Update in Diffuse Parenchymal Lung Disease 2006 - ATS Journals

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Jan 10, 2007 - IPF but characterized by prominent ground-glass on HRCT with little or no ..... capacity to activate pro–hepatocyte growth factor, a factor that.
Update in Diffuse Parenchymal Lung Disease 2006 Athol U. Wells1 and Cory M. Hogaboam2 1

Interstitial Lung Disease Unit, Royal Brompton Hospital, London, United Kingdom; and 2Immunology Program, Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan

CLINICAL ADVANCES In 2006, there were important advances in the understanding of diffuse parenchymal lung diseases (DPLDs), especially in relation to the idiopathic interstitial pneumonias (IIPs), including idiopathic pulmonary fibrosis (IPF) and nonspecific interstitial pneumonia (NSIP). Among other DPLDs, the topics of particular interest centered on sarcoidosis, parenchymal disease associated with connective tissue disease, and lymphangioleiomyomatosis (LAM). Insights on disease prevalence, diagnosis, prognostic evaluation, and management are considered separately for the IIPs and for other DPLDs. IIPs

Prevalence of disease. Epidemiology is necessarily an inexact science. Previous statements of the incidence and prevalence of IPF have largely centered on death certification and disease registries (1, 2). Clinical diagnostic criteria, which are sensitive but not specific for IPF, capture other disorders with the clinical features of IPF, including NSIP, other IIPs, and patients with undiagnosed hypersensitivity pneumonitis (HP). Imprecision in the estimation of the prevalence of IPF is well illustrated in a recent evaluation of a U.S. health care claims database (3). Based on narrow case definitions, requiring the performance of a biopsy procedure (surgical or transbronchial biopsy) or high-resolution computed tomography (HRCT), the incidence and prevalence of IPF in the United States were estimated to be 6.8 per 100,000 and 14 per 100,000, respectively. However, with more liberal diagnostic criteria, these figures rose strikingly to 16.3 per 100,000 and 42.7 per 100,000, respectively. As the true figure lies somewhere between these estimates, IPF appears to be substantially more prevalent than previously reported, a conclusion supported by a reported incidence of 6.8 per 100,000 in the United Kingdom, in 2000–2003 (4). It is not clear whether these findings primarily represent changes in clinician diagnostic thresholds or whether there has been a real increase in disease prevalence. However, this uncertainty should not obscure the fact that IPF appears to be approximately as prevalent as a number of the more common malignancies, all of which attract a much larger share of community and research resources. Acute exacerbations of IPF have historically been viewed as rare events, a perception challenged by a surprisingly high prevalence of rapid deterioration in the inactive arms of three intervention studies (5–7). A 2-year frequency of acute exacerbations of approximately 10% has now been reported in a cohort of 147 patients with IPF (8), underlining the need for a reappraisal of the risk factors and management of this often-lethal disorder.

(Received in original form January 10, 2007; accepted in final form January 10, 2007 ) Correspondence and requests for reprints should be addressed to Cory M. Hogaboam, Ph.D., Immunology Program, Department of Pathology, Room 4057, BSRB, 109 Zina Pitcher Place, University of Michigan Medical School, Ann Arbor, MI 48109. E-mail: [email protected] Am J Respir Crit Care Med Vol 175. pp 655–660, 2007 DOI: 10.1164/rccm.200701-052UP Internet address: www.atsjournals.org

