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Lesson 13, Volume 16—Treatment of Idiopathic Pulmonary Fibrosis: New Directions

By Mark Wurfel, MD, PhD; and Ganesh Raghu, MD, FCCP

Effective December 31, 2004, PCCU Volume 16 is available for review purposes only. CME credit for this volume is no longer being offered.

Objectives

  1. Gain a better understanding of the current concepts in the pathogenesis of pulmonary fibrosis.
  2. Understand the new strategies that are evolving, with a shift toward treatment aimed at aborting fibrosis and aberrant fibroblast proliferation rather than inflammation.
  3. Understand the need for prospective clinical trials utilizing new agents that have promising preliminary results.

Key words

corticosteroids; cytokines; growth factors; pulmonary fibrosis

Abbreviations

ET = endothelin; IFN = interferon; reduced GSH = glutathione; IL = interleukin; IP-10 = interferon-g inducible protein-10; IPF = idiopathic pulmonary fibrosis; mRNA = messenger RNA; NAC = N-acetylcysteine; TGF-b = transforming growth factor-b; TNF = tumor necrosis factor; UIP = usual interstitial pneumonia

In spite of several decades of study, idiopathic pulmonary fibrosis (IPF) remains a devastating and unremitting disease with no effective therapy. Median survival is < 4 to 5 years after the onset of symptoms in spite of treatment with current regimens that consist primarily of anti-inflammatory and immunosuppressive agents.1,2 However, some important concepts have arisen from clinical observation and experimental data. Firstly, there are few histologic or experimental data showing an important role for inflammatory leukocytes in the establishment and propagation of the fibroproliferative process,3-6 and treatments directed at the inflammatory component have had only modest efficacy in uncontrolled trials.7 Secondly, while normal lung fibroblasts are quiescent, fibroblasts isolated from patients with IPF demonstrate greatly enhanced proliferation and matrix deposition.8,9 This likely represents an inappropriately vigorous wound-healing response, on the part of the fibroblast, to epithelial cell injury. Given the apparent primacy of fibroblast dysregulation in the development of IPF, this discussion outlines the factors involved in the initiation and propagation of abnormal fibroblast activity and therapeutic interventions directed at controlling and, possibly, reversing this process. Current concepts in the pathogenesis of IPF have recently been reviewed.10,11

IPF is defined as an idiopathic interstitial pneumonia occuring in adults (usually beyond the fifth decade of life) characterized by dyspnea, hypoxia, radiologic evidence of diffuse pulmonary infiltrates, and the histologic finding of usual interstitial pneumonia (UIP). A recent consensus opinion has clarified the diagnosis and clinical features of IPF.12 The salient features of UIP are as follows: (1) temporal heterogeneity, as well as areas of fibrotic parenchyma and microscopic honeycombing found adjacent to normal lung; (2) fibroblast foci, or discrete aggregates of actively proliferating fibroblast and myofibroblasts found just beneath areas of alveolar damage and basement membrane destruction; and (3) a paucity of inflammatory cells. Fibroblast foci are believed to represent a form of abnormal wound healing following an as-yet-undefined alveolar insult. These cell clusters are sites of excess matrix deposition and wound contraction resulting in alveolar collapse.5 The histologic picture of UIP highlights the central role of the fibroblast and the relative unimportance of inflammation in the propagation of IPF.

One important hindrance to the study of IPF pathogenesis has been the lack of an animal model that develops chronic restrictive physiology and fibrosis that resembles UIP histologically. The most widely used animal model is bleomycin-induced pulmonary fibrosis following intratracheal instillation in rodents. However, as demonstrated in a recent article by Borzone et al,13 the chronic lung damage seen after bleomycin instillation in rats lacks a restrictive component. The acute histologic findings most closely resemble diffuse alveolar damage, while the chronic histology demonstrates peribronchiolar inflammation and fibrosis with emphysematous changes more consistent with COPD. Therefore, a good deal of caution must be exercised in the extrapolation of results from this model to the human disease. Of note, Kolb et al14 have recently shown that transient expression of interleukin-1b (IL-1b) in rats resulted in severe progressive fibrosis with the development of structures resembling fibroblast foci. This laboratory has also demonstrated that transient overexpression of transforming growth factor-b (TGF-b) in the rat lung induces moderate inflammation and vigorous fibrosis.15 As these models more closely resemble the histology of human pulmonary fibrosis, they may be of future use in preclinical studies of antifibrotic therapeutic agents.

