Pulmonary and Critical Care Updates Update in Diffuse Parenchymal Lung Disease 2009 Oliver Eickelberg1 and Moise´s Selman2 1 Comprehensive Pneumology Center, University Hospital, Ludwig Maximilians University Munich, Asklepios Hospital Gauting and Helmholtz Zentrum Mu ¨ nchen, Munich, Germany; and 2Instituto Nacional de Enfermedades Respiratorias ‘‘Ismael Cosı´o Villegas,’’ Me´xico DF, Me´xico
Diffuse parenchymal lung diseases (DPLD), usually referred as interstitial lung diseases, entail a heterogeneous group of more than 150 different entities that share common clinical, radiologic, physiologic, and pathologic manifestations but differ in their underlying etiology and molecular pathophysiology. DPLD may develop in response to a variety of causes, such as in response to drugs, in the frame of collagen-vascular diseases, or in response to inorganic (asbestos, silica) or organic (avian proteins, thermophilic bacteria) dusts. In contrast, the etiology of the idiopathic interstitial pneumonias (IIP), including nonspecific interstitial pneumonia and idiopathic pulmonary fibrosis (IPF), remains unknown. The prevalence and incidence of DPLD is often underestimated: More than 800,000 patients may suffer from DPLD in the Western World, and 80% of them are diagnosed with sarcoidosis, IIP, or hypersensitivity pneumonia, or their symptoms are seen as secondary to collagen-vascular disease. IPF, which represents the most aggressive form of DPLD, is characterized by an average survival time of 3 to 5 years after diagnosis. Fibroblast foci, aggregates of activated myofibroblasts, represent the hallmark lesions of IPF, which promote excessive extracellular matrix deposition. Fibroblast foci occur in subepithelial layers, close to areas of alveolar epithelial cell injury and repair, suggesting that impaired epithelial–mesenchymal crosstalk contributes to the pathobiology of IPF. Indeed, it is well accepted that repetitive injury and subsequent repair of alveolar epithelial type II (ATII) cells, in the presence or absence of local inflammation, represent a key pathogenic mechanism in IPF, which leads to aberrant growth factor activation and perpetuation of the fibrotic response. Hence, IPF might be considered as an imperfect or aberrant repair process. During the last years, we have witnessed important advances in our understanding of the molecular mechanisms underlying IPF, although this understanding has not translated well into the therapeutic arena. The speed of discovery makes us hopeful that changes will come along soon. In this update, we highlight discoveries that have been published in this and other journals during the last year, primarily in the areas that we believe will shape our understanding, and thus therapeutic options, of IPF in future years. We discuss the experimental and translational advances including developmental aspects, cell plasticity including epithelial-mesenchymal transition, and epigenetic silencing, followed by clinical advances including diagnostic tools, predictors of outcome, and therapeutic (Received in original form January 27, 2010; accepted in final form February 25, 2010) Correspondence and requests for reprints should be addressed to Oliver Eickelberg, M.D., Comprehensive Pneumology Center, Ludwig Maximilians University Hospital and Helmholtz Zentrum Mu ¨ nchen Max-Lebsche-Platz, 31 81377 Munich Germany. E-mail: oliver.eickelberg@helmholtz-muenchen.de or Moise´s Selman, Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502, CP 14080, Me´xico DF, Me´xico. E-mail: mselmanl@yahoo.com.mx Am J Respir Crit Care Med Vol 181. pp 883–888, 2010 DOI: 10.1164/rccm.201001-0124UP Internet address: www.atsjournals.org
challenges. Finally, we underscore important findings regarding DPLD other than IPF that appeared in this journal during the last year.