Classification and diagnosis. The standardization of terminology and diagnostic criteria in the IIPs (9, 10) has helped clinicians throughout the world to better understand each other and has catalyzed the performance of large multinational studies of new agents in IPF, which require precise case definitions. However, the American Thoracic Society/European Respiratory Society (ATS/ERS) reclassification is not always easy for nonspecialist physicians to apply, and it has been suggested that a simpler subdivision of the IIPs into three broad groups, based on likely outcome, would be more user friendly (11). The diagnostic reference standard is multidisciplinary evaluation, with participation by clinicians, radiologists, and histopathologists. The pivotal diagnostic role of HRCT was recently underlined by the finding that clinical diagnoses of DPLDs, made by experienced physicians, changed in approximately 50% of cases with the addition of HRCT data, and there was a striking increase in agreement on the diagnosis of IPF (12). However, diagnostic problems posed by NSIP in that study were typical of those encountered in routine practice. The cardinal difficulty is the perception that NSIP can be associated with diverse clinicoradiologic profiles, with some patients having features of organizing pneumonia (13) or HPs (14), and others presenting with the clinical features of IPF but characterized by prominent ground-glass on HRCT with little or no honeycombing (15). Strong, indirect support for the clinical subclassification of NSIP comes from a study of gene expression profiles, in which distinct “signatures” identified in IPF and HP were applied to NSIP cases (16). In patients with NSIP with an HP-like inflammatory profile, there was clinical support for an HP pathogenesis. In other NSIP cases, the profile was believed to represent an idiopathic NSIP “signature,” although the data can also be interpreted as indicative of a fibrotic IIP continuum, with NSIP cases clustering at one end of an IPF/ NSIP spectrum (17). Thus, there appears to be a common clinical and scientific basis for the reevaluation of the entity of NSIP, and an ATS/ERS workshop will shortly report on this question. Histologic observations in IPF. A high profusion of fibroblastic foci in usual interstitial pneumonia has been associated with higher mortality in patients with IPF in several reports (18–21). Until recently, fibroblastic foci were considered to be discrete sites of lung injury or repair. However, on the basis of morphometric analysis with three-dimensional reconstruction, fibroblastic foci appear to be highly interconnected and may represent the edge of a complex reticulum extending from the pleura into the underlying parenchyma (22). The polyclonality of foci in this study was indicative of a reactive, and not a malignant, process. The significance of these findings is not yet clear as they have yet to be integrated into a pathogenetic hypothesis. It remains uncertain whether the novel concept of a “fibroblastic reticulum” applies equally to patients with less profuse fibroblastic foci (23). However, the observation represents a striking change in current morphologic perceptions and is likely to stimulate a good deal of future work. Prognostic evaluation in IPF. The six-minute-walk test has emerged as an important addition to prognostic evaluation, with significant oxygen desaturation identifying a subgroup of patients with a much higher mortality (24–26). It is not yet known

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whether this observation denotes incipient pulmonary hypertension, itself a malignant prognostic determinant (27, 28). It appears that the six-minute-walk test might have particular utility as a basis for prioritizing lung transplantation. In patients with less severe disease, the six-minute-walk distance has had limited prognostic value in IPF (24, 25), but in a study of patients listed for transplantation, a walk distance of less than 207 m was associated with a fourfold increase in mortality and was more prognostically accurate than FVC levels (29). Six-minute-walk data have also clarified the best use of serial pulmonary function tests in routine monitoring, Since the ATS/ ERS reclassification of the IIPs, a number of studies have disclosed the prognostic power of serial functional trends in predicting mortality (30–34). In most studies, a significant decline in FVC was the most adverse prognostic factor, but a decline in carbon monoxide diffusing capacity (DlCO) has also been variably prognostically significant. In a recent report of approximately 200 patients with IPF, decline in FVC was the serial change that most accurately predicted mortality in IPF, provided that desaturatiion to 88% did not occur at baseline six-minutewalk testing (35). By contrast, DlCO trends predicted mortality more consistently than FVC trends in patients with baseline sixminute-walk desaturation to 88% or lower. Treatment. In the last 5 years, novel pathogenetic concepts have led to a number of trials of new agents in the treatment of IPF. However, there is relatively little to report in 2006. Studies of management strategies in the IIPs were confined to existing agents. One group reported that the use of interferon␥1b for 2 years, controlled by colchicine, was associated with a striking reduction in mortality in IPF and a lesser decline in FVC levels, although serial DlCO levels and HRCT findings did not differ between the two treatment groups (36). These observations provided limited support for the efficacy of interferon-␥1b in IPF, suggested by marginal mortality trends in an earlier study (37), but they must be interpreted with caution due to limitations in study design (38). Indirect support for the notion that controlling gastroesophageal reflux might be therapeutically important in IPF came from the intriguing prospective observation that nearly 90% of patients with IPF have acid reflux, which is often clinically occult (39). It was suggested that earlier treatment of acute exacerbations of IPF with pulsed intravenous corticosteroid therapy might improve the outcome, based on a small clinical series (40). However, the greater continuing focus in 2006 was on the interpretation of studies performed in the last 2 to 3 years and this applied especially to a study of high-dose acetyl cysteine in IPF, reported in late 2005 (41). There was a clearly significant difference in lung function trends favoring the active treatment arm in this study, but the applicability of these findings to routine practice generated very divergent opinions, ranging from relative nihilism (42) to robust optimism (43). Other DPLDs

