LUNG DISEASE

One of the most distressing symptoms that anyone can experience is shortness of breath-dyspnea. Patients describe themselves as `not getting enough air.' This triggers a series of physiological and behavioral reactions that include increased heart rate, blood pressure and hormonal secretions accompanied by a feeling of general panic. Shortness of breath is a common symptom of many respiratory illnesses.

Just as the gut separates and absorbs food into the body, the lungs are a passage for the exchange of used air and fresh air. But there's a crucial difference between food and oxygen-we can't store oxygen. We must meet a second-by-second demand for the life-giving element or die within minutes. The body responds immediately to any interference with this exchange.

Over 30 million Americans are affected by chronic lung disease. Dozens of illnesses can affect the respiratory system, and pulmonary (lung-related) medicine is vast and complicated. It deals with congenital problems like cystic fibrosis, acquired diseases like bronchitis and self-inflicted problems like smoking. The importance of GSH in the respiratory system cannot be overstated. We can't address every known respiratory problem but we will discuss a large number of common and not-so-common ailments, including: 

ANTIOXIDANTS AND THE LUNGS

As you will see in the following pages, inflammation of the lung is common to most pulmonary diseases, whether the disorder is acute-like toxic exposure-or chronic-like cystic fibrosis. The processes of infection in asthma, bronchitis or pneumonia all lead to inflammation. Many traditional medications attempt to reduce this inflammation. The body's inflammatory response itself generates free radicals, and antioxidants are increasingly used to complement conventional treatments. The researchers PE. Morris and G.R. Bernard drew attention to this complementary treatment in an article aptly called "Significance of glutathione in lung disease and implications for therapy," in which they reviewed the great weight of evidence that supports such research. There is a fragile balance in the lungs between oxidants and antioxidants.

Oxidative stress is high in the lungs for many reasons. For a start, this center of oxygen interchange produces very large numbers of oxyradicals. Secondly, white blood cells are highly active in the lining of the lungs, where they release huge quantities of oxidative products, both because of their high metabolic rates and the way they combat biological and chemical invaders. Finally, antioxidants in the fluid lining of the lungs play a large part in our front-line defense against airborne pollutants, many of which are powerful sources of free radicals.

When white blood cells encounter, for example, a bacteria, they release caustic substances like peroxides. This is biochemical warfare, and the white blood cell and the surrounding tissues use GSH to defend themselves. When oxidant levels grow too high or GSH levels too low, the inevitable result is tissue damage. Remember that GSH is the most critical of all naturallyoccurring antioxidants (see chapter r) and that it effectively supports exogenous antioxidants such as vitamins C and E. Unlike glutathione, exogenous antioxidants are derived from the outside environment and are not native to the body, but together they soak up free radicals.

Generally, most tissues and organs must manufacture their own glutathione from dietary or drug-delivered precursors. However, the lining of the respiratory tree- which usually requires high levels of GSH-can absorb GSH directly. To take advantage of this unusual ability, a topical GSH aerosol has been developed and used successfully to treat a number of diseases, including adult respiratory distress syndrome (ARDS), pulmonary fibrosis and HIV infection. In addition, the topical form of NAC (Mucomist)-a potent GSH precursor-has long been used as a treatment for cystic fibrosis.

Oral and intravenous GSH precursors are receiving a lot of attention from researchers and many papers have been published on the subject. Pulmonologists (lung doctors) are paying increasing attention to lung GSH content and learning a great deal about future applications. O. Ortolani and his team in Italy placed forty intensive care patients with respiratory difficulties on intravenous GSH, then compared their response to an equal number of untreated patients and found significant reductions in oxidative stress levels.

An experiment in preventive medicine was conducted by S. De Flora and his research team at the Institute of Hygiene and Preventive Medicine, University of Genoa. Patients were placed on a course of oral NAC tablets or placebo during the months of the influenza season. Although the number of people infected by the virus was unchanged, subjects receiving NAC experienced significantly fewer and less virulent symptoms.

