Histamine Plays an Essential Regulatory Role in Lung Inflammation and Protective Immunity in the Acute Phase of Mycobacterium tuberculosis Infection

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Passive smoking and lung cancer: a cumulative meta-analysis

Objective: To review the epidemiological evidence for the association between passive smoking and lung cancer. Method: Primary studies and meta-analyses examining the relationship between passive smoking and lung cancer were identified through a computerised literature search of Medline and Embase, secondary references, and experts in the field of passive smoking. Primary studies meeting the inclusion criteria were meta-analysed. Results From 1981 to the end of 1999 there have been 76 primary epidemiological studies of passive smoking and lung cancer, and 20 meta-analyses. There were 43 primary studies that met the inclusion criteria for this meta-analysis; more studies than previous assessments. The pooled relative risk (RR) for never-smoking women exposed to environmental tobacco smoke (ETS) from spouses, compared with unexposed never-smoking women was 1.29 (95% CI 1.17-1.43). Sequential cumulative meta-analysed results for each year from 1981 were calculated: since 1992 the RR has been greater than 1.25. For Western industrialised countries the RR for never-smoking women exposed to ETS compared with unexposed never-smoking women, was 1.21 (95% CI 1.10-1.33). Previously published international spousal meta-analyses have all produced statistically significant RRs greater than 1.17. Conclusions The abundance of evidence in this paper, and the consistency of findings across domestic and workplace primary studies, dosimetric extrapolations and meta-analyses, clearly indicates that non-smokers exposed to ETS are at increased risk of lung cancer. Implications: The recommended public health policy is for a total ban on smoking in enclosed public places and work sites.

Is there an association between chronic lung disease and abdominal aortic aneurysm expansion?

Background: Although there is evidence demonstrating an association between chronic obstructive pulmonary disease (COPD) and abdominal aortic aneurysm (AAA), it is not clear whether COPD predicts greater rates of expansion of established aneurysms. We sought such an association in a cohort of men with aneurysms detected in a population-based study of screening for aneurysms. Methods: In addition to regular aortic ultrasound scans, 179 men with AAA underwent full lung function testing in order to identify the presence of COPD and its subgroups, emphysema and other obstructive ventilatory defects (OVD). The rate of expansion of each aneurysm was calculated and the men were divided into 'rapid expanders' (3 mm or more per year) and 'slow expanders' (less than 3 mm per year). Any association with the presence of COPD or smoking was tested using a multivariate model. Results: Over a median follow-up period of 36 months the mean rate of aortic expansion for the cohort of 179 men was 2.1 mm/year. There was no significant difference in prevalence of COPD (68% overall) or having ever been a smoker (87% overall) between the rapid expanders and the slow expanders. Conclusions: Although there was a high prevalence of COPD among men with an AAA, there was no association between the rate of expansion of AAA and the presence of any form of this disease.

Surgical management of lung cancer in Western Australia in 1996 and its outcomes

Background: All cases of lung cancer diagnosed in Western Australia in 1996 in which surgery was the primary treatment, were reviewed. Reported herein are the characteristics of the patients, the treatment outcomes and a comparison of the management undertaken with that recommended by international guidelines. Methods: All patients with a new diagnosis of lung cancer in Western Australia in the calendar year of 1996 were identified using two different population-based registration systems: the Western Australian (WA) Cancer Registry and the WA Hospital Morbidity Data System. A structured questionnaire on the diagnosis and management was completed for each case. Date of death was determined through the WA Cancer Registry. Results: Six hundred and sixty-eight patients with lung cancer were identified; 132 (20%) were treated with surgery. Lobectomy was the most frequently performed procedure (71%), followed by pneumonectomy (19%). Major complications affected 23% of patients. Postoperative mortality was 6% (3% lobectomy, 12% pneumonectomy). At 5 years the absolute survival was as follows for stage I, II, IIIA, IIIB, respectively: 51%, 45%, 12%, 5%. Conclusions: Investigations and choice of surgery in WA in 1996 reflect current international guidelines. The survival of patients with resectable lung cancer remains unsatisfactory.

