Current Respiratory Medicine Reviews - Volume 10, Issue 2, 2014

Tuberculosis (TB) has been a widespread infectious disease since ancient times and remains a worldwide major health problem. TB morbidity with 8 to 9 million active cases per year and 1.3 deaths annually represent the largest number of incidences and of human deaths attributable to a single bacterial agent. Its causal agent Mycobacterium tuberculosis is able to survive in a latent state in infected individuals, thereby serving as a reservoir, waiting for the reactivation that usually occurs in immune-suppressed individuals, such as HIV patients. According to World Health Organization estimation, 2 billion people, almost one-third of the world’s population, are believed to be latently infected. An additional significant factor is the continued emergence of new multidrug resistant strains often associated to poor compliance due to the long, complex, toxic and expensive treatment. Thus, new anti-TB drugs and better therapeutic strategies are urgently needed. New drug candidates should short the standard regimens and being effective against drug resistant strains. In recent years, an emphasized research activity in the development of new TB drugs has being produced. Some compounds are presently in clinical development, while others are being investigated pre-clinically. The immune system is a critical factor for containment and cure of mycobacterial infection. Augmentation of protective immunity or decreasing the immune modulatory responses during late disease can be of value in the TB treatment. Thus, the use of immunotherapy with cytokines or bacterial derivatives as an adjunct to drug treatment may improve success rates for treatment of MDR-TB and shorten treatment time for drug-sensitive TB. The present review concentrates to describe the most promising new drugs against TB which are now in clinical trials, as well as the immunotherapeutic assays performed in humans.

Tuberculosis is essentially a curable disease but inspite of a WHO approved DOTS therapy, it still continues to ravage mankind. This situation is exacerbated by long course of chemotherapy, increasing drug resistance and co-emergence with HIV. The TB drug pipeline remained stagnant for a long time with no new drug approved till FDA approval for Bedaquiline. This situation has now improved with a number of agents in pre-clinical and clinical development against M. tuberculosis. In this review, we are focusing on some of the newer drugs in discovery and preclinical development against M. tuberculosis.

There are many chemotherapeutic interventions available for tuberculosis (TB) and are in use for more than five decades, but still there is an urgent need for novel drugs against new targets due to emergence of resistant strains. Moreover, the ability of Mycobacterium tuberculosis (Mtb) to survive within granulomas in a non-replicating latent stage prolongs the course of drug dose and hence increases the severity of the disease. The significant rerouting of metabolism is one of the key processes that help mycobacteria adapt to the hostile environment of host granuloma. In this review, we are focusing on some of the cofactor biosynthetic pathways of Mycobacterium tuberculosis and their utilization as drug targets.

Studies about in vitro pellicle formation by slow-growing, pathogenic mycobacteria has just gained a new momentum, and in Mycobacterium tuberculosis, cells growing in this environment showed enhanced tolerance to antitubercular drugs. c-di-GMP, an ubiquitous bacterial second messenger, regulates phenotypes such as motility, biofilm formation and expression of acute virulence factors in several microorganisms. Recently, enzymes encoded by Rv1354c and Rv1357c were shown to produce and degrade c-di-GMP in vitro, respectively. Here we review the processes in which c-di-GMP regulates biofilm production and virulence in some human pathogens, discuss the possibility of these same processes existing in Mycobacterium tuberculosis, and how these mechanisms could impact the outcome of tuberculosis infection.

Lungs are indispensable organs for the respiratory process, and maintaining their homeostasis is essential for human health and survival. However, during the lifetime of an individual, the lungs suffer countless insults that put at risk their delicate organization and function. Many cells of the immune system participate to maintain this equilibrium and to keep functional lungs. Among these cells, mast cells have recently attracted attention because of their ability to rapidly secrete many chemical and biological mediators that modulate different processes like inflammation, angiogenesis, cell proliferation, etc. In this review, we focus on recent advances in the understanding of the role that mast cells play in lung protection during infections, and of the relation of mast cell responses to type I hypersensitivity-associated pathologies. Furthermore, we discuss the potential role of mast cells during wound healing in the lung and its association with lung cancer, and how mast cells could be exploited as therapeutic targets in some diseases.

Introduction: Resistin is a novel adipokine that has been reported as an independent predictor for hypertension. Its role in patients with obstructive sleep apnea (OSA), however, has not been investigated yet. Aim: The aim of this study was to explore the role of resistin in non-diabetic OSA patients with nocturnal hypertension and to study its association with markers of obesity, insulin resistance and oxidative stress. Methods: A total of 54 non-diabetic hypertensive OSA patients participated in the study. OSA was newly detected by a standard polysomnography. Patients had controlled hypertension. According to ambulatory blood pressure monitoring (ABPM) they were divided into patients with normal nocturnal BP (25) and patients with nocturnal hypertension (29). Anthropometric, sleep study and glucometabolic parameters were defined. Resistin plasma levels were determined by an ELISA kit. Oxidative stress (urinary 8-isoprostane levels) were measured in addition by mass spectrometry (Cayman Chemical, USA). Results: Resistin plasma levels were higher in subjects with nocturnal hypertension in comparison to those with normal BP - (7.81±4.43 vs 4.90±2.92ng/mL). Resistin correlated neither to markers of adiposity, nor to those of insulin resistance. Its association with urinary isoprostane levels was of significance (p-0.036). Resistin was higher in patients with severe apnea, but was not associated with respiratory disturbance parameters. Conclusion: Our results suggest that hyperresistinemia is associated with higher levels of oxidative stress and may contribute to the pathogenesis of nocturnal hypertension in non-diabetic OSA patients. This may provide adequate cardiovascular risk assessment and improve the therapeutic control.

Introduction: Cardiovascular (CV) morbidity is increased in patients with obstructive sleep apnea (OSA). Oxidative stress and adipose tissue dysfunction are thought to be important factors for the accelerated atherosclerosis in OSA. The role of the various adipokines is however debated. Aim: The aim of the study was to check whether resitin may be a link between oxidative stress, adiposity and atherosclerosis in OSA patients. Methods: The common carotid artery (CCA) intima-media thickness (IMT), was measured by ultrasonography in 34 nondiabetic, non-hypertensive patients with untreated OSA. Oxidative stress (urinary 8-isoprostane levels) was measured by mass spectrometry (Cayman Chemical, USA). Insulin resistance was assessed by the homeostasis model assessment for insulin resistance (HOMA-IR). Resistin plasma levels were determined by an ELISA kit. Results: Urinary 8-isoprostanes, but not resistin were associated with the IMT after adjustment for CV risk factors, including HOMA-IR. Resistin levels increased with the degree of OSA severity, but did not correlate to markers of insulin resistance (HOMA-IR) or atherosclerosis. They were, however, associated with the time of sleep at SaO2<90% but not with the urinary 8-isoprostane levels. Conclusion: In non-diabetic, non-hypertensive OSA patients, resistin plasma levels do not correlate to markers of adiposity, insulin resistance or oxidative stress. IMT was associated only with the levels of oxidative stress (8-urinary isoprostanes).