Treatment data aside, clinical advances in 2006 were rather limited. There was an interesting observation of three patients with a previously unreported association between light-chain deposition disease and progressive obstructive pulmonary cystic disease, severe enough to require lung transplantation (44). Generalized fatigue was shown to be linked to global impairment in quality of life across a large sarcoidosis cohort, suggesting that the importance of this symptom is often undervalued in chronic disease (45). However, the most compelling data came from an LAM registry, containing more than 200 patients (46), easily the largest cohort systematically reported with this disease. Although most findings did not differ materially from earlier reports, the age range and variation in lung function impairment were wider than in previous series, with some patients having

little or no lung function impairment at presentation. As discussed in an accompanying editorial (47), the reasons for this apparent change in the pattern of disease are not yet clear, but it appears plausible that forme frustes of LAM may be more prevalent than previously appreciated. The most encouraging interventional study in 2006 involved the use of rituximab in a small group of patients with severe refractory Wegener’s granulomatosis (48). With lymphocytic depletion, a complete remission was invariable, with a clinical flare after B-lymphocyte reconstitution in only 1 of 10 cases. There is some difficulty in deconstructing the exact contributions made by rituximab and by high-dose corticosteroid therapy to short-term responsiveness, but the maintenance of remission in these patients was especially striking. In the remaining treatment studies, the unifying theme was the difficulty of assigning clinical significance to small but significant treatment effects on pulmonary function tests. The problem applied equally to a study of infliximab therapy in chronic pulmonary sarcoidosis (49) and to studies of oral (50) and intravenous (51) cyclophosphamide in patients with interstitial lung disease and systemic sclerosis. Certain key similarities existed between all three studies. The study designs were placebo controlled, but open therapy was also available for patients unwilling to participate. The three studied populations were characterized by relatively limited and, it must be suspected, relatively nonprogressive disease: a selection bias toward less progressive disease is increasingly recognized in placebo-controlled evaluation. In all three studies, positive treatment effects on FVC levels were only approximately 5%, but these were statistically significant in two studies (49, 50), although only marginally significant in the somewhat underpowered evaluation of intravenous cyclophosphamide in systemic sclerosis (51). It appears that, in progressive DPLD, a placebo-controlled design, widely viewed as optimal, may be inherently likely to engender inconclusive results, especially when open treatment is available. In both studies of cyclophosphamide in systemic sclerosis, functional deterioration appeared to be completely abolished by active treatment, but because disease was largely nonprogressive, the amplitude of the treatment benefit was small. A larger treatment benefit from oral cyclophosphamide was evident in patients with systemic sclerosis with more extensive disease on HRCT, providing useful guidance as to which patients to treat in clinical practice, as highlighted in an elegant accompanying editorial (52). However, the fact remains that a placebo-controlled design may seriously understate treatment effects when open therapy is also available, and this problem needs to be confronted urgently in chronic progressive fibrosing disorders, given the rapid recent and ongoing growth in numbers of therapeutic studies in this field.

PATHOBIOLOGICAL CONCEPTS Novel Therapeutic Targets in Preclinical Models of Pulmonary Fibrosis

Relevant therapeutic strategies for halting or even reversing the pathologic fibrosing response in the lung are desperately required, and experimental studies published in the Journal this year might provide some important clues as to how to address this clinical need. Bleomycin sulfate remains the pulmonary fibrosing agent of choice in the laboratory partly because the inflammatory and fibrotic events elicited by this antineoplastic antibiotic are sequential, providing a time course of 3 to 4 weeks during which novel therapeutics may be applied in a preventative and/or therapeutic manner (53). Chaudhary and colleagues (54) examined the preventative and therapeutic effects of two drugs, an antiinflammatory agent (i.e., prednisolone) and a putative