ASTHMA

Bronchial asthma causes constriction of the bronchioles (airway passages).  Asthma is always unpleasant and sometimes even fatal. The intensity of asthma attacks vary, but all are characterized by a feeling of tightness in the chest, shortness of breath, restlessness, coughing and wheezing. Although asthma is reversible and intermittent, it tends to recur and is generally considered a chronic condition. It is one of the most common causes of absenteeism and hospital admission in school-age children, among whom it is most prevalent. It currently affects about IS million Americans and is on the rise.

Asthma is variable in frequency and severity and can be triggered by a very wide variety of stimuli, including allergens (things that provoke an allergic response). These include dust, pollen, dander (tiny particles of animal skin, fur and feather), certain foods and drugs, viral infections, emotional stress, anxiety and even plain old exercise. Muscles within the walls of the bronchioles flex and go into spasm, the walls thicken, air passages become clogged by mucus, and air is trapped in the deepest airways (the alveoli). The wheezing sound is caused by air passing with difficulty through these narrowed passages. In its severest form, breathing becomes impossible and the patient suffocates.

Asthma sufferers should make an effort to identify and avoid the triggers that cause their attacks, whether allergic, infectious, toxic, or emotional. They can also take preventative medications-antihistamines and sodium cromoglycate. These minimize the effects of the allergic response. Once an attack is in progress other drugs are needed to reopen (dilate) the walls of 

the bronchioles. These are called bronchodilators and are commonly used in inhalers such as salbutemol or albuterol. Inhaled or ingested steroids are also available. They minimize the swelling and inflammation of the bronchial walls. In any case, once an attack has begun, treatment must be immediate and aggressive. The longer an attack lasts, the more the symptoms advance and the longer they take to reverse. There is little time to waste.

It has been long thought that low levels of glutathione and glutathione peroxidase levels play a role in the onset and progression of asthma. Numerous studies in asthmatics have identified such abnormalities in their red-blood GSH, white-blood cell GSH, serum GSH, platelet GSH and lung-fluid GSH. There is a direct correspondence between low glutathione levels and the severity of the asthma attack.

Dietary, environmental, and genetic factors that diminish the potency of the antioxidant systems in the lung increase the risk of asthma. This relationship between antioxidant levels and asthma is seen in situations of elevated free-radical activity. Examples are lead poisoning, excessive iron stores and G6PD-deficiency, as well as low levels of vitamin C, vitamin E, and selenium (a component of glutathione peroxidase).

The pulmonologist Dr. Carol Trenga recently presented to the American Lung Association an antioxidant cocktail that helped asthmatics particularly sensitive to air pollutants. European physicians have long used GSH precursors in the treatment of asthma, particularly as a mucolytic (phlegm thinner) to break down thick secretions. In a double-blind study, inhaled bronchodilators were tested with and without NAC. The NAC (GSH-enhanced) group experienced greater improvement in lung function than the control group.

BRONCHITIS, EMPHYSEMA, AND COPD

Bronchitis is an inflammation or obstruction of the bronchi, the larger airways that eventually branch out to become the bronchioles (the site of asthma). It resembles asthma in some ways, their common symptoms being shortness of breath, a phlegm-producing cough, chest discomfort and occasional wheezing. Bronchitis has two distinct forms-acute or chronic. They differ in important ways.

Acute bronchitis is almost always caused by infection, either viral or bacterial. Coughing, chest pains, fever and chills are common complaints. In the healthy individual, it is usually a short-lived illness that clears up once the infection is overcome. If the infection is bacterial or mycoplasmal, antibiotics may be required. Occasionally, some inflammation remains, leading to a post-inflammatory cough that may persist for weeks. Inhaled steroids are often prescribed for this condition.

Like emphysema (described below), chronic bronchitis is an ongoing illness requiring frequent medical attention. Although it may be exacerbated by infectious disease, chronic bronchitis is usually caused by long-term exposure to lung irritants-toxins, allergens or repeated bouts of acute bronchitis. The most common cause of chronic bronchitis is cigarette smoke.

Lungs exposed to tobacco smoke are subject to several pathological processes. One of the most critical is the dysfunction or loss of cilia lining the airways. Cilia are microscopic hair-like structures that trap and remove dust, mucus and other debris. A single puff of a cigarette can paralyze these hairs, increasing the chances of subsequent lung injury and infection.

