Interstitial Lung Disease Due to Inhaled Organic Dusts

awareness of risk factors associated with adverse drug reactions improves. There is little information currently available that indicates why specific individuals are susceptible to a given toxic reaction; however, as our undentanding of the mechanism of drug-induced lung disease improves, it is likely that insight will be gained into this challenging problem of individual susceptibility Furthermore, as mechanisms are better delineated, it is likely that both our diagnostic and therapeutic approaches to these patients will improve, resulting in earlier diagnosis and more timely therapeutic intervention.

18

19 20

21

REFERENCES 1 Rosenow EC III, Martin WJ II. Drug-induced interstitial lung disease. In: Schwarz MA, King TE, eds, Interstitial lung disease. Philadelphia: BC Decker, 1986; 123-37 2 Van Barneveld PWC, Van der Mark ~ Sleijfer DT, Mulder NH, Schraffordt Koops H, Sluiter HJ, et ale Predictive factors for bleomycin-induced pneumonitis. Am Rev Respir Dis 1984; 130:1078-81 3 Lown ~ Sim SK. The mechanism of the bleomycin-induced cleavage of DNA. Biochem Biophys Res Commun 1977; 77: 1150-57 4 Sausville EA, Reisach J, Horwitz SB. Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Biochemistry 1978; 17:2740-46 5 Solaiman D, Rao EA, Petering DH, Sealy RC, Antholine WE. Chemical, biochemical and cellular properties of copper and iron bleomycins. Int J Radiat Oncol Bioi Phys 1979: 7:1519-21 6 BurgerRM, KentTA, HowitzSB, MunckE, PeisachJ. Mossbaur study of iron bleomycin and its activation intermediates. J Bioi Chem 1983; 258:1559-64 7 Halckinen PJ, Whiteley ~ Witschi HR. Hyperoxia, but not thoracic X-irradiation, potentiates bleomycin- and cyclophosphamide-induced lung damage in mice. Am Rev Respir Dis 1982; 126:281-85 8 Tryka AF, Skornik WA, Godleski JJ, Brain JD. Potentiation of bleomycin-induced lung injury by exposure to 70% oxygen. Am Rev Respir Dis 1982; 126:1074-79 9 Berend N. Protective effects of hypoxia on bleomycin lung toxicity in the rat. Am Rev Respir Dis 1984; 130:307-8 10 Chandler DB, Barton JC, Briggs DD III, Butler ~ Kennedy JI, Grizzle WE, et ale Effect of iron deficiency on bleomycininduced lung fibrosis in the hamster. Am Rev Respir Dis 1988; 137:85-89 11 Chandler DB, Fulmer JD. The effect of deferoxamine on bleomycin-induced lung fibrosis in the hamster. Am Rev Bespir Dis 1985; 131:596-98 12 Martin WJ II, Kachel OL. Bleomycin-mediated pulmonary endothelial ceU injury: protection by the iron chelator deferoxamine, but not EOTA. J Lab Clin Med 1987; 110:153-58 13 Lazo JS, Merrill ww, Pham ET, Lynch TJ, McCallister JO, Ingbar DH. Bleomycin hydrolase activity in pulmonary cells. J Pharmacol Exp Ther 1984; 231:583-88 14 Holmberg L, Boman G, Bolliger LE, Eriksson B, Spross R, Wessling A. Adverse reactions to nitrofurantoin: analysis of 921 reports. Am J Med 1980; 69:733-38 15 Mason ~ Holtzman JL. The role of catalytic superoxide formation in the O. inhibition of nitroreductase. Biochem Biophys Res Commun 1975; 67:1267-74 16 Mason ~ Holtzman JL. The mechanism of microsomal and mitochondrial nitroreductase: electron spin resonance evidence for nitroaromatic free radical intermediates. Biochemistry 1975; 14:1626-32 17 Sasame HA, Boyd MR. Superoxide and hydrogen peroxide

