Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

https://www.who.int/respiratory/copd/GOLD_WR_06.pdf

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Global strategy for asthma management and prevention

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway1–8. The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

The L-Arginine-Nitric Oxide Pathway

Allergic rhinitis is a symptomatic disorder of the nose induced after allergen exposure by an IgE-mediated inflammation of the membranes lining the nose. It is a global health problem that causes major illness and disability worldwide. Over 600 million patients from all countries, all ethnic groups and of all ages suffer from allergic rhinitis. It affects social life, sleep, school and work and its economic impact is substantial. Risk factors for allergic rhinitis are well identified. Indoor and outdoor allergens as well as occupational agents cause rhinitis and other allergic diseases. The role of indoor and outdoor pollution is probably very important, but has yet to be fully understood both for the occurrence of the disease and its manifestations.

In 1999, during the Allergic Rhinitis and its Impact on Asthma (ARIA) WHO workshop, the expert panel proposed a new classification for allergic rhinitis which was subdivided into 'intermittent' or 'persistent' disease.

This classification is now validated. The diagnosis of allergic rhinitis is often quite easy, but in some cases it may cause problems and many patients are still under-diagnosed, often because they do not perceive the symptoms of rhinitis as a disease impairing their social life, school and work.

The management of allergic rhinitis is well established and the ARIA expert panel based its recommendations on evidence using an extensive review of the literature available up to December 1999. The statements of evidence for the development of these guidelines followed WHO rules and were based on those of Shekelle et al. A large number of papers have been published since 2000 and are extensively reviewed in the 2008 Update using the same evidence-based system. Recommendations for the management of allergic rhinitis are similar in both the ARIA workshop report and the 2008 Update. In the future, the GRADE approach will be used, but is not yet available.

Another important aspect of the ARIA guidelines was to consider co-morbidities. Both allergic rhinitis and asthma are systemic inflammatory conditions and often co-exist in the same patients. In the 2008 Update, these links have been confirmed.

The ARIA document is not intended to be a standard-of-care document for individual countries. It is provided as a basis for physicians, health care professionals and organizations involved in the treatment of allergic rhinitis and asthma in various countries to facilitate the development of relevant local standard-of-care documents for patients.

/pdf/allergic-rhinitis-and-its-impact-on-asthma-aria-2008-update-13eqfzaw4u.pdf

Allergic rhinitis and its impact on asthma (ARIA) 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen)

Resveratrol, a constituent of red wine, has long been suspected to have cardioprotective effects. Interest in this compound has been renewed in recent years, first from its identification as a chemopreventive agent for skin cancer, and subsequently from reports that it activates sirtuin deacetylases and extends the lifespans of lower organisms. Despite scepticism concerning its bioavailability, a growing body of in vivo evidence indicates that resveratrol has protective effects in rodent models of stress and disease. Here, we provide a comprehensive and critical review of the in vivo data on resveratrol, and consider its potential as a therapeutic for humans.

Therapeutic potential of resveratrol: the in vivo evidence.

We studied the role of histamine H3-receptors on neurogenic microvascular leakage in guinea pig airways by measuring extravasation of Evans blue dye. In guinea pig airways the major component of the neurogenic leakage is nonadrenergic noncholinergic (NANC) mediated, due to release of tachykinins. Anesthetized guinea pigs were pretreated with propranolol and atropine to block the beta-adrenergic and cholinergic responses and with mepyramine and cimetidine to block histamine H1- and H2-receptors, respectively. Vagal stimulation significantly increased leakage of dye in trachea (Tr), main bronchi (MB), and central (cIPA) and peripheral intrapulmonary airways (pIPA). The selective H3-receptor agonist (R)-alpha-methylhistamine (alpha-MeHA, 0.3-3 mg/kg iv) did not alter basal leakage but inhibited NANC-mediated leakage in a dose-dependent manner with a maximal inhibition of 56.9 (Tr, P less than 0.01), 66.7 (MB, P less than 0.01), 67.5 (cIPA, P less than 0.01), and 58.2% (pIPA, P less than 0.05) at 1 mg/kg. Pretreatment with phentolamine (2.5 mg/kg iv) had no effect on the inhibitory response produced by alpha-MeHA, but the H3-receptor antagonist thioperamide (5 mg/kg ip) blocked its effect. Exogenous substance P (1 microgram/kg iv) caused comparable plasma leakage to NANC-mediated response but was not inhibited by alpha-MeHA. We conclude that H3-agonists inhibit neurogenic leakage by prejunctional inhibition of neuropeptide release from airway sensory nerves.

Histamine H3-receptors inhibit neurogenic microvascular leakage in airways

Heterotopic tracheal allografts in small rodents have been shown to share many characteristics with the development of obliterative bronchiolitis (OB) in the clinic and therefore provide a suitable animal model for the study of OB. The model facilitates the examination of the pathogenesis of the disease and the elucidation of the cellular and molecular mechanisms involved in its development. The model provides a less technically demanding alternative to whole lung transplantation in small rodents and should lead to a speedier identification of new treatments that might prevent the development of post-transplantation OB in the clinic.

/pdf/the-heterotopic-tracheal-allograft-as-an-animal-model-of-b2oijfqobo.pdf

The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis

Modulation of the TRPV4 ion channel as a therapeutic target for disease

New Glucocorticosteroids with an Improved Therapeutic Ratio

Background 
Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory airway disease often associated with cigarette smoke (CS) exposure. The disease is increasing in global prevalence and there is no effective therapy. A major step forward would be to understand the disease pathogenesis. The ATP-P2X7 pathway plays a dominant role in murine models of CS induced airway inflammation, and markers of activation of this axis are upregulated in patients with COPD. This strongly suggests that the axis could be important in the pathogenesis of COPD. The aim of this study was to perform a detailed characterisation of the signalling pathway components involved in the CS-driven, P2X7 dependent airway inflammation.


Methods 
We used a murine model system, bioassays and a range of genetically modified mice to better understand this complex signalling pathway.


Results 
The inflammasome-associated proteins NALP3 and ASC, but not IPAF and AIM2, are required for CS-induced IL-1β/IL-18 release, but not IL-1α. This was associated with a partial decrease in lung tissue caspase 1 activity and BALF neutrophilia. Mice missing caspase 1/11 or caspase 11 had markedly attenuated levels of all three cytokines and neutrophilia. Finally the mechanism by which these inflammatory proteins are involved in the CS-induced neutrophilia appeared to be via the induction of proteins involved in neutrophil transmigration e.g. E-Selectin.


Conclusion 
This data indicates a key role for the P2X7-NALP3/ASC-caspase1/11-IL-1β/IL-18 axis in CS induced airway inflammation, highlighting this pathway as a possible therapeutic target for the treatment of COPD.

/pdf/role-of-the-inflammasome-caspase1-11-il-1-18-axis-in-3i4hsthdh4.pdf

Maria G. Belvisi

Papers

Histamine H3-receptors inhibit neurogenic microvascular leakage in airways

The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis

Modulation of the TRPV4 ion channel as a therapeutic target for disease

New Glucocorticosteroids with an Improved Therapeutic Ratio

Role of the Inflammasome-Caspase1/11-IL-1/18 Axis in Cigarette Smoke Driven Airway Inflammation: An Insight into the Pathogenesis of COPD