As chronic bronchitis progresses. the lung's ability to exchange oxygen and carbon dioxide diminishes. In an attempt to compensate for the loss of pulmonary function, energy demands increase, the chest muscles work harder and the heart pumps faster. This in turn can lead to secondary diseases such as pulmonary hypertension, heart failure and emphysema.

Emphysema progresses slowly over time and is usually the result of prior lung disease. Chronic cough and shortness of breath are typical symptoms. Although it may occasionally be caused by hereditary factors, environmental exposures, chronic asthma or chronic bronchitis, emphysema most often results from years of heavy smoking. It is the most common cause of death from respiratory disease in North America.

Emphysema shares many symptoms with chronic bronchitis. In fact, the two diseases usually overlap to some degree. They are often classed together under the heading COPD (chronic obstructive pulmonary disease). However, they differ anatomically. Emphysema results in irreversible damage to alveoli-tiny sac-like structures where the actual exchange of oxygen and carbon dioxide occurs. Alveoli are counted in the millions, like bubbles in a bubble bath. Emphysema causes them to burst one by one. They then coalesce into fewer, larger sacs. As a result, their total surface area dwindles, 

decreasing the amount of air that can be exchanged by each breath.

It is well known that most lung diseases are characterized by weak antioxidant activity and impaired glutathione-related enzyme systems. Taking advantage of this information, a group of French researchers tested to see whether GSH screening could predict a predisposition to pulmonary diseases. They tested subjects for the absence of a gene (GSTM 1) responsible for a specific GSH enzyme. About 47% of the French population lacks this gene. They found that heavy smokers with moderate chronic bronchitis were missing this gene 66% of the time and that smokers with severe chronic bronchitis were deficient in 71% of cases. They concluded that factors diminishing GSH function-in this case a hereditary factor-put individuals at higher risk for respiratory problems.

Other studies determined that COPD patients were very sensitive to low GSH levels after even light exercise, demonstrating the precarious balance of glutathione in these patients and the great importance of maintaining adequate stores of GSH.

N.C. Hansen and his team at Odense University in Denmark conducted a double-blind study of the general well-being of patients with mild chronic bronchitis. They gave them oral NAC during the winter months, and placebo to a similar group. Of the two groups, the GSH-enhanced group did much better on a GHQ (general health questionnaire). Several other research teams have studied the use of oral NAC as a preventative measure. Although it didn't significantly reduce the number of chronic bronchitis attacks, their severity-measured by symptoms and days off work-was greatly reduced.

In a large open study of over two thousand patients, K.P. Volkl and B. Schneider from Hanover Medical School in Germany showed that the use of NAC led to clear improvements in symptoms and pulmonary function. The four-week study included patients with acute and chronic bronchitis, bronchial asthma and emphysema. All groups had similar improvement in their disease.

SMOKING AND GSH

There is no longer any doubt that cigarette smoking is a major risk factor for chronic bronchitis, emphysema, COPD, cancer and cardiovascular disease. One of the ways in which cigarette smoke damages the body is by profoundly raising the extent of oxidative stress in the lungs.

A single puff of cigarette smoke contains billions of free radicals and can literally "burn up" antioxidants. But this isn't the worst of it. A still greater source of oxidative stress results from the lung inflammation resulting from smoking. The total oxidative damage caused by smoke corresponds directly to the degree of lung injury, respiratory compromise, morbidity and mortality found in individual patients.

Pharmacologists are investigating the use of inhaled GSH to prevent the onset or progression of emphysema in smokers. As a GSH precursor, NAC is receiving equal attention. Double blind studies in smokers using NAC demonstrate the enhanced ability of their lungs to clear away thick secretions in their airways.

R.B. Balansky at the Institute of Hygiene and Preventive Medicine in Italy exposed rats to high levels of cigarette smoke. This led to decreased body weight, intense pathological damage of the terminal airways, inflammation of the bronchial and bronchiolar linings, alveolar damage, emphysema, white blood cell abnormalities and pre-cancerous lesions. Rats given daily NAC at the same time suffered significantly less damage, demonstrating the protective role of GSH against lung damage and the onset of cancer.

Smokers are also more prone to the development of infectious bronchitis and pneumonia. Chronic bronchitis in smokers results in increased bacterial colonization. Treatment with NAC has decreased both the frequency of infectious episodes and the virulence of the bacteria.

