Biochemistry, Pathology and Genetics of Pulmonary Emphysema (eBook)

Proceedings of an International Symposium Held in Sassari, Italy, 27-30 April 1980

J. Bignon, G. L. Scarpa (Herausgeber)

eBook Download: EPUB

2013 | 1. Auflage
428 Seiten
Elsevier Science (Verlag)
978-1-4831-5795-5 (ISBN)

Infos

Biochemistry, Pathology and Genetics of Pulmonary Emphysema documents the proceedings of an international symposium held in Sassari, Italy, 27-30 April 1980. Research on the origins of emphysema has acquired more importance than functional diagnostic studies. There are various hypotheses concerning the development of emphysema. Some cases of emphysema are linked to defects in metabolic functions of the vessels while others are linked to a disturbance in repair processes. The papers in this volume are organized into four sections. Section 1 contains studies on the pathology and biochemistry of lung connective tissue. Section 2 deals with animal models. Section 3 on proteases and antiproteases includes studies on the characteristics and identification of biological specimens, and alpha1-proteinase inhibitor. Section 4 takes up the risk factors and therapeutic approaches for lung disease. Other papers in the volume were presented during two roundtable discussions on the biochemistry of connective tissue components in emphysema and therapeutic approaches.

Textauszug

PATHOLOGICAL AND PATHOGENETIC ASPECTS OF CHRONIC OBSTRUCTIVE LUNG DISEASE

ASPECTS PATHOLOGIQUES ET PATHOGÉNÉTIQUES DES MALADIES PULMONAIRES OBSTRUCTIVES CHRONIQUES

J. Bignon and H. de Grémoux*

ABSTRACT

Elastase-induced emphysema mimics the histological and biochemical aspects of panlobular emphysema in humans. Experimental animal data such as these, and the association between α1-antiproteinase deficiency and emphysema, have led many investigators to postulate that this acquired, progressive disorder is the result of a chronic elastase-antielastase imbalance. Most of the recent studies on this problem have investigated the role played by cigarette smoke and other pollutants, since 1) those agents increase the recruitment of macrophages and neutrophils and the release of elastase within bronchiolar and alveolar structures, and 2) pollutants may inactivate α1-antiproteinase by an oxidative pathway. This elastinolytic injury does not result in a decrease in the elastin content of the lung because active resynthesis leads to the formation of a disorganized network of elastic fibres.

Animal models

antiprotease

chronic obstructive lung disease

emphysema

protease

During the past decade, it was demonstrated that two major conditions are responsible for the limitation of airflow in chronic obstructive lung disease : emphysema and small airway disease. In structural terms, emphysema is characterized by a permanent increase in the size of the alveolar spaces of the acinus, beyond the terminal bronchiole, which may or may not be accompanied by rupture of the alveolar wall [2, 14, 72]; small airway disease is characterized by narrowing or tortuosity of the peripheral bronchioles in relation to inflammatory hypertrophic or atrophic changes in the airway wall [5, 33]. These two lesions are usually associated, so that it is practically impossible to make an accurate diagnosis in living persons [72].

Of the exogenous agents (pollutants, microorganisms, allergens) that have been significantly associated with the development of airflow limitation (fig 1), those which are linked most closely to the pathogenesis of emphysema and small airway disease are inhaled pollutants, particularly tobacco smoke, and exacerbations of acute infectious bronchitis. There is, however, wide variations in individual response to these etiological agents, since only a small proportion of subjects develop the disease [20]. The source of these differences is probably the peripheral lung, the « black box », where airborne pollutants challenge the cells and macromolecules of the alveolar membrane, bronchiolar wall and circulating blood or interstitial fluid.

Fig. 1 Diagram summarizing the pathogenesis of chronic obstructive lung disease (COLD). CRI : childhood respiratory infection; ANTI P : antiproteinase; aat : α1-antiproteinase; a2m : α2-macroglobulin; b. inh. : low molecular weight bronchial inhibitor; p : proteinase.

Two biochemical events that may be associated with this condition have so far been investigated : 1) qualitative defects (congenital or acquired) in connective tissue synthesis, and 2) the protease-antiprotease imbalance. We will review briefly what is known and what still remains in the « black box » concerning how these molecular systems are involved in the pathogenesis of emphysema and small airway disease.

On the basis of experimental and human data, a number of pathogenetic hypotheses for pulmonary emphysema have been formulated [6]; only a few of them will be described, and it should be kept in mind that several factors can act together synergistically.