22

23

24

25 26 27

28

29 30

31

32 33

34

production and NADPH oxidation stimulated by nitrofurantoin in lung microsomes: possible implications for toxici~ Life Sci 1979; 24:1091-96 Boyd MR. Biochemical mechanisms in chemical-induced lung injury: role of metabolic activation. CRC Crit Rev Tdxicol 1980; 7:103-76 Martin WJ II. Nitrofurantoin: evidence of the oxidant injury of lung parenchymal cells, Am Rev Respir Dis 1983; 127:482-86 Martin WJ II, Powis G~ Kachel DL. Nitrofurantoin stimulates oxidant production in pulmonary endothelial cells. J Lab Clin · Med 1985; 105:23-29 Boyd MR, Catignani GL, Sasame HA, Mitchell JR, Stilco AW. Acute pulmonary injury in rats by nitrofurantoin and modification by vitamin E dietary fat and oxygen. Am Rev Respir Dis 1979; 120:93-99 Frank L, Summerville J, Massaro D. Protection from oxygen toxicity with endotoxin: role of the endogenous antioxidant enzymes of the lung. J Clin Invest 1980; 65:1104-10 Padmanabhan R, Gudapaty R, Liemer IE, Schwartz BA, Hoida! JR. Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of Iiposome-encapsulated superoxide dismutase or catalase. Am Rev Respir Dis 1985; 132:16467 Turrens JR, Crapo JD, Freeman BA. Protection against oxygen toxicity by intravenous injection ofliposome-entrapped catalase and superoxide dismutase. J Clio Invest 1984; 73:87-95 Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity: recognition and pathogenesis-part I. Chest 1988; 93:1061-75 Martin WJ II, Rosenow EC III. Amiodarone pulmonary toxicity: recognition and pathogenesis-part II. Chest 1988; 93:1242-48 Marchlinsld FE, Cansler TS, Waxman HL, Josephson ME. Amiodarone pulmonary toxicity. Ann Intern Med 1982; 97:83945 Kennedy JI, Myers JL, Plumb Vj, Fulmer JD. Amiodarone pulmonary toxicity: clinical, radiologic, and pathologic correlations. Arch Intern Med 1987; 147:50-55 Venet A, Caubarrere I, Bonan G. Five cases of immunemediated amiodarone pneumonitis. Lancet 1984; 1:962-63 Israel-Biet D, Venet A, Caubarrere I, Bonan G, Danel C, Chretien J, et ale Bronchoalveolar lavage in amiodarone pneumonitis: ceUuIar abnormalities and their relevance to pathogenesis. Chest 1987; 91:214-21 Akoun GM, Mayaud CM, Milleron BJ, Perrot lY. Drug-related pneumonitis and drug-induced hypersensitivity pneumonitis (letter). Lancet 1984; 1:1362-63 Ettensohn OB, Roberts NJ, Condemi JJ. Bronchoalveolar lavage in gold lung. Chest 1984; 85:569-70 Leatherman ~ Michael AF, Schwartz BA, Hoida! JR. Lung T-cells in hypersensitivity pneumonitis. Ann Intern Med 1984; 100:390-92 Semenzato G, Agostini C, ZambeUo R, Trentin L, Chilosi M, Pizzolo G, Marcer G, Cipriani A. Lung T-cells in hypersensitivity pneumonitis: phenotypic and functional analyses. J Immunol 1986; 137:1164-72

Interstitial Lung Disease Dueto Inhaled Organic Dusts· Roy Ibtterson, M.D., F.C.C.l; and Kathleen E. Harris, B.S.

*From the Section of Allergy-Immunology, Department of Medicine, Northwestern University Medical School, Chicago. Supported by the Ernest S. Bazley Trust and u.S. Public Health Service grant AI 11403. Reprint requests: Dr Ibtterson, Northwestern University Medical School, 303 E. Chicago Ave, Tarry 3-711, Chicago, IL 60611 CHEST 1100 1 1 1 JUL~ 1991

243

Table I-GeU arad Coomba Claaification ofH _ &tIctionl Applied to Lung DiIetJBe Type

Mechanism

Term

Example of Disease

I II

Anaphylactic Cytotoxic

III

Toxic antigen-antibody complexes

19E antibody-sensitized mast cells CeDular antigen or hapten &xed to antibody reacts and damages cells IgG antibody plus antigen is toxic

IV

Lymphocyte-mediated

Lymphocyte stimulation with lymphokine release

ceo; IgG

dusts may cause pulmonary disease in the I nhaled organic interstitial tissues, or both. We shall review airwa~