ADULT RESPIRATORY DISTRESS SYNDROME (ARDS)

ARDS is acute, life-threatening respiratory failure following pulmonary injury. It leads to profound dyspnea (shortness of breath), pulmonary edema (fluid accumulation in the lungs) and hypoxemia (oxygen starvation). This all-too-common medical emergency is caused by a number of different acute processes that directly or indirectly damage the lung. They include bacterial or viral pneumonias, inhalation of stomach contents or other toxins, direct trauma to the chest, sepsis (overwhelming generalized infection), profound circulatory shock, drowning and many other medical conditions. Even with appropriate therapy the survival rate is only about So%. Long-term complications include the eventual development of pulmonary fibrosis.

ARDS is a very complicated inflammatory process of which edema is only one facet. In the past, physicians treated this disorder aggressively with corticosteroids, because of their well-known anti-inflammatory properties. Unfortunately, randomized trials have shown that steroids are relatively ineffective against this disease. A hunt is on for useful treatments.

For several reasons, ARDS patients experience high levels of oxidative stress and subsequent depletion of antioxidants and glutathione. One cause may be the release of free radicals at the injury site by endotoxins. Endotoxins are produced by certain bacteria, though only released when the bacteria die. However, most of this oxidative stress probably comes from inflammation. Some white blood cells (neutrophils) are very active at sites of inflammation, producing very large amounts of reactive oxygen species, such as free oxygen radicals, hydrogen peroxide, `hot' oxygen, and others.

Recognizing the severe oxidant-antioxidant imbalance and GSH depletion that comes with this condition, many researchers have put NAC under the spotlight. G.R. Bernard and his team at Vanderbilt University tested the usefulness of intravenous NAC for the lungs. Both in the lab and in clinical trials they found increased oxygen delivery, improved lung compliance (elasticity) and an improvement in the condition of pulmonary edema patients. Trials with another GSH precursor-OTZ (Procysteine)-led to similar results and reduced the duration of lung injury.

In a larger double-blind study, PM. Suter's group at the University of Geneva used intravenous NAC on intensive care patients. Compared to a control group, the NAC patients showed significant improvement in oxygenation and required less time on mechanical ventilators (life support).

PULMONARY FIBROSIS

Pulmonary fibrosis is called fibrosing alveolitis or interstitial fibrosis, among other things. It is a non-specific condition in which the lungs respond to damage by the production of scar tissue (fibrosis). This leads to stiffness of the lungs and difficulties clearing secretions. It also interferes with gas exchange. Its causes include numerous bacterial, viral or fungal infections and inhaled toxins, dusts (organic and inorganic) and chemicals. Occasionally stomach contents can be inhaled to the detriment of the lungs. Other diseases are involved less often, such as certain autoimmune disorders (mistaken immune response to healthy processes), sarcoidosis (a multi-system inflammatory disorder), or collagen-vascular diseases (rheumatoid arthritis, lupus, polyarteritis nodosa, scleroderma and dermatomytosis). This disease is often an unwanted result of radiation therapy or chemotherapy. The standard treatments have limited success.

Oxidative stress plays an important role in the causes and conditions of many types of pulmonary fibrosis. J. Behr and his group of pulmonologists from the University of Munich studied this phenomenon both in laboratory cultures and in pulmonary fibrosis patients. Because pulmonary fibrosis is an inflammatory disorder, their treatment includes therapy to suppress the immune inflammatory response. With the help of NAC, patients' pulmonary function tests improved and the number of oxidative breakdown products fell. By using aerosolized NAC, Z. Borok from the NIH (National Institute of Health) reversed the oxidant-antioxidant imbalance in pulmonary fibrosis patients. Both NAC and aerosol GSH have shown success in this situation. Clearly, both oral and inhaled NAC can successfully raise pulmonary GSH levels.

In pulmonary fibrosis, fibroblasts-cells in part responsible for the fibrous scar tissue-grow excessively in both number and activity. Tissue cultures

made of these cells revealed that the presence of GSH down-regulated their growth, implying that GSH may slow the progress of pulmonary fibrosis.

CASE STUDY

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