What is Emphysema?
Emphysema is characterized by destruction of gas exchanging airspaces, i.e. the respiratory bronchiol,alveolar ducts, and alveolai. Their walls become perforated and later obliterated with airspaces.1
Classifications
Emphysema is classified into distinct pathologic types, 1
1. Centriacinar emphysema.
2. Panacinar emphysema.
Centriacinar emphysema
The type most frequently associated with cigarette smoking is characterized by enlarged airspaces found (initially) in association with respiratory bronchioles. Centriacinar emphysema is most prominent in the upper lobe and superior segments of lower lobes and is often quite focal .1 ,2
Panacinar emphysema.
Panaicinar emphysema refers to abnormally large airspaces evenly distributed within and across acinar unites.Panacinar emphysema is usually observed in patients with Alpha-1-antitrypsin deficiency, with has a predilection for the lower lobes .1, 2

Pathogenesis of emphysema.
It is important to know pathogenesis in order to prevent, and having treatments.
The pathogenesis of emphysema can be dissected into three interrelated events,
1. Chronic exposure to cigarette smoke may lead to inflammatory cell recruitment within the lung,
2. Those inflammatory cells release electrolytic proteinases that damage the extracellular matrix of the lungs,
3. Ineffective repair of elastin and perhaps other extracellular matrix components results in pulmonary emphysema.2

Cigarette Smoking.
Cigarette smoking causes a number of changes to occur in the lung, many of which are still poorly understood. Among these are changes in the number and character of immune cells in the alveolar spaces and in the function and composition of pulmonary surfactant. The latter is becoming an increasingly significant issue given the abundance of recent findings that surfactant regulates immune cell function in the lungs.3
The most accepted theory for the pathogenesis of emphysema involves an imbalance between proteases and antiproteases.3
Historically, neutrophils and neutrophil proteaseshave been thought to play a major part in the development of this disease; however, evidence is emerging that macrophages also play an important role in the pathogenesis of smoking-related emphysema .4 Cells of the monocyte/macrophage lineage have the ability to secrete several members of the matrix metalloproteinase (MMP) family, including MMP-1 (collagenase 1), MMP-3 (stromelysin), MMP-7 (matrilysin), MMP-9 (gelatinase B), MMP-12 (macrophage metalloelastase), and MMP-14.5 It has been demonstrated that patients with emphysema and/or chronic obstructive pulmonary disorder (COPD) have elevated levels of MMP-9 and that alveolar macrophages were the major source of the MMP-9. 6, 7

Despite the fact that MMP-9 is also known as gelatinase B, it has been shown to have substantial elastolytic activity as well .Although most attention has been paid to the matrix degrading and remodeling functions of the MMPs, recent evidence suggests that they are also involved in the regulation of the inflammatory response and other biological processes.8,9
Surfactant protein A (SP-A) is a member of a family of C-type lections recently termed “collections” because of the presence of a caliginous domain. This molecule is the most abundant surfactant protein in the alveolar space and plays roles in the structure, metabolism, and function of surfactant. It is also an important regulator of local host defense mechanisms that make up the innate immune system .10
SP-A levels in the alveolar spaces are altered by a variety of factors and circumstances. 8 Among these are increased oxygen, ozone, and nitrogen dioxide .Often, these changes in SP-A levels are accompanied by changes in the levels of various surfactant lipids. SP-A modulates a number of immune cell functions, including cell proliferation, cytokine production, the expression of cell surface markers, and the generation of oxidative activity.11 SP-A may also participate in adaptive immune responses .The mechanism of action is still unclear, but it is possible that many of its functions may be mediated via cell surface receptors.9
Cigarette smoking accelerates the progression of emphysema in patients with AAT deficiency. Symptoms develop about 10 years earlier in AAT-deficient individuals who smoke regularly.

Nrf2-deficient mice are highly susceptible to cigarette smoke-induced emphysema.
Inflammation, protease/anti-protease imbalance and oxidative stress play important roles in the pathogenesis of emphysema.12 Nrf2 counteracts oxidative tissue damage and inflammation through transcriptional activation via the anti-oxidant responsive element (ARE).
To clarify the protective role of Nrf2 in the development of emphysema, the susceptibility of Nrf2-knockout mice to cigarette smoke induced emphysema was examined. In Nrf2-knockout mice, emphysema was first observed at 8 weeks and exacerbated by 16 weeks following Cigarette Smoke-exposure, whereas no pathological abnormalities were observed in wild-type mice. Neutrophilic lung inflammation and permeability lung damage were significantly enhanced in Nrf2-knockout mice 8 weeks after Cigarette Smoking exposure.12
Importantly, neutrophil elastase activity in bronchoalveolar lavage fluids was markedly higher in Nrf2-knockout mice preceding the pronounced neutrophil accumulation.12 The expression of secretory leukoprotease inhibitor, a potent inhibitor of neutrophil elastase, was inducible in wild-type, but not in Nrf2-knockout mice.
This protease/anti-protease imbalance, together with the lack of inducible expression of ARE-regulated anti-oxidant/anti-inflammatory genes, may explain the predisposition of Nrf2-knockout mice to neutrophilic inflammation. Indeed, specific activators of Nrf2 induced the expression of the SLPI gene in macrophages. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/ anti-oxidant balance, but also inflammation and the protease/anti-protease balance.12