Pulmonary and Critical Care Updates

antifibrotic agent (i.e., imatinib mesylate or Gleevec, a plateletderived growth factor receptor [PDGFR]/cAbl/cKit kinase inhibitor), in a rat model of bleomycin-induced fibrosis. Oral prednisolone ablated the inflammatory response to bleomycin when administered from Day 1 after challenge, but failed to attenuate lung fibrosis when administered more than 10 days after bleomycin challenge. Conversely, the oral administration of imatinib mesylate effectively diminished both the inflammatory and fibrotic phases of this model. Ishii and colleagues (55) focused on the antiinflammatory and antifibrotic effects of another tyrosine kinase associated with the epidermal growth factor receptor (EGFR). Using AG1478, an oral EGFR tyrosine kinase inhibitor, for up to 14 days after the administration of bleomycin, they noted that the lung fibrotic response was significantly reduced, and postulated that this was due, in part, to the direct inhibitory effect of this compound on fibroblast activation. Consistent with the theme of targeting novel intracellular kinase signaling pathways during tissue remodeling events, Inayama and colleagues (56) addressed the role of IMD-0354, an inhibitor of the I␬B kinase-␤ after bleomycin-induced pulmonary fibrosis. This inhibitor prevents the degradation of the “inhibitor of ␬B” (I␬B), thereby preventing the translocation of activated nuclear factor (NF)-␬B into the cell nucleus. When administered daily for 28 days to mice with implanted osmotic pumps containing bleomycin, IMD-0354 markedly attenuated the pulmonary fibrotic response induced by this agent. However, IMD-0354 showed less effect when administered for the first 14 days of this model or when administered from Days 15 to 28 after bleomycin challenge. Tabata and colleagues (57) presented another promising antifibrotic therapeutic approach. They showed that all-trans-retinoic acid exhibited both preventative (i.e., antiinflammatory) and therapeutic (i.e., antifibrotic) effects in both models of radiationand bleomycin-induced pulmonary fibrosis, and these effects were associated with significantly reduced interleukin-6 and transforming growth factor-␤, as well as the inhibition of lung fibroblast proliferation and differentiation. Although the precise mechanism through which all-trans-retinoic acid works is unknown, these investigators suggest that it may modulate p38 mitogen-actived protein kinase (MAPK) and/or NF-␬B– dependent pathways. Another promising and novel strategy in targeting pulmonary fibrosis stems from Avivi-Green and colleagues’ (58) study in which the response of discoidan domain receptor-1 (DDR1)– deficient mice to an intrapulmonary challenge with bleomycin was examined. DDR1 is a tyrosine kinase receptor, which is present most abundantly on the basolateral surface of bronchial epithelium where it is in contact with type IV collagen. The activation of this receptor follows its binding to components of collagen; its activation leads to p38 and ERK (extracellular signal-regulated kinase) MAPK inflammatory signaling cascades in inflammatory cells, such as monocytes and macrophages. In this study, mice lacking DDR1 were resistant to bleomycininduced lung inflammation and fibrosis, as well as p38 MAPK activation. Taken together, these preclinical studies raise the distinct possibility that selective pharmacologic targeting of intracellular pathways involving tyrosine kinase receptors and/ or signaling pathways downstream from these receptors might provide benefit in clinical fibrotic disease. Novel Gene Identification in IPF

The IIPs represent between 40 and 50% of all interstitial lung diseases, and histologic categorization of IIPs remains a major challenge to pathologists (59). Of late, considerable attention has been directed toward the profiling of patient lung biopsy material for genetic “fingerprints,” which might aid in the identi-

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fication of novel biomarkers for diagnostic and classification purposes. Selman and coworkers (60) profiled open lung biopsies from patients with IPF, NSIP, and HP using customized oligonucleotide DNA microarrays. Their findings revealed that unique gene expression signatures differentiate IPF from HP. Specifically, IPF is a disease associated with increased expression of tissue remodeling, epithelial genes, and myofibroblast genes, whereas HP has increased expression for genes associated with inflammatory and immune cells and processes. Importantly, this group found that most of the NSIP biopsies showed a gene signature that differed from both IPF and HP, but they also noted that some of the NSIP biopsies had gene profiles more similar to IPF, whereas some were closer to HP. With the concern that the analysis of whole lung biopsies may dilute region-specific changes in gene expression, Kelly and colleagues (61) used laser capture microdissection to examine gene expression in fibroblastic foci, adjacent epithelium, and hyperplastic type 2 pneumocytes in IPF biopsies. Their analysis showed that tissue inhibitor metalloproteinase (TIMP)-1, matrix metalloproteinase (MMP)-1, MMP-2, MMP-7, MMP-9, and osteopontin were increased to varying degrees in these compartments, particularly in fibroblastic foci, relative to control alveolar material. Interestingly, the increase in TIMP-1 gene expression detected in fibroblastic foci was not present when whole biopsy material was also analyzed. Although the importance of T cells in IPF remains controversial, Pignatti and coworkers (62) showed that the expression of chemokine receptors on T cells derived from IPF bronchoalveolar lavage (BAL) fluid samples expressed significantly lower CXC chemokine receptor-3 (CXCR3) and higher CC chemokine receptor-4 (CCR4) compared with T cells from other non-IPF, sarcoidosis, and healthy control groups. These findings are of importance given previous preclinical data showing that CXCR3 and its ligands (i.e., CXCL9, CXCL10, and CXCL11) limit (63–65), whereas CCR4 ligands (CCL17 and CCL22) promote (66), the development of fibrosis in bleomycintreated mice. Together, these studies showed that several gene and/or protein expression profiling techniques are advancing our understanding of putative mechanisms leading to the unrelenting fibrosis in IPF. Abnormal Activation and Regulation of IPF Pulmonary Fibroblasts