Conventional Therapy

The strongest evidence arguing against an important role for inflammation in the pathogenesis of IPF is the disappointing results from anti-inflammatory therapy, particularly corticosteroids (reviewed by Mapel et al7). This outcome is of little surprise given the paucity of inflammatory cells seen in UIP. The use of oral corticosteroids for IPF dates back to the 1950s and, in spite of a lack of prospective, placebo-controlled data to support its efficacy, continues to be the mainstay therapy. Several small, uncontrolled trials have demonstrated a modest subjective benefit in 20 to 30% of patients treated.7 A recent study has confirmed this finding in a group of patients with a histologic diagnosis of UIP.16 However, this study also showed a very high incidence of adverse effects attributable to steroid therapy, a significant factor that mitigates the modest benefits experienced by a minority of patients with IPF. Currently, there is no role for lone corticosteroid therapy in the treatment of IPF.

In an effort to minimize the doses of corticosteroids used in the treatment of IPF, adjunct therapy with the immunosuppressive agents azathioprine and cyclophosphamide have been studied. Two prospective, randomized trials have compared each of these drugs in combination with steroids to steroids alone.17,18 Azathioprine used as adjunctive therapy in newly diagnosed IPF caused a modest clinical improvement and lengthened survival. In contrast, cyclophosphamide did not show a benefit in either outcome. No studies address the effect of azathioprine or cyclophosphamide alone in the treatment of IPF. It is on the basis of these studies that a recent consensus statement recommends the combination of corticosteroids (prednisone 0.5 mg/kg/d tapered to 0.125 mg/kg/d over 3 months) and azathioprine (2 to 3 mg/kg/d, maximum 150 mg/d) or cyclophosphamide (2 mg/kg/d, maximum 150 mg/d) as first-line therapy for IPF.12 Regardless, the data supporting conventional anti-inflammatory therapy for IPF is limited at best, and the benefits relative to the adverse effects are small.

Colchicine and D-penicillamine have also been investigated as adjunctive therapy with prednisone. Colchicine, an antimicrotubular agent, inhibits collagen formation19 and increases collagen degradation20 by fibroblasts in vitro. It also suppresses the release of fibronectin from alveolar macrophages isolated from IPF patients.21 Early retrospective studies showed equivalence between colchicine and prednisone, while a subsequent prospective trial confirmed equivalence, demonstrating there was no measurable benefit to either treatment.22 Because colchicine is well tolerated, with minimal serious adverse effects other than dose-related diarrhea, some clinicians have prefered to use colchicine instead of corticosteroids, while acknowledging that colchicine is as ineffective as corticosteroids. This logic may be particularly relevant when the combination of azathioprine and corticosteroids is otherwise contraindicated.

D-penicillamine appears to inhibit collagen deposition by interfering with the intramolecular cross-linking of mature collagen,23 and may inhibit collagen accumulation in rats following intratracheal bleomycin.24 However, in the only prospective trial examining penicillamine in combination with prednisone for IPF, there was no benefit to the addition of penicillamine.25 Given the toxic side-effect profile of penicillamine, including loss of taste, stomatitis, and nephrotoxicity, penicillamine has no current role in the treatment of IPF.

Lung transplantation is also an option for the appropriate patient with IPF.

Potential New Therapies

As emphasized above, IPF is characterized by the presence of fibroblast foci, increased fibroblast proliferation, increased extracellular matrix deposition, and a notable paucity of inflammatory cells. Given these histologic findings, agents directed at suppressing the aberrant fibrotic response may improve the functional status and outcome in patients with IPF. Using the murine model of bleomycin-induced fibrosis and descriptive studies in patients with IPF, several pathways have been implicated in the promotion of fibroproliferation: (1) cytokines and growth factors such as TGF-b, interferon-g (IFN-g), tumor necrosis factor-a (TNF-a), and IL-1b; (2) angiogenic chemokines such as IL-8; and (3) mediators of apoptosis such as Fas ligand have all been implicated in the pathophysiology of IPF. Although the relative importance of these pathways is not yet understood, we can begin to model the complex process that leads to pulmonary fibrosis (Fig 1). A recent National Institutes of Health workshop discussed the potential of several antifibrotic agents based on these pathways.26 A point emphasized in this discussion was the need for multicenter clinical trials to determine the efficacy of these agents. It is hoped that the efficacy of some of the potentially therapeutic agents mentioned below will be proven in such a trial.

