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Characterization of lung inflammation and its impact on macrophage function in aging.

Systemic inflammation that occurs with increasing age (inflammaging) is thought to contribute to the increased susceptibility of the elderly to several disease states. The elderly are at significant risk for developing pulmonary disorders and infectious diseases, but the contribution of inflammation in the pulmonary environment has received little attention.

In this study, we demonstrate that the lungs of old mice have elevated levels of proinflammatory cytokines and a resident population of highly activated pulmonary macrophages that are refractory to further activation by IFN-γ. The impact of this inflammatory state on macrophage function was determined in vitro in response to infection with M.tb. Macrophages from the lungs of old mice secreted more proinflammatory cytokines in response to M.tb infection than similar cells from young mice and also demonstrated enhanced M.tb uptake and P-L fusion. Supplementation of mouse chow with the NSAID ibuprofen led to a reversal of lung and macrophage inflammatory signatures.

These data indicate that the pulmonary environment becomes inflammatory with increasing age and that this inflammatory environment can be reversed with ibuprofen.

Look at the lung: can chest ultrasonography be useful in pregnancy?

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This study aimed to evaluate the clinical value of chest ultrasound (US) in the detection, diagnosis and follow-up of pathologic processes of both peripheral lung parenchyma and pleural space in pregnant women.

FINDINGS: Pregnant women admitted to Obstetric Pathology Hospital Department for respiratory diseases were enrolled. Chest US examination was performed when there was a respiratory disease highly suggestive of pneumonia and/or pleural effusion and chest X-ray (CXR) should have been obtained. Three chest US patterns were identified: lung consolidation (LC), pleural effusion (PE) and focal sonographic interstitial syndromes (SIS). When chest US pathologic signs were reported, one or more subsequent chest US examinations were performed to follow-up the patient until their complete resolution. Sixteen inpatients underwent 54 chest US evaluations. We identified: 9 LCs, 6 PEs and 11 SISs. Total number of CXRs was 7 (10 females avoided X-rays exposure and one underwent 2 CXR evaluations on the advice of Gynecologist). Chest US follow-up, during and after therapy, showed complete resolution of echographic patterns previously described.

CONCLUSIONS: Chest US evaluation during pregnancy is a useful diagnostic tool to detect and monitor respiratory diseases, avoiding excessive X-rays exposure.

Bosentan in Pulmonary Hypertension Associated with Fibrotic Idiopathic Interstitial Pneumonia (BPHIT).

Rationale: Pulmonary hypertension (PH) associated with fibrotic idiopathic interstitial pneumonia (IIP) confers important additional morbidity and mortality. Objectives: To evaluate the safety and clinical efficacy of the dual endothelin-1 receptor antagonist (ERA) bosentan in this patient group.

Methods: In a randomized, double-blind, placebo-controlled study, 60 patients with fibrotic IIP and right heart catheter confirmed PH were randomized 2:1 to bosentan (n=40) or placebo (n=20). The primary study end point was a fall from baseline pulmonary vascular resistance index (PVRi) of 20% or more over 16 weeks.

Main Results: Sixty patients (42 men; mean age 66.6±9.2 years), with a mean pulmonary artery pressure of 36.0 (±8.9) mmHg, PVRi 13.0 (±6.7) Wood Units.m2 and reduced cardiac index of 2.21 (±0.5) L/min/m2 were recruited to the study. Accounting for deaths and withdrawals, paired right heart catheter (RHC) data were available for analysis in 39 patients (bosentan=25, placebo=14). No difference in the primary outcome was detected, with seven (28.0%) patients receiving bosentan, and four (28.6%) receiving placebo achieving a reduction in PVRi of ≥20% (p=0.97) at 16 weeks. There was no change in functional capacity or symptoms between the two groups at 16 weeks, nor any difference in rates of serious adverse events or deaths (three deaths in each group).

Conclusions: This study shows no difference in invasive pulmonary haemodynamics, functional capacity or symptoms between the bosentan and placebo groups over 16 weeks. Our data does not support therefore the use of the dual ERA, bosentan in patients with PH and fibrotic IIP. Clinical trial registration available at www.clinicaltrials.gov, ID NCT00637065.

The new concepts on overcoming drug resistance in lung cancer.

LCLung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies.

With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance.

In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.

Benefits and harms of roflumilast in moderate to severe COPD

Background

Roflumilast, a phosphodiesterase 4 inhibitor, has been approved for the prevention of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear which patients will have a favourable benefit–harm balance with roflumilast. Our aim was to quantitatively assess the benefits and harms of roflumilast (500 µg/day) compared with placebo.

 Methods

We used summary data released by the US Food and Drug Administration to estimate the treatment effects of roflumilast. Data from trials and observational studies were used to estimate the baseline risks for COPD exacerbations and gastrointestinal, neurological and psychiatric harms associated with roflumilast. Using simulation, we calculated the probability that roflumilast provides net benefit. We examined the impacts of different baseline risks for exacerbations and the severity of exacerbations, and varied weights (ie, relative importance) for outcomes and treated death as a competing risk in the analyses.

 Results

The probability that roflumilast provides net benefit approximates 0% across different age categories of men and women with varying baseline risks for exacerbations. Using different weights for outcomes did not change the probability that roflumilast provides a net benefit. Only in the sensitivity analysis restricted to the prevention of severe exacerbations was there a probability of >50% that roflumilast provides a net benefit if the baseline risk of having at least one severe exacerbation per year exceeds 22%.

 Conclusions

Our results suggest that roflumilast only provides a net benefit to patients at a high risk of severe exacerbations. Guideline developers should consider different recommendations for patients with COPD at different baseline risks for exacerbations.

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