macrophage/neutrophil/epithelial cell interactions. The different acute and chronic inflammatory disease states caused by dysregulated/impaired resolution of lung inflammation will be discussed. Furthermore, the resolution of lung inflammation during neutrophil/eosinophil-dominant lung injury or enhanced resolution driven via pharmacological manipulation will also be considered.

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis.

Apoptosis of inflammatory cells is a critical event in the resolution of inflammation, as failure to undergo this form of cell death leads to increased tissue damage and exacerbation of the inflammatory response. Many factors are able to influence the rate of apoptosis in neutrophils, eosinophils, monocytes and macrophages. Among these is the signalling molecule nitric oxide (NO), which possesses both anti- and proapoptotic properties, depending on the concentration and flux of NO, and also the source from which NO is derived. This review summarises the differential effects of NO on inflammatory cell apoptosis and outlines potential mechanisms that have been proposed to explain such actions.

Pharmacological manipulation of granulocyte apoptosis: potential therapeutic targets.

Resolution of inflammation involves the clearance of excess or effete inflammatory cells by a process of physiological programmed cell death (apoptosis) and the subsequent recognition and removal of apoptotic cells by phagocytes. The therapeutic induction of apoptosis for the resolution of chronic inflammation and the general pharmacology of apoptosis have become subjects of increasing interest. In this article, some of the unique and important differences in the control of apoptosis of various inflammatory cells (particularly neutrophil and eosinophil granulocytes) are highlighted. It is suggested that apoptosis can be specifically regulated pharmacologically and could be exploited to develop new drug therapies.