DOES MITOCHONDRIA-TARGETED HYDROGEN SULFIDE PREVENT AND/OR REVERSE CIGARETTE SMOKE-INDUCED LUNG INJURY? IMPLICATIONS FOR COPD.

Lead Research Organisation: University of Exeter
Department Name: Institute of Biomed & Clinical Science

Abstract

Chronic obstructive pulmonary disease (COPD) is a long term disease affecting the lungs that gets worse over time (i.e. it is a 'progressive disease') and it is irreversible. There are no effective treatments that halt the progression of COPD or reverse the disease. COPD is characterised by extensive inflammation in the airways leading to, and within the lungs and results in long term breathing problems such as persistent shortness of breath due to poor airflow in and around the lungs, and the build-up of mucus in the airways. In 2015 COPD was responsible for ~ 3.17 million deaths worldwide (5% of all deaths globally that year). In the UK, almost 1.2 million people (~2% of the population; 4.5% of all people >40 yrs old) are living with COPD making it the second most common lung disease, after asthma (see Impact Summary). In 2014, the direct costs of lung diseases to the NHS alone was £9.9 billion and when days off work, nursing costs, specialist care costs are included, this figure rises to £154.2 billion of which £46.6 billion (29%) is due to attributed to COPD. This represents a significant cost to family and society e.g. time off work as the disease progresses, disability allowances, and care for individuals (healthcare services and family). Due to the persistent inflammatory nature of COPD, patients also have a 6 fold greater chance of developing lung cancer, greatly adding to stress and anxiety to the patient and their families and carers.

The major risk factor in the development of this disease in Western countries is mainstream or second hand cigarette smoke (CS) with ~ 80% of all COPD deaths linked to this cause. CS exposure not only causes inflammation, it damages cells in the lung that can regulate inflammatory processes (e.g. macrophages). Specifically, CS damages a specific part of these cells (the mitochondria) that control 'energy production' (in the form of ATP). Normally energy production in cells is tightly controlled and highly efficient but n mitochondria are damaged, metabolic fuel (e.g. from food) is wasted and mitochondria become leaky and cause a build up of highly toxic "free radicals" which exacerbate inflammation and need to be removed from the body (or prevented from forming). We have also found that CS depletes macrophages and mitochondria of a newly identified anti-inflammatory molecule usually found in our body and used by mitochondria as an "emergency fuel" source when cells become stressed. This molecule is called hydrogen sulfide (H2S). We have therefore made novel compounds (called mtH2SD) which specifically target mitochondria within cells and deliver tiny doses of H2S. Our preliminary studies have shown these compounds can rescue mitochondria (and macrophages) from CS-induced damage in isolated cells and prevent CS-induced inflammation, lung damage and improve lung function in mice (e.g. mtH2SD stopped CS-induced COPD) and critically, prevented CS-induced destruction of the tiny air sacs in our lungs (mtH2SD prevented emphysema).

Using a series of novel mtH2SD we have made, isolated cell experiments and experiments using unique mouse models of experimental COPD, we will look at how mtH2SD (a) prevent and (b) rescue the lung from the detrimental effects of CS exposure in COPD. We will also determine the best route to get the compounds to the lungs. We hope data from our project will lead to new and effective treatments for a serious and debilitating disease of rapidly growing global importance (i.e. COPD induced by CS exposure but also caused by air pollution in an increasingly industrialised and polluted planet).

Technical Summary

Chronic obstructive pulmonary disease (COPD) is a non-curable progressive chronic respiratory disease characterised by pulmonary inflammation in the peripheral airways and lung parenchyma that results in continual irreversible lung tissue damage and airflow limitation. The major risk factor in the development in COPD in Western countries is cigarette smoke (CS) with ~ 80% of all COPD deaths linked to this cause. Thus, interventions to prevent/reverse the damage to the lung caused by CS could offer a novel treatment option in COPD and related lung diseases. CS has very recently been shown to deplete lung levels of the newly identified endogenous anti-inflammatory and antioxidant molecule, hydrogen sulfide (H2S). We therefore propose that COPD is a condition of "H2S deficiency" and COPD progression can be prevented/suppressed or treated with mitochondria-targeted H2S. Our preliminary data show CS exposure to macrophages depleted cellular and mitochondrial H2S levels, and removal of endogenous H2S exacerbated CS-induced mitochondrial oxidant production and inflammasome activation/activity. These effects were attenuated by novel mitochondria-targeted H2S donors (mtH2SD) we have developed. We further determined the effect of mtH2SD in experimentally induced COPD (using CS exposure over 8 weeks) and show mtH2SD suppressed CS-induced inflammation and loss of lung function, and prevented alveolar destruction. Thus, we will synthesise novel mtH2SD which target mitochondria and generate H2S by different processes. We will examine their effects on CS-induced mitochondrial dysfunction and inflammasome activation/activity in human macrophages and elucidate the molecular mechanisms for these observations. We will then establish the efficacy of mtH2SD in unique in vivo CS-induced lung inflammation and CS-induced experimental COPD models. These studies will determine whether targeting H2S to mitochondria using mtH2SD prevent, suppress and/or reverse CS-induced lung injury in COPD.