Lung histology and quantification of emphysema
The trachea and lung of terminally anesthetized mice were removed and inflated with 4% paraformaldehyde in PBS to a pressure of 25 cm H2O. The tissues were then embedded in paraffin was stained with hematoxylin and eosin. Air space enlargement was quantified by the mean linear intercept in 20 randomly selected fields of tissue sections. The density of the alveolar surface area per unit volume of lung parenchyma was also calculated as previously described.10, 12
Bronchoalveolar lavage (BAL)
The lungs of terminally anesthetized mice were lavaged with six sequential 1 mL aliquots of PBS. The supernatant of the first BAL was used for determining the albumin concentration.The NE activity of the supernatant was measured by spectrophotometry at 405 nm using the synthetic substrate N-methoxysuccinyl-Ala-Ala- Pro-Val-paranitroanilide .13The remaining pool of BAL was centrifuged and resuspended in PBS. Cells were counted using a hemocytometer and a differential cell count was performed by standard light microscopy based on staining.12
Lung mechanics
Terminally anesthetized mice were tracheostomized and the trachea was cannulated. After opening the chest wall, the cannula was connected to a computer-controlled small animal ventilator.14 The compliance was determined by recording the relaxation pressures during inflation and deflation in 0.1 mL steps between 0 and 25 cm H2O.11 Due to variation in the weight of each animal, the lung volumes were normalized by body weight. Pressures from the normalized compliance curves were then extrapolated at 0.1 mL increments and used to establish the mean static lung compliance in each group.8,11

Measurement of alpha-1 anti-trypsin activity
The activity of alpha-1 anti-trypsin was calculated by determining the trypsin inhibitory capacity against bovine trypsin in the serum as previously described.15

Discussion
In the present study, mice lacking Nrf2 developed overt emphysema within 16 weeks of Cigarette Smoke exposure, while wild-type Balb/c mice were resistant to Cigarette Smoke-induced emphysema. During the development of emphysema, NE activity in the BAL was significantly higher in Nrf2–/– mice. Furthermore, neutrophil accumulation in the BAL was increased, at least partly because of the decreased clearance of neutrophils. These results indicate that Nrf2 protects against the development of emphysema by regulating not only the oxidant/anti-oxidant balance, but also inflammation and the protease/anti-protease balance.12

What is alpha-1 antitrypsin deficiency emphysema?
Alpha-1 related emphysema is caused by an inherited lack of a protective protein called alpha-1 antitrypsin (AAT) that is produced by the liver.

In normal and healthy individuals, AAT protects the lungs from natural enzymes such as neutrophil elastase. Neutrophil elastase is an enzyme that normally serves a useful purpose in lung tissue , it digests damaged or aging cells and bacteria in order to provide for healing. However, once it is done digesting those proteins, it does not stop, and attacks the lung tissue. Alpha-1-antitrypsin, in sufficient amounts, will trap and destroy the neutrophil elastase before it has a chance to begin damaging the delicate lung tissue. Without enough AAT, the lung tissue continues to be destroyed.15
If allowed to progress, this form of emphysema becomes chronic and eventually fatal. Symptoms of alpha1-antitrypsin (AAT) deficiency emphysema are limited to the respiratory system.
The initial symptoms of AAT deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma. If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.Dyspnea is the symptom that eventually dominates AAT deficiency.
Similar to other forms of emphysema, the dyspnea of AAT deficiency is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.
Patients with AAT deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal AAT levels.17
Cigarette smoking accelerates the progression of emphysema in patients with AAT deficiency. Symptoms develop about 10 years earlier in AAT-deficient individuals who smoke regularly.
By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of AAT deficiency have been disappointing. Between 1968 and 2003 a significant improvement has not been noted in the average interval (approximately 8 y), although improvement has been shown in the AAT deficiency detection in older individuals.11

Physical:
No single physical sign confirms a diagnosis of AAT deficiency emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.
Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.
Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradox.
Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.
Patients with mild emphysema generally have no abnormal findings on physical examination.
Even moderate disease may be evident only when a complicating acute infection occurs.
Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease.
Mild-to-moderate disease is easily missed if the physician relies solely on physical findings.