ANIMAL DATA

1. Emphysema has been induced in various species after intratracheal instillation or inhalation of various proteolytic enzymes from plants (papain) [27], bacteria (brinase, pronase) and mammalian cells (pancreatic and leucocytic elastases) [13, 29, 38]. Only elastolytic enzymes, mostly when instillated in the airways, are able to induce emphysema [74]; collagenase does not induce emphysema [44].

    A typical picture of panacinar emphysema is produced consistently in hamsters by a single injection of porcine pancreatic elastase [29]. The pathological events of the first few days are characterized by diffuse, acute, inflammatory intra-alveolar exudation of red blood cells and particularly of leukocytes, which is associated with disruption of the alveolar wall (fig. 2). This intra-alveolar attraction of leukocytes during the first days was confirmed by a study of bronchoalveolar lavage after inhalation of papain; this showed a marked rise in polymorphonuclear (PMN) leukocytes, peaking at 24 h, followed four days later by a progressive increase in the alveolar macrophage count [55]. The inflammatory changes diminish regularly over two to three weeks, leaving behind diffuse panacinar emphysema without cell infiltrate; pulmonary capacity and static compliance have been shown to increase up to the 26th week, indicating a slow progression of the emphysema [69].

Fig. 2 Early inflammatory reaction during the three days following an intratracheal instillation of porcine pancreatic elastase (0.2 µg ml) in the hamster.

    These pathological observations and the fact that emphysema can be produced in dogs with an aerosol of leukocyte homogenates [52] suggest that elastase- or papain-induced emphysema might develop in two steps : 1) there is an early inflammatory lung injury which is associated with the release of chemotactic factors; 2) subsequently, during the next few days, the leukocytes and macrophages attracted into the alveolar spaces might be responsible for an endogenous elastase release associated with the progressive development of emphysema. This hypothesis is still under controversy (see Ch. KUHN, this meeting, p. 127).

    The elastase-induced emphysema is, however, too aggressive a model : there is a need to develop animal models that mimic the human elastase-α1-antiproteinase (AP) imbalance, which associates an α1-AP defect (as obtained recently with chloramine-T [18] or D-galactosamine [8]) with a continuous alveolar release of elastase by leukocytes or alveolar macrophages.

    There is both structural and biochemical evidence that changes take place in elastic lung tissue in experimental emphysema induced by elastolytic enzymes : use of special stains for elastic tissue and light microscopy revealed disorganization or disappearance of elastic fibres in alveolar walls [29, 43], and electron microscopy showed destruction of the amorphous core of elastic fibres although the surrounding microfibrils were intact [39]. However, these early lesions appeared to have been repaired after two to four weeks; and, at this time, biochemical analysis showed no quantitative changes in the elastin content of the lung [41, 46] and a relative decrease only in non-polar amino acids of the amorphous core of elastin [51]. During the healing phase, after acute elastase-induced injury, active resynthesis of elastin has been demonstrated [25, 46].

2. Another model has been designed to investigate the role of genetic or acquired defects in elastin and collagen anabolism in emphysema. Administration of various drugs (D-penicillamine, β-lathyrogen) or a copper-deficient diet to experimental animals can induce defects in the cross-linkage of elastin and collagen fibres (fig. 3). In young rats, such treatments can induce emphysema [32, 61]. This model requires further development, since it could help in understanding the cellular and molecular mechanisms involved in the synthesis of lung connective tissue and their interaction with genetic (blotchy or skin-tight mouse) and/or toxic factors.

Fig. 3 Schematic representation of the synthesis of elastic fibers in order to indicate how lathyrogens and D-penicillamine can work to induce emphysema.

3. Many exogenous irritants have been used to induce pulmonary emphysema in animals [13]. Nitrogen oxide- [22] and cadmium- [68] induced emphysema are useful models for understanding the mechanisms leading to various inflammatory reactions, the release of protease and to emphysematous changes, which are not yet clearly understood.

4. There is no strong evidence that an acute, systemic lung injury occurring, for example, after intravenous injection of an endotoxin can lead to pulmonary emphysema; however, in one experiment, repetitive insults with intravenously administered endotoxin for nine consecutive weeks induced a marked sequestration of pulmonary leukocytes and a slight increase in the alveolar linear intercept [76].

HUMAN DATA

Many hypotheses have been suggested to explain the pathogenesis of human emphysema [6]. In this chapter, we will review the clinical, pathological, biochemical and...

Produkt-Details

• Erscheint lt. Verlag: 22.10.2013
• Sprache: englisch
• Themenwelt: Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie ► Krankheiten / Heilverfahren
• Themenwelt: Medizinische Fachgebiete ► Innere Medizin ► Pneumologie
• ISBN-10: 1-4831-5795-4 / 1483157954
• ISBN-13: 978-1-4831-5795-5 / 9781483157955