examples of these diseases and the proposed mechanisms. The major mechanisms involved in these diseases are immunologic in nature, with the appropriate type of hypersensitivity reaction classified as in the Gell and Coombs cIassmcation.1 The inhaled dusts are generally inert except in the presence of an immune response generated by the host. To give an example of an inert protein capable of causing mild or serious asthma on an immunologic basis, the common problem of cat asthma may be used. The important agents in these inhalant dusts are generally proteins of animals or plants, although reactive chemicals used as plasticizers or chemicals used in the paint industry may cause mild or serious immunologic lung disease. Table 1 illustrates the Cell and Coombs classification ofhypersensitivity reactions applied to lung diseases. In certain exposures, more than one type of hypersensitivity reaction may result in an inflammatory reaction in the airways or the interstitium. Examples of such diseases with complex immunopathogenesis are shown in Table 2. A concept that deserves major emphasis even in this summary is the formation of hapten-self-protein conjugates that serve as antigens. While the understanding of foreign proteins as inhaled antigens is not difficult, the concept of a reactive chemical, such as trimellitic anhydride, reacting to form a complex of trimellityl-selfprotein with new antigenic determinants is newer and more difficult. Such complexes are antigenic and cause 3 types of immunologic lung disease, and trimellitic anhydride serves as the model in all respects. 5 The most clearly described allergic chemical asthma is due to IgE antibody against trimellityl-albumin with new antigenic determinants. An even newer concept of great potential importance is that a reactive chemical, such as toluene diisocyanate, can react with the cell surface or proteins bound to the cell surface of a highly reactive cell, such as a mast cell. In this circumstance, IgG antibody may generate an immediate-

H_

Table 2-Emmpla ofPulmona,." lIBtJctiona tDitIa Multiple Tata of Immunologic Inoolvement Disease Allergic bronchopulmonary aspergillosisU Trimellitic anhydride (TMA) hemorrhagic pneumonia"

Antigen Antigens of

Aspergillus fumigatus TMA fixed to

ceo

Cat asthma Hemorrhagic pneumonitis due to reactive chemicals Hypersensitivity pneumonitis (certain stages) Hypersensitivity pneumonitis (certain stages)

type reaction clinically analogous to an IgE-mediated reaction. The potential of this mechanism to define poorly understood inhalational disease is great. Of major importance is that failure to diagnose these diseases may lead to serious progressive interstitial lung disease followed by 6brosis, which may be fatal. Some features of these diseases that are important in making a diagnosis are listed in Table 3. When a physician is aware of the disease, suspects the disease, finds a course compatible with the disease, and carries out appropriate diagnostic evaluations, the diagnosis can be made, and chronic progressive destructive lung disease may be avoided. Appropriate serologic studies are an important aid in establishing the diagnosis. The presence of antibodies does not allow one to make a diagnosis. The physician makes the diagnosis by correlation of clinical and immunologic data. In some cases of hypersensitivity pneumonitis, specialized laboratories and occasionally research laboratories with special technology are necessary to perform appropriate studies. However, caution is necessary in selecting an appropriate laboratory Some commercial laboratories may recommend inappropriate tests or are de6cient in quality control of complex immunoassays, and results may be misleading. They may report false-positive or false-negative serologic results. Examples of interstitial lung disease due to inhalation of materials generating an immune response with an inflammatory or destructive lung disease are listed in 18ble 4. This list is, of course, not inclusive, and many other exposures, particularly occupational, are listed in standard texts, such as reference 8. The importance of these diseases is as follows: With the exception of allergic bronchopulmonary aspergillosis, which we estimate occurs in 1% to 2% of cases of asthma, these hypersensitivity lung diseases are uncommon. Because they are uncommon, the diagnosis of inhaIational lung disease may not be suspected. For example, in the first cases listed in Table4, a child was not considered to have hypersensitivity pneumonitis until a lung biopsy was interpreted as consistent

Immunopathogenetic Factors

Table 3-Irnportant FetJtura in DitJgnoN ofLMng DiIetJBe Due to IraIuJMl Organic Dum

19E-sensitized mast cells, toxic antigen and IgG antibody complexes IgG directed against TMA reacts with TMA-ceD complex with cell damage

Physicians awareness of the disease Physician's suspicion of-the disease in an individual case History of the course of the disease History of exposures (work, hobby, and other environmental exposures) Appropriate serologic studies Correlation of the above information to make the diagnosis

Table 4-Emmple. oflntentitial Lung Diaeaae Due to

lnhakd Materiala

Hypersensitivity pneumonitis in children due to inhalation of bird proteins" Interstitial lung disease due to inhalation of hexamethylene diisocyanate" Allergic bronchopulmonary aspergillosis due to inhalation of fungal spores and subsequent colonization of mucus with Aspergillus fumigatuSJ

with that diagnosis. A search for the cause was then made, and exposure to bird droppings was identified. The second case" in Table 4 was thought to be consistent with trimellitic anhydride lung disease; that diagnosis could not be established, but isocyanate lung disease was eventually diagnosed. If the diagnosis of inhalationallung disease is established, the disease can be controlled by avoidance of exposure. If significant lung damage has not occurred, further progressive lung damage may be prevented by environmental control. 9 There may be significant reversal of disease and prevention of progression of allergic aspergillosis by judicious use of prednisone therapy In summary, pulmonary diseases due to inhaled organic dusts may be the result of a wide spectrum of occupational and other environmental exposures. The immunologic mechanisms involved and the antigens may vary widely. Early diagnosis is a major goal since prevention of progression to fibrotic lung disease may be achieved in almost all patients. REFERENCES

