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From Anti-inflammatory Drugs Through Antifibrotic Agents to Lung Transplantation : A Long Road of Research, Clinical Attempts, and Failures in the Treatment of Idiopathic Pulmonary Fibrosis FREE TO VIEW

Moisés Selman, MD, FCCP
Author and Funding Information

Affiliations: Mexico City, Mexico
 ,  Dr. Selman is with the Instituto Nacional de Enfermedades Respiratorias in Mexico City.

Correspondence to: Moisés Selman, MD, FCCP, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, Col. Sección XVI, México DF, CP 14080, México; e-mail: mselman@conacyt.mx



Chest. 2002;122(3):759-761. doi:10.1378/chest.122.3.759
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Idiopathic pulmonary fibrosis (IPF) is a unique type of chronic fibrosing lung disease of unknown etiology that is characterized by the injury and activation of alveolar epithelial cells, the formation of distinctive subepithelial fibroblast/myofibroblast foci, and aberrant extracellular matrix remodeling.1Usual interstitial pneumonia is the singular histopathologic lesion of IPF, and it is characterized at low-power magnification by patchy involvement of the lung parenchyma with concomitant areas of healthy lung, interstitial inflammation, fibrosis, and honeycombing. Actually, temporal heterogeneity is a cardinal feature of usual interstitial pneumonia, suggesting that multiple microinjuries have occurred at different times during a long period. This increasingly common disease belongs to the family of idiopathic interstitial pneumonias, and it is by far the most aggressive interstitial lung disease. Indeed, incident cases of IPF have a remarkably limited prognosis with a median survival time of < 3 years.2 In this context, it is important to emphasize that IPF is a progressive and irreversible illness, and, until now, there has been no available drug that has been capable of modifying the progressive natural course of IPF and its usual terminal outcome.

Based on the assumption that IPF is the result of a chronic, unsolved inflammation, the mainstay of therapy has been the use of corticosteroids with or without immunosuppressive drugs, primarily azathioprine and cyclophosphamide.3 However, it is now clear that therapy with anti-inflammatory drugs does not provide objective benefit and, moreover, that these drugs are associated with a myriad of adverse effects that worsen the quality of life.

Newer approaches include the use of two agents that seem to directly affect fibroblast functions and to block extracellular matrix accumulation. One agent is interferon (IFN)-γ, a cytokine that down-regulates the expression of some profibrotic growth factors and interstitial fibrillar collagens, and decreases bleomycin-induced pulmonary fibrosis.4In a pioneer study, Ziesche et al5 suggested that the prolonged use of IFN-γ may be effective in IPF patients. In a randomized, double-blind trial that included 18 patients who were treated for 1 year, the authors demonstrated that therapy with IFN-γ plus low doses of prednisolone induced a significant improvement in pulmonary function, oxygenation, and symptoms, whereas the conditions of those patients who were treated with corticosteroids alone deteriorated. In addition, a noteworthy decrease of several fibrogenic growth factors was found in the lung tissue after 6 months of therapy. A subsequent review of these patients by an independent panel suggested that not all of them had experienced IPF, but some presented nonspecific interstitial pneumonia, an idiopathic lung disorder with a better prognosis than IPF. However, the results were promising, and currently a large multicenter trial is about to be concluded.

The other drug currently under clinical exploration is pirfenidone, an agent reported to inhibit fibroblast proliferation and collagen synthesis, and to ameliorate bleomycin-induced and cyclophosphamide- induced lung fibrosis.67 In a small clinical trial in consecutive IPF patients that showed deterioration despite conventional therapy, Raghu et al8 found that pirfenidone was able to stabilize both respiratory function and symptomatology. A multicenter study is currently underway.

In the last 20 years, lung transplantation has emerged as a feasible option for selected patients with IPF, and it is now a recognized therapeutic option. This procedure can prolong life and, more importantly, may improve the quality of life of patients with end-stage lung disease and severe respiratory insufficiency. In a literature review, Lanuza et al9concluded that lung transplant recipients exhibited a better quality of life than lung transplant candidates, although a number of the reviewed studies displayed methodological defects and/or lacked of information regarding correlation with the type of lung disease and physiologic variables. Nevertheless, it is generally thought that IPF patients surviving lung transplantation achieve not only a considerable improvement in lung function but also a substantial improvement in most dimensions of health-related quality of life, in either single or bilateral lung transplantation.1011

In this context, many lung transplant programs have emerged, and the lists of patients waiting for transplantation are growing progressively. Unfortunately, many limiting factors, such as a scanty supply of donor lungs, chronic graft dysfunction, and recurrent disease in the graft, remain for transplantation to become a long-term solution.12Primarily, chronic lung rejection that is characterized by bronchiolitis obliterans, a rapidly progressive inflammatory disorder of the small airways that provokes severe airflow limitation, has become a major obstacle for the long-term survival of lung allograft recipients.13

