Metformin can be repurposed as host-directed therapy for tuberculosis.

Recent discoveries suggesting essential bioactivities of nitric oxide (NO') in the lung are difficult to reconcile with the established pulmbnary cytotoxicity of this common air pollutant. These conflicting observations suggest that metabolic intermediaries may exist in the lung to modulate the bioactivity and toxicity of NO'. We report that S-nitrosothiols (RS-NO), predominantly the adduct with glutathione, are present at nano-to micromolar concentrations in the airways of normal subjects and that their levels vary in different human pathophysiologic states. These endogenous RS-NO are longlived, potent relaxants of human airways under physiological 02 concentrations. Moreover, RS-NO form in high concentrations upon administration of NO gas. Nitrite (10-20 ,M) is found in airway lining fluid in concentrations linearly proportional to leukocyte counts, suggestive of local NO' metabolism. NO itself was not detected either free in solution or in complexes with transition metals. These observations may provide insight into the means by which NO is packaged in biological systems to preserve its bioactivity and limit its potential 02-dependent toicity and suggest an important role for NO' in regulation of airway luminal homeostasis.There is accumulating evidence that nitric oxide (NO') is produced in mammalian airways: constitutive and inducible forms of NO synthase have recently been identified in the lung (1, 2), oxides of nitrogen (NOx) are produced by airway cells (3), and exhaled NO gas can be measured in nonsmoking volunteers (4). Potential sources of NO' include the lung parenchyma itself [smooth muscle, mast cells, nerves, and epithelium (1-3, 5-8)] as well as the cellular constituents of airway lining fluid [macrophages and neutrophils (1, 2, 9-11)]. NO has well established vasodilator properties that may play a role in the physiological regulation of blood flow and pressure in the pulmonary circulation (12). Although more disputed (13), the smooth muscle relaxant effects of NO' in airways suggest that it may have an additional role as a bronchodilator (14)(15)(16).NO', a common air pollutant and component of cigarette smoke, has been viewed as highly toxic to the lung, in part as a consequence of the high ambient 02 tension (17)(18)(19)(20)(21)(22). The reactions of NO with ambient 02 and superoxide (02 ) yield more reactive NO,, including nitrogen dioxide (NO) and peroxynitrite (OONO-), which are implicated in bronchiolitis and lung edema (17,20,21,23,24). There is additional concern that the oxidative metabolism of NO may lead to formation of carcinogenic nitrosoamines (25,26). Notably, these oxidative reactions of NO also result in the rapid loss of its smooth muscle relaxant activity (27, 28).The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.An alternative metabolic pathway for NOI of potential biological relevance involves the reaction wit...

Histochemical activity and immunoreactivt of nitric oxide synthase (NOS, EC 1.14.13.39) have been recently demonstrated in human lung epithelium. However, the molecular nature of NOS and the regulation and function of the enzyme(s) in the airway is not known. A549 cells (human alveolar type I epithelium-like), BEAS 2B cells (transformed human bronchial epithelial cells), and primary cultures of human bronchial epithelial cells all exhibited constitutive NOS activity that was calcium dependent and inhibitable by the NOS inhibitor NG-monomethyl-L-arginine. Nitric oxide production by epithelial cells was enhanced by culture in the presence of interferon y, interleukin 1p, tumor necrosis factor a, and lipopolysaccharide; the NOS activity expressed under these conditions showed less dependence on calcium, reminiscent of other inducible forms of NOS. Two distinct NOS mRNA species, homologous to previously identified constitutive brain (type I) and inducible hepatic (type II) NOS, were demonstrated by reverse transcription-polymerase chain reaction in all cell lines. Northern analysis confirmed the expression of inducible NOS mRNA. Cell culture with epidermal growth factor, a principal regulator of epithelial cell function, decreased inducible NOS activity by posttranscriptional action but did not affect constitutive NOS activity. The coexistence of constitutive and inducible NOS in human alveolar and bronchial epithelial cells is consistent with a complex mechanism evolved by epithelial cells to protect the host from microbial assault at the air/surface interface while shielding the host from the induction of airway hyperreactivity.In addition to its role in regulating airway tone (1-4), the airway epithelium is an important interface between higher organisms and their extracellular environments. Once considered a simple physical barrier to noxious agents, it is now well appreciated that the epithelium has evolved complex metabolic mechanisms to deal with constant assault by viruses, bacteria, inflammatory stimuli, and environmental pollutants. Thus, epithelial cells transport antibodies, rapidly proliferate in response to injury, actively propel a protective layer of mucus with their surface cilia, and can exhibit selected activities of immunologically active macrophages, including the expression and/or secretion of several cytokines, growth factors, and adhesion molecules (5-11). Epidermal growth factor (EGF) has been implicated as a principal regulator of these physiological responses through its control of epithelial cell proliferation, differentiation, and inflammatory responses (12, 13).The divergent roles of nitric oxide (NO) as a servoregulator of smooth muscle tone and cytotoxin important in host defense (14) make it an attractive candidate to regulate the multifaceted cellular biology of the airway epithelium. The diverse actions of NO have been explained by the differential expression and activity of enzymes involved in its synthesis, their regulation, and its chemistry in different biological milie...

LTBI treatment had a differential effect on T-cell responses to ESAT-6 and CFP-10 as measured by the T-SPOT.TB. The quantitative response to CFP-10 may be a useful LTBI treatment-monitoring tool.

Persistent air-leak in patients with spontaneous pneumothorax (SP) is not uncommon and may present a management dilemma in those who are unfit or unwilling for surgery. Video-assisted thoracoscopic surgery (VATS) has been advocated in the management of patients with broncho-pleural fistulae (air-leak persisting beyond 7 days): however the optimum time for surgical intervention remains unclear. We reviewed the records of 130 episodes of SP in 115 patients over a 2-year period to determine clinical course and outcome, particularly with respect to duration of air-leak. There were 90 first episodes and 40 recurrent episodes. Eighty-one episodes (62%) occurred in patients with underlying lung disease (secondary pneumothorax). Initial management consisted of chest-tube drainage in 104 episodes (80%) occurring in 90 patients, percutaneous needle aspiration in five patients (4%) and observation in 21 episodes (16%) in 20 patients. In the group treated with chest-tube drainage, there was spontaneous resolution of air leak and lung re-expansion in 90 episodes (87%). The overall incidence of broncho-pleural fistula was 34.6%. In the primary SP group. 75% of air-leaks ceased by 7 days and 100% by 15 days. In the secondary SP group, 61% of air-leaks resolved by 7 days and 79% by 14 days, after which time resolution of air-leak proceeded at a much slower rate. Five patients underwent surgery while nine patients were discharged with residual pneumothoraces. There were no major complications or mortality. Based on our findings, we advocate surgery for patients with air-leak persisting beyond 14 days, while favouring a conservative approach before this time, as the majority of air-leaks (especially in patients with primary pneumothorax) would resolve by 14 days.