Association of tumor necrosis factor-alpha polymorphisms and ozone-induced change in lung function

Ozone is a major air pollutant with adverse health effects which exhibit marked inter-individual variability. In mice, regions of genetic linkage with ozone-induced lung injury include the tumor necrosis factor-alpha (TNF), lymphotoxin-alpha (LTA), Toll-like receptor 4 (TLR4), superoxide dismutase (SOD2), and glutathione peroxidase (GPX1) genes. We genotyped polymorphisms in these genes in 51 individuals who had undergone ozone challenge. Mean change in FEV1 with ozone challenge, as a percentage of baseline, was -3% in TNF -308G/A or A/A individuals, compared with -9% in G/G individuals (p = 0.024). When considering TNF haplotypes, the smallest change in FEV1 with ozone exposure was associated with the TNF haplotype comprising LTA +252G/TNF -1031T/TNF -308A/TNF -238G. This association remained statistically significant after correction for age, sex, disease, and ozone concentration (p = 0.047). SOD2 or GPX1 genotypes were not associated with lung function, and the TLR4 polymorphism was too infrequent to analyze. The results of this study support TNF as a genetic factor for susceptibility to ozone-induced changes in lung function in humans, and has potential implications for stratifying health risks of air pollution.

Cochrane systematic reviews of treatments for lung cancer

Morbidity and mortality from lung cancer is a major burden to global health. The integration of expert clinical experience, patient preference and high-quality evidence, including Cochrane systematic reviews, can only help improve outcomes from this highly lethal condition.

Amphetamine modulates cellular recruitment and airway reactivity in a rat model of allergic lung inflammation

Asthma is characterized by pulmonary cellular infiltration, vascular exudation and airway hyperresponsiveness. Several drugs that modify central nervous system (CNS) activity can modulate the course of asthma. Amphetamine (AMPH) is a highly abused drug that presents potent stimulating effects on the CNS and has been shown to induce behavioral, biochemical and immunological effects. The purpose of this study was to investigate the effects of AMPH on pulmonary cellular influx, vascular permeability and airway reactivity. AMPH effects on adhesion molecule expression, IL-10 and IL-4 release and mast cell degranulation were also studied. Male Wistar rats were sensitized with ovalbumin (OVA) plus alum via subcutaneous injection. One week later, the rats received another injection of OVA-alum (booster). Two weeks after this booster, the rats were subjected to AMPH treatment 12 h prior to the OVA airway challenge. In rats treated with AMPH, the OVA challenge reduced cell recruitment into the lung, the vascular permeability and the cellular expression of ICAM-1 and Mac-1. Additionally, elevated levels of IL-10 and IL-4 were found in samples of lung explants from allergic rats. AMPH treatment, in comparison, increased IL-10 levels but reduced those of IL-4 in the lung explants. Moreover, the tracheal responsiveness to methacholine (MCh), as well as to an in vitro OVA challenge, was reduced by AMPH treatment, and levels of PCA titers were not modified by the drug. Our findings suggest that single AMPH treatment down-regulates several parameters of lung inflammation, such as cellular migration, vascular permeability and tracheal responsiveness. These results also indicate that AMPH actions on allergic lung inflammation include endothelium-leukocyte interaction mechanisms, cytokine release and mast cell degranulation. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Prolonged recruitment manoeuvre improves lung function with less ultrastructural damage in experimental mild acute lung injury

The effects of prolonged recruitment manoeuvre (PRM) were compared with sustained inflation (SI) in paraquat-induced mild acute lung injury (ALI) in rats. Twenty-four hours after ALI induction, rats were anesthetized and mechanically ventilated with VT = 6 ml/kg and positive end-expiratory pressure (PEEP) = 5 cmH(2)O for 1 h. SI was performed with an instantaneous pressure increase of 40 cmH(2)O that was sustained for 40 s, while PRM was done by a step-wise increase in positive inspiratory pressure (PIP) of 15-20-25 cmH(2)O above a PEEP of 15 cm H(2)O (maximal PIP = 40 cmH(2)O), with interposed periods of PIP = 10 cmH(2)O above a PEEP = 15 cmH(2)O. Lung static elastance and the amount of alveolar collapse were more reduced with PRM than SI, yielding improved oxygenation. Additionally, tumour necrosis factor-alpha, interleukin-6, interferon-gamma, and type III procollagen mRNA expressions in lung tissue and lung epithelial cell apoptosis decreased more in PRM. In conclusion, PRM improved lung function, with less damage to alveolar epithelium, resulting in reduced pulmonary injury. (C) 2009 Elsevier BLV. All rights reserved.