EXPERIMENTAL AND TRANSLATIONAL ADVANCES Developmentally Active Pathways in IPF
IPF was long considered to be a ‘‘burned-out’’ disease, resembling an irreversible final scar. Recently, however, whole genomic approaches have uniformly documented that IPF is characterized by a very specific genomic ‘‘footprint,’’ with an array of genes differentially expressed when compared with control lungs. Among other findings, these arrays have revealed that developmentally active signaling pathways are aberrantly activated or dysregulated in IPF. These include well known pathways, such as Wnt, fibroblast growth factor (FGF), bone morphogenetic protein, or transforming growth factor (TGF)-b signaling, but also less prominent pathways, such as hepatocyte growth factor (HGF), hedgehog, snail, or twist signaling pathways. In 2008, these findings prompted Selman and colleagues to consider IPF as a disease characterized by aberrant recapitulation of developmental programs (1). In 2009, this hypothesis was further confirmed by a variety of studies published in this and other journals, as outlined below. FGF signaling plays a crucial role in lung development, where it is required for proper epithelial and mesenchymal expansion during branching morphogenesis. Lungs do not form in the absence of FGF-10, and mice with decreased FGF-10 levels exhibit markedly hypoplastic lungs. Gupte and colleagues could show that overexpression of FGF-10 during experimental pulmonary fibrosis prevented ATII cell injury and protected mice from fibrotic transformation (2), essentially highlighting FGF-10 as a protective factor for the alveolar epithelium during injury. On the other hand, Mitani and colleagues showed that the transcriptional coactivator with PDZ-binding motif (TAZ), a soluble intracellular mediator that links cytoplasmic signaling events to transcriptional regulation in the nucleus, is required for proper lung development and alveolarization (3). Mice deficient in TAZ exhibited airspace enlargement and emphysematous changes but were protected against bleomycin-induced lung fibrosis, likely through an aberrant expression of connective tissue growth factor. It is critical that similar observations for FGF-10 or TAZ be reported in patients with IPF in the future. Two important studies focusing on b-catenin/Smad and Wnt1inducible signaling pathway protein (WISP)1 have implicated Wnt signaling in experimental lung fibrosis and IPF (4, 5). Kim and colleagues demonstrated an epithelial integrin-dependent crosstalk between b-catenin and Smad signaling and showed that epithelial a3 integrin was required for b-catenin phosphorylation, b-catenin/Smad2 interaction, and epithelial-mesenchymal transition (EMT) (5). Increased b-catenin phosphorylation was also detected in patients with IPF. Ko¨nigshoff and colleagues have shown that WISP1, a downstream effector of Wnt, is a potent
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profibrotic effector in IPF (4). These results suggest that this pathway may be a promising target for therapeutic intervention in IPF. Up-regulation of WISP1 is also observed in colitis and gastric carninoma, rectal cancer, and cardiomyocyte hypertrophy. Epithelial–Mesenchymal Transition and the Source of Fibroblasts in IPF
Although the fibroblast focus is considered to represent areas of active fibrogenesis, the origin of the mesenchymal cells in this lesion is still heavily debated. Three major theories attempt to explain the genesis of these activated (myo)fibroblasts: First, local proliferation of resident mesenchymal cells are thought to increase the fibroblast pool in response to fibrogenic cytokines and growth factors. Second, bone marrow–derived circulating progenitors (e.g., fibrocytes) are thought to traffic to the injured lung, where they may serve as progenitors for fibroblasts. And third, resident ATII cells, via the process of EMT, can undergo a phenotypic transformation to fibroblast-like cells. To undergo EMT, an ATII cell must remodel its cell–cell and cell–matrix adhesion contacts, reorganize its actin cytoskeleton, induce mesenchymal gene expression, and acquire motile capacity. These processes are under tight transcriptional control, maintained by factors such as Twist, NF-kB, Rho, Rac, Snai, or GSK-3b. Some recent studies have investigated in detail the mechanisms of EMT in IPF. Pozharskaya and colleagues demonstrated increased Twist expression in IPF lungs with concomitant infection by Epstein-Barr virus, largely in hyperplastic ATII cells that exhibited evidence of EMT in vivo (6). Epstein-Barr virus infection also triggered EMT in a Wnt5a/CUX1-dependant manner in a lung epithelial cell line (7). Jayachandran and colleagues reported increased Snai expression in experimental lung fibrosis and IPF in hyperplastic ATII cells showing evidence of EMT (8). In vitro, Snai and Twist controlled EMT in primary ATII cells, highlighting these transcription factors as key mediators of EMT in the lung. Shukla and colleagues have identified HGF as a potent inhibitor of EMT in a lung epithelial cell line and in primary murine ATII cells (9). In this study, HGF induced the expression of Smad7 in a mitogen-activated protein kinase– dependent manner. Smad7 expression counteracted EMT by inhibiting TGF-b signaling, the most important profibrotic EMT mediator identified thus far. Mercer and colleagues have highlighted the hyperplastic pulmonary epithelium as well by showing that these cells are able to express the chemokine CCL2 in experimental and idiopathic pulmonary fibrosis (10). The epithelium was thus also suggested to further aggravate fibroblast activation via mediator secretion. Along these lines, Germano and colleagues have shown in the Journal that reconstitution of the lung with epithelial progenitors (prominin-1/CD133-positive cells) protected them from experimental pulmonary fibrosis (11), indicating that interfering with epithelial mediator release, as well as reconstituting normal epithelia, is a valid therapeutic strategy. Although these studies have provided detailed evidence of signaling pathways controlling EMT in vitro and in vivo, we are left in doubt about the relevance of EMT in the setting of IPF. It is unclear to what extent EMT contributes to the onset, progression, or perpetuation of pulmonary fibrosis. An earlier study by Kim and colleagues estimated an overall twofold increase in mesenchymal cells 3 weeks after inducing experimental lung fibrosis with TGF-b1 (12). In this study, it was suggested that epithelialderived mesenchymal cells accounted for nearly all of this in vivo increase of fibroblasts. This phenomenon was also addressed in a key study in the Journal by Tanjore and colleagues (13). Here, the authors investigated in parallel the contribution of EMT and bone marrow progenitors to the pool of S100A4-positive fibroblasts in the bleomycin model. Interestingly, EMT and bone