Figure 1. A conceptual model of IPF pathogenesis and mechanisms of new therapeutic interventions. Injury to alveolar epithelium and resident macrophages leads to expression of profibrotic and proangiogenic cytokines and growth factors promoting proliferation and differentiation of fibroblasts and progression to pulmonary fibrosis. Ang II = angiotensin II.

Pirfenidone

In vitro, pirfenidone inhibits TGF-b-stimulated collagen synthesis, decreases extracellular matrix production, and blocks the mitogenic effect of profibrotic cytokines on adult human lung fibroblasts derived from patients with IPF.27 It has also been shown to ameliorate bleomycin-induced pulmonary fibrosis in a hamster model28 in which pirfenidone attenuated TGF-b29 and collagen expression30 at the transcriptional level. In a prospective, open-label study, pirfenidone was investigated in the treatment of patients with advanced and terminal stages of IPF who had failed or refused conventional therapy.31 Lung function and diffusing capacity of carbon monoxide stabilized in the majority of patients examined 1 year after initiation of therapy, and adverse effects were relatively minor, requiring discontinuation in only 11% of patients treated. One- and 2-year survival rates with treatment were 78% and 63%, respectively. While these findings suggest a benefit to patients with IPF, this apparent benefit may have been a survivorship effect. A multicenter trial is necessary to determine whether pirfenidone is efficacious in the treatment of IPF. It is hoped that an ongoing multicenter clinical trial will provide useful results.

TGF-b Inhibitors

TGF-b likely plays a crucial role in the progression of fibrotic disease. It is secreted by activated epithelial cells, macrophages, and endothelial cells32,33 in an inactive form bound to latency-associated peptide.34 TGF-b is released from latency-associated peptide after it is bound by thrombospondin-1 found in platelet granules35 or the aVb6 integrin expressed on epithelial cells.34 The active molecule stimulates fibroblast chemotaxis, differentiation, and collagen synthesis.9,36 Pulmonary levels of TGF-b are elevated after intratracheal instillation of bleomycin in mice and rats.32,37 Fibrosis in this model is significantly attenuated by administration of anti-TGF-b antibodies38 or soluble TGF-b receptor.39 TGF-b messenger RNA (mRNA) and protein production is greatly increased in epithelial cells and macrophages of patients with IPF,33,40 as are circulating levels of TGF-b.41 While no therapy currently available specifically targets TGF-b, IFNg treatment does lower TGF-b expression in the lungs of IPF patients with an associated improvement in pulmonary function.42 These data suggest that other therapies targeting TGF-b, such as a soluble decoy receptor, could be very useful in treating IPF.

IFN

IFN-g (type II IFN) a cytokine produced by activated T-helper, type 1 cells, is an important activator of cell-mediated immunity. In contrast to this proinflammatory role, IFN-g is also capable of directly inhibiting collagen synthesis by lung fibroblasts in vitro43 and attenuates collagen deposition in bleomycin-induced fibrosis.32,33 IFN-g inhibits transcription of the TGF-b gene, and inhibits TGF-b-induced gene expression through the induction of Smad7, an intracellular signaling molecule.44 Of interest, transient overexpression of Smad7 in vivo attenuates bleomycin-induced fibrosis.45 Activation of Smad7 may be a crucial mediator of IFN-g antifibrotic activity and thus may represent a target for pharmacologic modulation. A recent small, unblinded study compared IFN-g1b in combination with low-dose steroid treatment vs steroids alone and showed a small improvement in lung volumes and a small decrease in oxygen requirements in the group given combination therapy.42 Influenza-like symptoms were the most common side effect and all patients completed the 1-year study. This study is encouraging and it is hoped that the ongoing phase III multicenter randomized controlled clinical trial will confirm these results. IFNb-1a (type I IFN), which uses a combination of receptors and intracellular signaling molecules distinct from IFN-g, was assessed in a recent phase II multicenter trial. The results of this trial failed to show efficacy in the treatment of IPF patients with advanced disease (unpublished data). Because IFN-g exaggerates bleomycin-induced injury in mice,46,47 there is no enthusiasm for conducting clinical studies in IPF.