On the other hand, since most IPF patients die within few years after diagnosis, one critical issue for lung transplant success is the determination of the optimal referral time. This concern is particularly important since there are no temporary support mechanisms for patients with end-stage lung disease as there are for end-stage renal failure. Therefore, one important problem relates to the limited window of opportunity that exists in which to refer IPF patients for lung transplantation, which is reflected in the excessively high mortality rate for patients waiting for transplantation.14For example, the recently published Eurotransplant experience15demonstrated that the global mortality rate of a large cohort of patients with several chronic lung disorders, since being listed, amounted to 46% at 2 years. Importantly, the higher mortality rate was observed for patients with end-stage lung disease due to pulmonary fibrosis. For this reason, the US organ allocation system (United Network for Organ Sharing Registry) gives IPF patients a 3-month waiting advantage compared with patients with other chronic lung diseases.16

However, it is not easy to predict survival in IPF patients who are potentially qualified for lung transplantation, and studies evaluating the role of cardiopulmonary function have been inconsistent. Thus, for example, some reports have suggested that hemodynamics and respiratory function do not predict survival, while others have shown that survival is significantly related to a number of different clinical and functional data, including evidence of pulmonary hypertension on the chest radiograph, reduced lung volume, and the presence of gas exchange abnormalities with exercise.1718 Moreover, in contradiction to previous reports,19 King et al18 found that diffusing capacity of the lung for carbon monoxide was not an independent predictor of survival in the multivariate analyses. By contrast, others have suggested that in IPF patients < 65 years of age, the best prediction of survival is derived from a combination of the percent predicted for the diffusing capacity of the lung for carbon monoxide and the high-resolution CT scan fibrosis score.14 Several reasons may contribute to these discrepancies, including the natural biological heterogeneity of the disease, the period that has elapsed before diagnosis, and previous medical treatment. Additionally, in some studies all patients were required to undergo a surgical lung biopsy, while in others the diagnosis of disease in a number of patients relied on clinical and high-resolution CT scan findings.14,18 Therefore, in the former studies, the authors probably did not include patients who were too ill or were considered to be at high risk for complications from anesthesia or surgery. Still, the question about which parameters have the best potential for optimizing the timing of referral for transplantation remains open.

In this issue of CHEST (see page 779), Timmer and colleagues retrospectively reviewed all lung transplant referrals for idiopathic interstitial pneumonias that were listed by the United Network for Organ Sharing at the University of California San Diego over a 10-year period. The aim of the authors was to find a parameter that would discriminate between patients who survived and underwent transplantation, and those who died while waiting for transplantation. Forty-eight transplant candidates who met the inclusion criteria were evaluated, and, at the end, 28 were still alive while 20 had died. The results of the study showed, for the first time, that the severity of hypoxemia at rest was the only significant difference between both groups. However, a prospective trial to confirm the clinical relevance of the study for predicting survival is needed.

In summary, the experience accumulated in the last 60 years with both medical and surgical (transplant) treatments in patients with IPF reemphasizes our current ignorance on the mechanisms leading to the end stage in this unique disease. Thus, even in the absence of a complicating disorder, the median survival time after diagnosis is < 3 years.2 Drugs have been unable to improve the condition of these patients in the long term, and the global survival rate for patients undergoing lung transplantation, taking into consideration newly listed transplant candidates as well as those who have already undergone transplantation, is relatively poor. In this context, therapeutic trials of newer putative antifibrotic drugs are required straight away. As well, earlier transplant referral and listing should improve the opportunity for better outcomes. Finally, there is an urgent need for incremental research regarding the pathogenic mechanisms involved in alveolar epithelial injury, fibroblast behavior, extracellular matrix remodeling, and other unsuspected processes that take place in the unique microenvironment of the lungs of IPF patients.

References

Selman, M, King, TE, Pardo, A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med134,136-151. [PubMed]
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203. [PubMed]
 
Gross, TJ, Hunninghake, GW Idiopathic pulmonary fibrosis.N Engl J Med2001;345,517-525. [PubMed] [CrossRef]
 
Gurujeyalakshmi, G, Giri, SN Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression.Exp Lung Res1995;21,791-808. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Iyer, SN, Gurujeyalakshmi, G, Giri, SN Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.J Pharmacol Exp Ther1999;291,367-373. [PubMed]
 
Kehrer, JP, Margolin, SB Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice.Toxicol Lett1997;90,125-132. [PubMed]
 
Raghu, G, Johnson, WC, Lockhart, D, et al Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med1999;159,1061-1069. [PubMed]
 
Lanuza, DM, Lefaiver, CA, Farcas, GA Research on the quality of life of lung transplant candidates and recipients: an integrative review.Heart Lung2000;29,180-195. [PubMed]
 