Planned Impact

Our research has the potential to lead to the development of a new treatment for COPD and related chronic inflammatory lung diseases for which there is no effective cure or treatment and may have a positive impact on a number of important beneficiaries e.g.:
(1) In the longer term this work should benefit sufferers of COPD and their families. Current therapies (e.g. short and long acting bronchodilators, steroid inhalers) only treat disease symptoms rather than the underlying cause. MtH2SD may prevent/reverse lung damage in COPD and we anticipate these could be used as either a sole or adjunctive treatment.
(2) Healthcare professionals including physicians and respiratory specialist nurses will benefit from increased patient satisfaction and greater patient confidence since current therapies for COPD are limited.
(3) Society: COPD contributes to 3.17 million deaths worldwide each year with >90% occurring in low-to-middle income countries. In the UK, approximately 1.2 million people (~2% of the population; 4.5% of all people >40 yrs old) are living with diagnosed COPD making it the second most common lung disease, after asthma costing the NHS £46.6 billion annually; a significant cost to society e.g. time off work as the disease progresses, disability allowances, and care for individuals (healthcare services and family). Additionally, sufferers usually experience depression and anxiety and the cost of treating these associated conditions would be reduced.
(4) The NHS: Current therapies are expensive and limited.This cost could be significantly reduced as mitochondrial H2S donors are relatively cheap to produce. The development of a new therapy may also alter the way COPD (and related disorders) are managed e.g.if the progression of lung inflammation and COPD/emphysema can be prevented or slowed then routine screening, treatment and hospital costs would be less frequent. The development of COPD increases the risk of lung cancer by 6 fold. Preventing this would alo be of huge benefit to this common and devastating disease.
(5) Pharmaceutical industry: A widely used therapy to halt or even reverse the progression of COPD could generate considerable income for the pharmaceutical industry and may also generate interest in the therapeutic use of mtH2SD for other common conditions.
(6) The wider scientific community in the field of respiratory medicine/physiology, H2S and general pharmacology: This project will improve our understanding of the mechanisms involved in the development and progression of CS (and pollution)-induced COPD and a greater understanding of the biological function of H2S and targeting H2S to mitochondria. In the short term, this project will also have an impact on the scientific community through the advancement of methods to study the expanding field of H2S biology and pharmacology i.e. novel mtH2SDs. We have an established international track record of providing these, and other slow release H2S donors and controls, free of charge to national and international collaborators in a diverse range of projects.
(7) The Research Team: The project involves a wide range of scientific techniques (e.g. in vitro, in vivo, chemistry, cell biology, biochemistry, immunology, histology, physiology etc) in a rapidly growing and highly topical area of research. It will provide extensive and highly competitive training and experience and progress personal development and future employability for all involved.
(8) Public engagement: The potential to develop a new therapy for a debilitating and feared disease will engage public interest and raise awareness of the researchers themselves, UoE and the MRC.
(9) Our mtH2SDs may be translated in the mid-to-long term into therapeutic entities and/or commercially exploitable tools which will benefit the national economy. We currently have two patents granted on our H2S donors (WO2013045951 and WO2015185918 A1); with two more applications submitted (2017).

Publications

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Title novel compounds for sulfide research 
Description We have made available novel slow release and mitochondria targeted hydrogen sulfide donor molecules and their respective controls for collaborators and other researchers worldwide e.g. AP39, AP123, AP67, AP72, GYY4137 etc. New tools (2020): mitochondria-targeted hydrogen sulfide fluorophores and we are looking to patent additional molecules (not listed here for confidentiality) 
Type Of Material Technology assay or reagent 
Year Produced 2013 
Provided To Others? No  
Impact Slow release H2S releasing molecules for research purposes. We have made these available to collaborators and other researchers worldwide in related and unrelated fields (including for use in plants). Example publications are below (see CV for collaborations). Mitochondria-targeted hydrogen sulfide fluorophores will help researchers detect/measure mitochondrial H2S in their systems, in vivo and in vitro (also for use in plants).