A rogue fibroblast with aberrant proliferative, migratory, and synthetic properties is believed to be at the center of the pathologic lung scarring that characterizes IPF. Histologically distinct areas comprising foci of fibroblasts and matrix, also known as fibroblastic foci, have garnered considerable interest and speculation as to their diagnostic importance and origin. As discussed previously, Cool and colleagues (22) provide compelling evidence that these histologic features are part of the leading edge of a complex and interconnected reticulum apparently formed by the polyclonal proliferation of fibroblasts penetrating from the pleura into the parenchyma. Explanations for this reactive response by such cells are not forthcoming but other studies in the Journal this year highlight two major defects in regulatory mechanisms controlling the proliferative, synthetic, and migratory properties of IPF fibroblasts. First, Marchand-Adam and coworkers (67) documented that IPF fibroblasts have a diminished capacity to activate pro–hepatocyte growth factor, a factor that limits lung fibrosis. Interestingly, this defect in IPF fibroblasts was partially corrected with the exogenous addition of prostaglandin E2 (PGE2). Second, White and colleagues (68) observed that IPF fibroblasts had diminished PTEN (phosphatase and tensin homolog deleted on chromosome 10); PTEN possesses protein phosphatase properties and regulates the phosphorylation of a number of cellular kinases. The loss of PTEN was

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associated with the increased expression of ␣-smooth muscle actin, cell proliferation, and collagen generation. Although the overt activity of IPF fibroblasts may be due to their loss of important regulatory factors and/or mechanisms, Prasse and colleagues (69) showed that these cells might also be responding to the byproducts of overtly activated alveolar macrophages. They found that alveolar macrophages are a major source of CCL18, a human CC chemokine, that drives collagen production in fibroblasts, and this increased collagen generation provided further stimulus for the alveolar macrophage to generate more CCL18. The authors referred to this sequence of events as a vicious positive-feedback circle. In sum, these studies provide significant insights, but also raise additional questions as to the origin and the propagation of the rogue IPF fibroblast lacking appropriate synthetic, migratory, and proliferative properties. IPF and Carcinogenesis

Lung cancer is a major factor in the poor prognosis for patients with IPF. The studies presented by Terasaki and associates (70) revealed that 8-nitroguanine, a nitrated nucleotide and a putative biomarker for DNA and RNA damage induced by nitric oxide, was abundantly expressed in epithelial cells overlying dense fibrotic lesions in IPF biopsies. These data suggested that nitrative stress caused by the formation of 8-nitroguanine was demonstrable in epithelial cells present in IPF biopsies, and such stress combined with oxidative injury may increase the risk of lung cancer neoplasia in this disease. Sarcoidosis

The inflammatory profile associated with sarcoidosis has been extensively studied and T-helper 1 lymphocytes and activated macrophages are major contributors to granuloma formation, which characterizes this disease. Genomic proteomic analyses have given insight into this unique immune disease. Kriegova and colleagues (71) extended this form of analysis to a largescale proteomic examination of BAL fluid samples from patients with chest X-ray stage I, II, or III sarcoidosis. They confirmed that surface-enhanced laser desorption/ionization time-of-flight mass spectroscopy was a highly reproducible technique for protein detection in BAL fluid samples from patients with sarcoid. Human serum albumin, ␣1-antitrypsin, and protocadherin-2 precursor were sarcoidosis-associated proteins detected in greater abundance in sarcoid versus healthy BAL fluid samples. The lack of the lipid-derived mediator PGE2 has been associated with a number of abnormal lung remodeling events. Hill and coworkers (72) provided a gene polymorphism study focused on prostaglandin–endoperoxide synthase 2 (PTGS2), a key enzyme in PGE2 synthesis. They observed that the dysregulation in the expression of PTGS2 in sarcoidosis was due to a polymorphism within this gene. Thus, these two studies add to the growing understanding of the remodeling and immune mechanisms provoking sarcoidosis. Conflict of Interest Statement : Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

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