Causes:
AAT deficiency is an uncommon medical problem. The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome.) Fortunately, not every individual with AAT deficiency develops clinically significant disease. 2,3
The major biochemical activity of the AAT molecule is inhibition of several neutrophil-derived proteases (e.g., trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as AAT deficiency, and doctors and patients often refer to those who are affected as “alphas.”12
Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus.
Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction.
In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. Individuals with the AAT genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema. 7, 9
Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation. Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease. Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.15
The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor locus.
Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 mol/L or 150-350 mg/dL).16
The most common form of AAT deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of AAT in these patients are about 3.4-7 mol/L, 10-15% of normal serum levels. Serum levels greater than 11 mol/L appear to be protective. Emphysema develops in most (but not all) individuals with serum levels less than 9 mol/L .
Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ AAT deficiency are 75-120 mg/dL.13
Patients with the null gene for AAT will not produce any AAT and are high risk for emphysema (100% by the age of 30 y). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of AAT in the hepatocytes. The null gene is the least common of the known alleles associated with AAT deficiency.
Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.
People who have Alpha-1 antitrypsin deficiency will pass on one abnormal gene to their children, who will become “carriers” and will not have Alpha-1 unless they receive another abnormal gene from their other parent.12, 17

Who is most at risk?
It is estimated that there are 100,000 Americans today who were born with Alpha-1 antitrypsin deficiency.2 AAT related emphysema may afflict a majority of these individuals. However, AAT deficiency is often under diagnosed or misdiagnosed. As many as 3% of individuals with chronic obstructive pulmonary disease (COPD) may have undiagnosed Alpha-1 antitrypsin deficiency.3 If AAT deficient individuals also smoke, their risk of developing emphysema is greatly increased.18

AAT deficiency related emphysema can lead to liver diseases. The most serious liver disease are cirrhosis and liver cancer.4

Worldwide, it is estimated that 116 million people (25 million Americans) are carriers of the disease.5 The World Health Organization (WHO), The American Thoracic Society (ATS) and the European Respiratory Society (ERS) recommends that all individuals with COPD, as well as adults and adolescents with asthma (an estimated 20 million Americans) be tested for AAT deficiency or Alpha-1.11

How does emphysema develop?
While there are different causes of emphysema (such as smoking and Alpha-1 antitrypsin deficiency), the physical signs and symptoms in each case are similar.

Emphysema begins with the destruction of alveoli, small sac-like structures (resembling bunches of grapes) in the lungs where oxygen from the air is exchanged for carbon dioxide in the blood. The walls of the alveoli are thin and fragile, and are easily damaged.2,3

The damage is irreversible and results in permanent “holes” in the tissues of the lower lungs. As alveoli are destroyed, the lungs are able to transfer less and less oxygen to the bloodstream, causing shortness of breathe during exercise and eventually even at rest.3

The lungs also lose their elasticity, so the patient experiences great difficulty exhaling. The bronchial tubes leading to the air sacs may collapse, which traps air in the lungs. This is the condition known as emphysema.11
What are the signs and symptoms?
The onset of Alpha-1 related emphysema symptoms often appear between ages 32 and 41 but may appear later. The most common signs and symptoms of the disease are:

* Shortness of breath
* Wheezing
* Chronic cough and sputum (phlegm) production (chronic bronchitis)
* Recurring chest colds
* Eyes and skin turning yellow (jaundice)
* Swelling of the abdomen or legs
* Decrease exercise tolerance
* Non-responsive asthma or year-round allergies
* Unexplained liver problems or elevated liver enzymes
* Bronchiectasis. 8

The early age at which the disease is present and the fact that the disease most frequently appears in the lower rather than the upper lung regions helps distinguish Alpha-1-related emphysema from other types of emphysema.

How is alpha-1 related emphysema treated?
In December 1987, the first specific treatment for Alpha-1 related emphysema was approved. Replacement therapy (also called augmentation therapy) raises the level of AAT in the blood and provides the lungs with a protective shield against neutrophil elastase, the destructive enzyme.18

The replacement therapy is derived from human plasma that has been screened and tested for viral markers. During the manufacturing process the product is heat-treated to minimize the risk of viral transmission.

Therapy must be taken throughout a patient’s life for its protective effect. If a patient chooses to stop therapy, his or her lungs will return to the prior imbalanced state of neutrophil elastase and AAT.

Replacement therapy is intended only for AAT deficient patients who have begun to show symptoms of emphysema. It is not recommended for those without AAT deficiency who develop emphysema as a result of cigarette smoking or other environmental factors.

While replacement therapy does not cure Alpha-1 related emphysema, it does appear to slow the progression of this disease.
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