TNF-a Antagonism

Another mediator likely to play an important role in IPF is TNF-a. TNF-a levels are increased in BAL fluid from IPF patients,48 and TNF-a production is increased in alveolar macrophages from patients with IPF.49 TNFa production is also up-regulated in pulmonary epithelia from IPF patients.50 It is mitogenic and chemotactic for fibroblasts,36,51 but in contrast with TGF-b, suppresses collagen synthesis.52 In the murine bleomycin-induced fibrosis model, a combined genetic deficiency of the p75 and p55 TNF-a receptors protects against fibrosis.53 In response to transient pulmonary overexpression of TNF-a using an adenoviral vector, mice demonstrate a significant inflammatory and fibrotic response.54 However, in this model, TGF-b production is stimulated soon after infection with the TNF-expressing adenovirus. Thus, it is unclear whether TNF-a acts independently to stimulate fibrosis or merely through its ability to induce TGF-b production. Furthermore, chronic overexpression of TNF-a in a transgenic mouse caused only mild fibrosis and expansion of airspaces consistent with emphysema.55 These data are not definitive but suggest a role for TNF-a in the pathogenesis of IPF. As antagonists of TNF-a activity are already in use in the treatment of several inflammatory disorders (eg, Crohn's disease, rheumatoid arthritis), consideration should be given to testing what effect blocking TNF-a function would have in IPF. In a small series of patients with IPF, such treatment was associated with clinical improvement.56 Well-designed clinical studies to assess the efficacy of TNF-a antagonists seem warranted.

Antiangiogenic Factors

An additional class of soluble mediators appears to affect fibrosis through their angiogenic activity. Neovascularization in IPF was first documented in human specimens in 1963 by Turner-Warwick.57 Recent evidence shows that IL-8 and IFN-g-inducible protein-10 (IP-10), members of the cysteine X cysteine (CXC) motif chemokine family, may affect fibrosis through angiogenic mechanisms. IL-8 and its murine functional homologue, macrophage inflammatory protein-2, share the ability to induce neovascularization in vivo,58 while IP-10 inhibits angiogenesis.59 In murine bleomycin-induced fibrosis, neutralizing antibodies against macrophage inflammatory protein-2 significantly reduce fibrotic tissue.60 In contrast, IP-10 was found to be down-regulated in the bleomycin-treated mice, and treatment with exogenous IP-10 resulted in a reduction in pulmonary fibrosis.61 IL-8 is markedly elevated in the BAL fluid and serum of human IPF patients,48,62,63 while IP-10 levels in IPF lung biopsy specimens are reduced.64 These findings indicate there is a proangiogenic environment present in IPF that may fuel the propagation of fibrosis and suggests that downward modulation of angiogenic activity in IPF may be therapeutically beneficial.

Blockade of the Fas-Fas Ligand Pathway

A prominent feature of IPF histopathology is alveolar epithelial cell damage in direct proximity to fibroblast foci. Histologic studies have shown an increased prevalence of alveolar epithelial cells undergoing apoptosis in patients with IPF. This loss of epithelial integrity has been proposed to lead to uncontrolled fibroblast proliferation and differentiation65 through the loss of the physical barrier to intra-alveolar cytokines, uncontrolled deposition of fibrinous clots, and the loss of antiproliferative factors such as prostaglandins of the E series. Complicating this picture is the finding that lung fibroblasts isolated from IPF patients are also capable of secreting factors that promote epithelial cell apoptosis.66 Thus, epithelial cell apoptosis may represent part of a vicious cycle leading to lung fibrosis.

One mechanism believed to be involved in epithelial apoptosis is the Fas/Fas ligand system. In vitro, binding of Fas ligand, expressed upon activated leukocytes, to Fas, expressed upon alveolar epithelium, can induce apoptosis.65 In vivo, genetic deficiency of Fas or Fas ligand attenuates fibrosis in response to intratracheal administration of bleomycin in mice.67 Fas ligand mRNA is up-regulated in the cells present in BAL fluid from IPF patients.68 Complicating this picture, Fas has also been shown to play a role in fibroblast proliferation.69,70 Where Fas ligand is produced in the lungs of IPF patients is still an unanswered question. These data suggest a role for Fas/Fas ligand in both the epithelial cell death and the fibroblast proliferation seen in IPF. Pharmacologic blockade of this pathway may be a useful therapy in IPF.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Antagonists

Angiotensinogen is synthesized by lung myofibroblasts in patients with IPF71 and can be converted to angiotensin II by alveolar epithelial cells.72 Angiotensin II is a potent inducer of epithelial cell apoptosis that can be blocked by angiotensin II receptor antagonists.71,72 Furthermore, angiotensin II has recently been shown to stimulate fibroblast proliferation via the induction and autocrine action of TGF-b.73 Treatment with angiotensin-converting enzyme inhibitors protects mice from bleomycin-induced pulmonary fibrosis.65 Given these findings and the proven safety of these drugs in large prospective trials, further studies employing angiotensin II blockade in IPF are warranted.