Stavem, K, Bjortuft, O, Lund, MB, et al Health-related quality of life in lung transplant candidates and recipients.Respiration2000;67,159-165. [PubMed]
 
Meyers, BF, Lynch, JP, Trulock, EP, et al Single vs bilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year institutional experience.Thorac Cardiovasc Surg2000;120,99-107
 
Sulica, R, Teirstein, A, Padilla, ML Lung transplantation in interstitial lung disease.Curr Opin Pulm Med2001;7,314-321. [PubMed]
 
Trulock, EP Lung transplantation.Am J Respir Crit Care Med1997;155,789-818. [PubMed]
 
Mogulkoc, N, Brutsche, MH, Bishop, PW, et al Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation.Am J Respir Crit Care Med2001;164,103-108. [PubMed]
 
De Meester, J, Smits, JMA, Persijin, GG, et al Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the Eurotransplant experience.J Heart Lung Transplant2001;20,518-525. [PubMed]
 
Dark, JH Priorities for lung transplantation.Lancet1998;351,4-5
 
Harari, S, Simonneau, G, DeJuli, E, et al Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation.J Heart Lung Transplant1997;16,460-463. [PubMed]
 
King, TE, Tooze, JA, Schwarz, MI, et al Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med2001;164,1171-1181. [PubMed]
 
Schwartz, DA, Helmers, RA, Galvin, JR, et al Determinants of survival in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1994;149,450-454. [PubMed]
 

Figures

Tables

References

Selman, M, King, TE, Pardo, A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy.Ann Intern Med134,136-151. [PubMed]
 
Bjoraker, JA, Ryu, JH, Edwin, MK, et al Prognostic significance of histopathologic subsets in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1998;157,199-203. [PubMed]
 
Gross, TJ, Hunninghake, GW Idiopathic pulmonary fibrosis.N Engl J Med2001;345,517-525. [PubMed] [CrossRef]
 
Gurujeyalakshmi, G, Giri, SN Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression.Exp Lung Res1995;21,791-808. [PubMed]
 
Ziesche, R, Hofbauer, E, Wittmann, K, et al A preliminary study of long-term treatment with interferon gamma-1b and low-dose prednisolone in patients with idiopathic pulmonary fibrosis.N Engl J Med1999;341,1264-1269. [PubMed]
 
Iyer, SN, Gurujeyalakshmi, G, Giri, SN Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis.J Pharmacol Exp Ther1999;291,367-373. [PubMed]
 
Kehrer, JP, Margolin, SB Pirfenidone diminishes cyclophosphamide-induced lung fibrosis in mice.Toxicol Lett1997;90,125-132. [PubMed]
 
Raghu, G, Johnson, WC, Lockhart, D, et al Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study.Am J Respir Crit Care Med1999;159,1061-1069. [PubMed]
 
Lanuza, DM, Lefaiver, CA, Farcas, GA Research on the quality of life of lung transplant candidates and recipients: an integrative review.Heart Lung2000;29,180-195. [PubMed]
 
Stavem, K, Bjortuft, O, Lund, MB, et al Health-related quality of life in lung transplant candidates and recipients.Respiration2000;67,159-165. [PubMed]
 
Meyers, BF, Lynch, JP, Trulock, EP, et al Single vs bilateral lung transplantation for idiopathic pulmonary fibrosis: a ten-year institutional experience.Thorac Cardiovasc Surg2000;120,99-107
 
Sulica, R, Teirstein, A, Padilla, ML Lung transplantation in interstitial lung disease.Curr Opin Pulm Med2001;7,314-321. [PubMed]
 
Trulock, EP Lung transplantation.Am J Respir Crit Care Med1997;155,789-818. [PubMed]
 
Mogulkoc, N, Brutsche, MH, Bishop, PW, et al Pulmonary function in idiopathic pulmonary fibrosis and referral for lung transplantation.Am J Respir Crit Care Med2001;164,103-108. [PubMed]
 
De Meester, J, Smits, JMA, Persijin, GG, et al Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the Eurotransplant experience.J Heart Lung Transplant2001;20,518-525. [PubMed]
 
Dark, JH Priorities for lung transplantation.Lancet1998;351,4-5
 
Harari, S, Simonneau, G, DeJuli, E, et al Prognostic value of pulmonary hypertension in patients with chronic interstitial lung disease referred for lung or heart-lung transplantation.J Heart Lung Transplant1997;16,460-463. [PubMed]
 
King, TE, Tooze, JA, Schwarz, MI, et al Predicting survival in idiopathic pulmonary fibrosis: scoring system and survival model.Am J Respir Crit Care Med2001;164,1171-1181. [PubMed]
 
Schwartz, DA, Helmers, RA, Galvin, JR, et al Determinants of survival in idiopathic pulmonary fibrosis.Am J Respir Crit Care Med1994;149,450-454. [PubMed]
 
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