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].

    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.

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].