Understanding chronic inflammatory lung diseases through molecular biology

Figure 1. Smoke damages the cell function on several levels, directly and indirectly. Long term damage of smoke off sets the balance of central cell regulating signal pathways (NFkB, mTor) and leads to inflammation and remodelling

Chronic inflammatory lung diseases are the most frequent non-communicable diseases worldwide. Currently, there are over 450 million people who suffer from either asthma, COPD (smoker’s lung) or fibrotic lung disorders.

The cause of the increasing incidences of asthma, COPD and fibrosis is largely unknown and cannot be well explained with our current available knowledge. In this issue, our focus will be on COPD.

The World Health Organization (WHO) estimated that currently 65 million people suffer from COPD causing 3 million premature deaths per year. Earlier studies indicated that the percentage of male COPD patients is larger than that of females, but this gender difference disappeared over the last decade.

The term COPD does not describe a single disease, but summarises chronic lung diseases causing airflow limitation. Patients who suffer from COPD describe symptoms as breathlessness, shortage of air, increase sputum production and frequent cough. It was assumed that COPD is mainly caused by tobacco smoking, but recent investigations provided evidence that poor quality of air (indoor and outdoor) or occupational exposure to fume, dust or vapour can lead to COPD. It was surprising for me to learn that the rate of COPD in countries like Nepal and Bangladesh are as high as in the European countries or the USA. In these countries, the major cause of COPD is the combination of cooking on opened fire, badly ventilated houses and tobacco smoking.

The disease affects more women than men and leads to premature death for those who are responsible for bringing up the family. Unfortunately, in these less developed countries, COPD is a major problem in rural areas, is largely under diagnosed and treatment starts most often far too late. Furthermore, medication is unaffordable for most of these COPD patients and relies on help from charity.

The dangers of COPD

COPD is an untreatable deadly disease, which cannot be stopped even by cessation of tobacco smoking. The damage done to the lung seems to be un-repairable and the available therapies only allow symptom control and slowing down the progress of the disease. Three classes of drugs are used for the therapy of COPD, including inhaled glucocorticoids, long acting β2-receptor agonists and muscarinic receptor antagonists. The effect of the drugs is a reduction of inflammation and relaxing of constricted airway tissues. However, there is no lasting effect on the pathological changes of the airway wall structure. The major reason for the lack of curative drugs for COPD is the fact that we do not understand the causative events that initiate the pathogenesis of the disease.

The question is: Why do we not understand the causes of COPD? Focusing on tobacco smoke, it may seem to be easy to find what it does to our lungs. However, the composition of tobacco smoke varies, which is the result of different formulas used during the production of tobacco products. In an average cigarette, its smoke contains up to 2,000 different chemicals, including polycyclic aromatic hydrocarbons, nitrosamines, oxides, phenols, amines, alkaloids, toluenes, benzenes, and aldehydes. The content of these toxins can be partially reduced by filter, but a large number of them are still inhaled into the airways. Thousands of studies investigated the effect of the single component on the lung in animal models or in isolated cell lines and described toxicology and pathophysiologies, which can contribute to the development of COPD. The problem with tobacco smoke is its composition, which may not be the sum of the effects caused by any individual component (Figure 1). Therefore, blocking or removing specific compounds from cigarette smoke did not reduce its overall effect on the lung. It can be doubted that the analysis of a single component of tobacco smoke will help to understand the damaging effect of smoking, and its removal is a useful strategy to prevent COPD.

As surprising as it sounds, tobacco smoking has been advised to relax the contraction of lung muscles in the early 20th Century and there are recent publications reporting beneficial anti-inflammatory effects from tobacco smoking on lung inflammation. However, these may be short lasting effects after a few cigarettes, while regular exposure to smoke results in malfunction of the lung.

The effects of smoke on the body

The first victim of smoke inhalation is the epithelial cells, which lines the bronchus wall and forms a barrier between inhaled air and the lung tissues. Smoke disrupts this barrier function on different levels: (i) The “tight junction” between epithelial cells becomes leaky and thereby smoke particles, viruses and bacteria can penetrate the bronchial wall and lead to local inflammation. (ii) Epithelial cells produce oxygen radicals to counteract the effect of smoke or ashes, which also stimulates local inflammation. (iii) Some chemicals contained in smoke can damage the genetic information (DNA) or the power house of the cells (mitochondria).

The balance of tissue building and tissue degrading enzymes is assumed to play an important part in the development of COPD. At early stages of the disease tissue degrading enzymes seem to be less active and lead to increased bronchial wall thickness, while at later stages the tissue degrading enzymes are more active and disrupt the structure of the peripheral lung. It is difficult to judge which of these damages caused by smoke are the most important and therefore, it is difficult to design a therapy for COPD. Most likely different stages of the disease need different therapies, but there is a lack of diagnostic methods, that allow to clearly define the stages of COPD.

In regards to molecular biology, recent studies indicated that smoke activates the same pro-inflammatory cellular signalling pathways that have been described for dust, allergens, or chemicals. A major focus of these new studies of tobacco smoke effects was on signalling, they revealed that a central part of cell responses was mediated via NFκB and IP3-Akt-mTOR proteins. Both signalling pathways are well studied, and their endpoints are inflammation and tissue remodelling. Unfortunately, these two pathways are also essential to maintain our body’s function. The major problem is to find drugs to re-establish the balance of such cellular signalling proteins in pathological conditions. Future drugs should have properties comparable to a steroid, which exerts its action only over a very short period of time (hours). Such limited duration of the drug will enable our bodies to adapt. Nevertheless, there is no such drug candidate in the pipeline of any pharmaceutical company.

Furthermore, it has to be recognised that not all smokers develop COPD and epidemiologic and genetic studies indicated that there may be a genetic pre-disposition for CODP. New studies provided data suggesting that epi-genetic events (modification of gene activity that is independent of the genetic information) can be activated by smoke. The lung’s tissue seems to be especially sensitive to such epi-genetic regulatory events during late pregnancy and early childhood. The question of why some people are more sensitive to such epi-genetic regulation than others remains to be answered by future investigations.

This situation can only be improved if sufficient funding is made available to independent researchers, who will go back to the basis and study what happens to the tissue of the human lung when it is exposed to smoke.

Special Report Author Details
Author: Prof. Dr. Michael Roth
Organisation: University Hospital Basel
Telephone: +41 (0) 61 265 2337
Email: Michael.Roth@usb.ch
Website: Visit Website
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