1 Coombs RRA, Gell PGH. Classification of allergic reactions responsible for clinical hypersensitivity and disease. In: Gell PGH, Coombs RHA, Lachman PI, eds. Clinical aspects of immunology. 3rd ed. Oxford, England: Blackwell Scientific Publications, 1975; 761-81 2 McCarthy DS, Pepys J. Allergic bronchopulmonary aspergillosis: clinical immunology-2: Skin, nasal and bronchial tests. Clin Allergy 1971; 1:415-32 3 Greenberger PA. Allergic bronchopulmonary; aspergillosis. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF, Yunginger J~ OOs. Allergy: principles and practice. 3rd ed. St Louis: CV Mosby, 1988; 1219-36 4 Patterson R, Addington ~ Banner AS, Byron GE, Franco M, Herbert FA, et ale Antihapten antibodies in workers exposed to trimellitic anhydride fumes: a potential immunopathogenetic mechanism for the trimellitic anhydride pulmonary diseaseanemia syndrome. Am Rev Respir Dis 1979; 120:1259-67 5 Zeiss CR, Patterson R, Pruzansky Jl, Miller MM, Rosenberg M, Levitz D. Trimellitic anhydride (TMA)-induced airway syndromes: clinical and immunologic studies. 1Allergy Clin Immunol 1977; 60:96-103 6 Patterson R, Greenberger PA, Castile RG, Yee WFH, Roberts M. Diagnostic problems in hypersensitivity lung disease. Allergy Proc 1989; 10:141-47 7 Patterson R, Nugent KM, Harris KE. Immunologic hemorrhagic pneumonia due to isocyanates. Am Rev Respir Dis, 1990; 141:22630 8 Middleton E, Reed CE, Ellis EF, Adkinson NF, Yunginger 1~ OOs. Allergy: principles and practice. 3rd 00. St Louis: CV Mosby, 1988 9 Patterson R, Zeiss CR. Trimellitic anhydride respiratory reactions, from suspicion to control: a story of cooperation (editorial). J Allergy Clin Immunoll983; 72:647-48

Cellular Processes in Lung Repair* Jesse R. Roman, M.D.; and john A. McDonald, Ph.D., M.D., F.C.C.l

T

issue response to injury entails the activation of repair mechanisms that promote removal of debris, granulation tissue formation, and tissue reorganization. This wound healing process is responsible for the restoration of normal tissue architecture and function after injury. In all tissues, wound healing is characterized by recruitment of mesenchymal cells into injured sites, angiogenesis, and reepithelialization. This is also true in lung, where the nature and extent of the injury, together with the ability of the host's repair mechanisms, will determine the final outcome. The extent to which these processes maintain the original architecture determines the recovery of lung function or the development of scar tissue. Current knowledge of the events occurring during lung repair has been enhanced by new developments in separate areas of biomedical research. These include the study of growth factor expression and biologic activities, the discovery of a new family of cell surface receptors involved in cell recognition of extracellular matrices, a better understanding of the effects of extracellular matrices on cell behavior, and the studies of other systems, such as skin wound healing. The mechanisms discussed will pertain mostly to interstitial lung disease, although some overlap is likely with those of other entities, such as emphysema. REPAIR MECHANISMS

Acute lung injury is characterized by loss of normal architecture (Fig 1), with destruction of both epithelial and endothelial sides of the. alveolus-eapillary barrier. This results in the extravasation of fluid and cells into the interstitium and alveolar spaces. I Once the insult has taken place, inflammatory cells are the first to appear at the *From the Department of Internal Medicine, Respiratory and Critical Care Division, Washington University School of Medicine, St Louis. Reprint requests: Dr. Roman, Pulmonary Division, Box 8052, 660S Euclid, St Louis 63110

FibrDblast -----..~

Type I Cell

Type I

Epithelial---' Cell Cspillilry

CDnnective

Tissue---...1IIr~

Fibers

FIGURE 1. Normal alveolar septum. (From Kuhn et a1. Am Rev Respir Dis 1989; 140:1693-1703. Reproduced by permission.) CHEST I 100 I 1 I JUL'Y, 1991

245