A comparison of methods to identify open-lung PEEP

Purpose: Many methods exist in the literature for identifying PEEP to set in ARDS patients following a lung recruitment maneuver (RM). We compared ten published parameters for setting PEEP following a RM. Methods: Lung injury was induced by bilateral lung lavage in 14 female Dorset sheep, yielding a PaO(2) 100-150 mmHg at F(I)O(2) 1.0 and PEEP 5 cmH(2)O. A quasi-static P-V curve was then performed using the supersyringe method; PEEP was set to 20 cmH(2)O and a RM performed with pressure control ventilation (inspiratory pressure set to 40-50 cmH(2)O), until PaO(2) + PaCO(2) > 400 mmHg. Following the RM, a decremental PEEP trial was performed. The PEEP was decreased in 1 cmH(2)O steps every 5 min until 15 cmH(2)O was reached. Parameters measured during the decremental PEEP trial were compared with parameters obtained from the P-V curve. Results: For setting PEEP, maximum dynamic tidal respiratory compliance, maximum PaO(2), maximum PaO(2) + PaCO(2), and minimum shunt calculated during the decremental PEEP trial, and the lower Pflex and point of maximal compliance increase on the inflation limb of the P-V curve (Pmci,i) were statistically indistinguishable. The PEEP value obtained using the deflation upper Pflex and the point of maximal compliance decrease on the deflation limb were significantly higher, and the true inflection point on the inflation limb and minimum PaCO(2) were significantly lower than the other variables. Conclusion: In this animal model of ARDS, dynamic tidal respiratory compliance, maximum PaO(2), maximum PaO(2) + PaCO(2), minimum shunt, inflation lower Pflex and Pmci,i yield similar values for PEEP following a recruitment maneuver.

A Previously Undescribed Syndrome Combining Fibular Agenesis/Hypoplasia, Oligodactylous Clubfeet, Anonychia/Ungual Hypoplasia, and Other Defects

We describe an apparently new genetic syndrome in six members of a family living in a remote area in Northeastern Brazil. This syndrome comprises: short stature Clue to a marked decrease in the length of the lower limbs (predominantly mesomelic with fibular agenesis/marked hypoplasia), grossly malformed/deformed clubfeet with severe oligodactyly, tipper limbs with acromial dimples and variable motion limitation of the forearms and/or hands, severe nail hypoplasia/anonychia sometimes associated with mild brachydactyly and occasionally with pre-axial polydactyly. This syndrome is apparently distinct from the syndrome of brachydactyly-ectrodactyly with fibular aplasia or hypoplasia (OMIM 113310), the syndrome of fibular aplasia or hypoplasia, femoral bowing and poly-, syn-, and oligodactyly (OMIM 228930), and from other previously described conditions exhibiting fibular agenesis/hvpoplasia. (C) 2008 Wiley-Liss, Inc.

Image reconstruction affects computer tomographic assessment of lung hyperinflation

Objectives: Lung hyperinflation may be assessed by computed tomography (CT). As shown for patients with emphysema, however, CT image reconstruction affects quantification of hyperinflation. We studied the impact of reconstruction parameters on hyperinflation measurements in mechanically ventilated (MV) patients. Design: Observational analysis. Setting: A University hospital-affiliated research Unit. Patients: The patients were MV patients with injured (n = 5) or normal lungs (n = 6), and spontaneously breathing patients (n = 5). Interventions: None. Measurements and results: Eight image series involving 3, 5, 7, and 10 mm slices and standard and sharp filters were reconstructed from identical CT raw data. Hyperinflated (V-hyper), normally (V-normal), poorly (V-poor), and nonaerated (V-non) volumes were calculated by densitometry as percentage of total lung volume (V-total). V-hyper obtained with the sharp filter systematically exceeded that with the standard filter showing a median (interquartile range) increment of 138 (62-272) ml corresponding to approximately 4% of V-total. In contrast, sharp filtering minimally affected the other subvolumes (V-normal, V-poor, V-non, and V-total). Decreasing slice thickness also increased V-hyper significantly. When changing from 10 to 3 mm thickness, V-hyper increased by a median value of 107 (49-252) ml in parallel with a small and inconsistent increment in V-non of 12 (7-16) ml. Conclusions: Reconstruction parameters significantly affect quantitative CT assessment of V-hyper in MV patients. Our observations suggest that sharp filters are inappropriate for this purpose. Thin slices combined with standard filters and more appropriate thresholds (e.g., -950 HU in normal lungs) might improve the detection of V-hyper. Different studies on V-hyper can only be compared if identical reconstruction parameters were used.