N-Acetylcysteine

Reduced glutathione (GSH) and its associated redox enzymes make up a major antioxidant system in the lung and GSH is present at high concentrations in the lung epithelial lining.74 GSH levels are significantly reduced in the lungs of IPF patients, potentially tipping the balance toward oxidant-mediated cell injury.75,76 N-acetylcysteine (NAC) is a precursor of GSH synthesis and, when given IV or orally, results in a significant increase in GSH measured in BAL fluid.77,78 In mice, augmentation of lung GSH by administration of inhaled NAC results in attenuated fibrosis after intratracheal bleomycin.79 In addition to antioxidant activity, NAC can directly inhibit growth factor–induced fibroblast proliferation in vitro.76 A clinical use for NAC is suggested by a prospective cohort study in which GSH levels were restored in IPF patients with high-dose oral NAC therapy for a 12-week period.78 NAC therapy was associated with an improvement in the combined end point of lung mechanics and oxygenation. NAC was well tolerated and all patients completed the study. It is hoped that an ongoing multicenter randomized clinical trial in Europe will determine the clinical utility of adding NAC to the combination of prednisone and azathioprine.

Endothelin Receptor Antagonists

Endothelin-1 (ET-1) is one of three forms of endothelin and represents the predominant form found in lung tissue. ET-1 is secreted by endothelial cells,80 epithelial cells,80 alveolar macrophages,81 and fibroblasts.82 Increased levels of mRNA for the precursor of ET-1 are found in the lungs of patients with IPF.83,84 Elevated plasma concentrations of ET-1 in IPF have also been reported.85 In rats, bleomycin-induced pulmonary fibrosis is associated with increased expression of ET-1 in bronchial and alveolar epithelium,86,87 and fibrosis is partially blocked by treatment with the endothelin receptor antagonist bosentan.87 These data suggest that ET-1 may play a role in the pathogenesis of IPF. In a small double-blind, placebo-controlled study, bosentan was found to be efficacious in the treatment of pulmonary hypertension and was well tolerated.88 Studies of bosentan in the treatment of IPF should be considered.

Relaxin

Relaxin is a protein that is secreted by the corpus luteum and placenta during pregnancy and involved in uterine remodeling, loosening of the pelvic ligaments, and ripening of the cervix in preparation for parturition.89 Relaxin inhibits TGF-b-induced collagen synthesis by fibroblasts and directly stimulates fibroblasts to produce collagenase.90 Recombinant human relaxin prevents the development of bleomycin-induced pulmonary fibrosis in mice.91 Recombinant human relaxin was recently used in a randomized, double-blind, placebo-controlled trial in the treatment of scleroderma.92 When given as a continuous subcutaneous infusion, relaxin was associated with a moderate improvement in skin thickness at the lower of two doses tested.92 Forced vital capacity and diffusion capacity were not significantly altered by relaxin therapy but, notably, patients with "severe" pulmonary fibrosis were excluded from the study. The most common adverse effects were a mild drop in hemoglobin level, irritation at the infusion site, menorrhagia, and metrorrhagia. Relaxin may be useful in the treatment of pulmonary fibrosis.

Conclusions

Currently, therapy for IPF most commonly consists of corticosteroids alone, an approach that clearly lacks efficacy and has a high degree of associated adverse effects. Thus, lone corticosteroid therapy should no longer be used in the treatment of IPF. A small minority of patients with new-onset IPF experience a marginal improvement with prednisone and azathioprine, but the vast majority continue to deteriorate. The change in focus toward understanding the fibroproliferative process has yielded several potential candidates for novel therapies. Collaborative efforts will be necessary to enroll large numbers of patients in well-designed clinical trials to determine the efficacy of these novel antifibrotic agents. It is hoped that the next decade will finally see significant advances in the treatment of this lethal disease.

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