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marrow progenitor recruitment accounted for approximately 33 and 20% of S100A4-positive fibroblasts, respectively (13). Extending these observations, one would have to assume that the remaining 50% of fibroblasts derive from resident fibroblasts or from an unidentified source. Although these studies provided key observations to our understanding of the relevance of EMT in vivo, key questions remain, primarily whether similar numbers occur in IPF. Epigenetic Silencing
Epigenetics is an essential process for the regulation of the gene function; it is defined as a stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence. Epigenetic mechanisms include DNA methylation on cytosine residues of CpG dinucleotides, posttranslational modifications of histones, chromatin remodeling, or alterations in nuclear architecture. Although epigenetic regulation has been documented in a number of diseases, studies in IPF remain scanty. Three recent papers have highlighted a putative linkage among epigenetic modifications and the activated and profibrotic phenotype of IPF fibroblasts (14–16). Sanders and colleagues showed that Thy-1, a receptor that suppresses the differentiation of fibroblasts to myofibroblasts and inhibits fibrogenic activities, is epigenetically silenced via hypermethylation of cytosine-guanine islands in the gene promoter (14). Furthermore, the loss of Thy-1 expression in fibroblastic foci in vivo correlated with hypermethylation of the promoter region of the Thy-1 gene. The other two studies investigated histone acetylation/deacetylation patterns, which are closely associated with active and repressive chromatin states, respectively, with profibrotic behavior of IPF fibroblasts. Coward and colleagues demonstrated diminished expression of cyclooxygenase 2 (COX-2) in IPF fibroblasts due to epigenetic abnormalities of histone acetylation (15). The inducible COX-2 and the constitutive isoform COX-1 produce prostaglandin-E2 from endogenous arachidonic acid. ProstaglandinE2 is a major eicosanoid product of lung fibroblasts and exhibits strong antifibrogenic activities, including the inhibition of fibroblast migration and proliferation and the reduction of collagen biosynthesis. It was found that defective histone acetylation due to reduced recruitment of histone acetyl transferases and increased recruitment of the histone deacetylases–containing corepressor complexes to the COX-2 promoter prevents activated transcription factors from binding to the COX-2 promoter, resulting in diminished COX-2 gene transcription in IPF. Guo and colleagues showed that differentiation of normal human lung fibroblasts to myofibroblasts was dependent on histone deacetylase (HDAC)-4 and required Akt phosphorylation (16). Lung fibroblasts stimulated with TGF-b1 expressed a-SMA, collagen, connective tissue growth factor, and TGF-b1. Broad HDAC inhibition or the specific knockdown of HDAC4 by siRNA blocked fibroblast to myofibroblast differentiation via reduction of Akt phosphorylation. HDAC inhibition did not affect the expression of connective tissue growth factor or TGF-b1, indicating that this epigenetic process does not participate in all TGF-b1–mediated cellular events. Therapeutic Approaches in Experimental Models
An aberrant response of alveolar epithelial cells is crucial in the pathogenesis of IPF, but therapies focused on these cells are scarce. Two recent papers suggest that molecules known to be active on epithelial cells may be useful for treatment. Gupte and colleagues explored the putative antifibrotic role of FGF10 (2). Using mice engineered for the inducible expression of FGF10 in the alveolar epithelium, they demonstrated that up-regulation of FGF10 during the inflammatory and fibrotic phases of bleomycin-
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induced lung injury leads to a strong attenuation of fibrosis. This response is likely the consequence of increased resistance of epithelial cells to injury and apoptosis. Aguilar and colleagues (17) explored the possible role of keratinocyte growth factor (KGF), also known as FGF-7, using a new stem cell–based approach with an inducible Tet-on lentiviral vector–mediated KGF gene delivery system. The authors showed the combined cell and gene therapy is able to deliver KGF to the injured lung parenchyma and importantly, that KGF attenuates bleomycininduced lung injury, inducing proliferation of alveolar type II cells and decreasing lung collagen levels. Interestingly, they also found that hematopoietic stem cells may be better vehicles than mesenchymal stem cells for gene therapy to ameliorate lung fibrosis. Oga and colleagues reported that inhibition of prostaglandin signaling, in particular prostaglandin F signaling, presents a valid therapeutic option in the bleomycin model (18). Another key study reported that targeting of NADPH oxidase 4 led to an abrogation of fibrogenesis in animal models (19). This, together with the reported findings on Wnt signaling and imbalanced coagulation (4, 20), presents four independent signaling schemes of great therapeutic value that will have to stand a test in clinical trials in the future.
CLINICAL ADVANCES Diagnostic Tools
There are two discriminative modalities for the diagnosis of IPF: (1) HRCT, which is characterized by the presence of reticular abnormalities, traction bronchiectasis, and honeycombing with basal and peripheral predominance, and (2) lung biopsy, which displays features of usual interstitial pneumonia upon histologic investigation. Novel studies may help to distinguish IPF from other fibrotic lung disorders in cases with atypical HRCT results or difficult-to-perform biopsy. In a recent article, Ohshimo and colleagues (21) showed that bronchoalveolar lavage (BAL) lymphocytosis may be useful. In an appropriate clinical setting, less than 30% of BAL lymphocytes showed a favorable discriminative power for the diagnosis of IPF, whereas higher levels of lymphocytes were seen in patients with hypersensitivity pneumonitis or idiopathic nonspecific interstitial pneumonia.
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Disease progression is highly variable in IPF. A subgroup of patients with IPF develops an accelerated clinical course with death only few years after the beginning of symptoms. Biomarkers of rapid progression have been examined in several studies (24–26). Boon and colleagues (25) generated the lung expression profiles using SAGE technology from six individuals with relatively stable (or slowly progressive) IPF and compared these profiles with six individuals with progressive IPF. They identified a set of 102 transcripts that were at least fivefold upregulated and a set of 89 transcripts that were at least fivefold down-regulated in the progressive group. The overexpressed genes included SP-A1, two members of the MAPK-EGR-1HSP70 pathway that regulate cigarette-smoke–induced inflammation, and Plunc (palate, lung, and nasal epithelium–associated), a gene not previously implicated in IPF. These findings indicate that molecular signatures of gene expression may be useful in the identification of markers associated with an accelerated course of IPF. T-cell subsets may also be useful to determine prognosis. In a recent study, a global deficiency in the number and function of CD41CD251FOXP31 T regulatory cells (Tregs) was found in peripheral blood and BAL from patients with IPF (27). The putative role of Treg reduction in the pathogenesis of the disease is unknown. However, a strong correlation between the compromised Treg function in BAL with parameters of disease severity (decreased FVC and DLCO) was observed. Cardiopulmonary function. Fell and colleagues tested the hypothesis that a decrease in O2max during baseline and shortterm longitudinal cardiopulmonary exercise tests predicts mortality in patients with IPF (28). The authors evaluated 117 patients with IPF and showed that patients with baseline maximal oxygen uptake less than 8.3 ml/kg/min had an increased risk of death (n 5 8; hazard ratio, 3.24; 95% confidence interval, 1.10–9.56) after adjusting for age, sex, smoking status, baseline FVC, and baseline DLCO, suggesting that this study may add prognostic information for patients with IPF. In another study, it was shown that patients displaying combined IPF and emphysema show a poorer survival rate compared with those with IPF alone (29). Mortality was associated with disproportionate pulmonary arterial hypertension (29). Indeed, in severe diffuse lung fibrosis, early mortality is correlated with increased pulmonary vascular resistance (30).
Potential Predictors of Outcome
Serum and BAL biomarkers. Reliable noninvasive biomarkers that may indicate the activity of lung fibrogenesis or predict its outcome are scarce. In this context, Prasse and colleagues explored the value of serum CCL18 concentrations to predict outcome in a cohort of 72 patients with IPF (22). CCL18 is a profibrotic CC-chemokine mainly produced by macrophages. It was observed that the baseline serum CCL18 concentration was strongly predictive of mortality. Serum CCL18 above 150 ng/ml was associated with an 8.0 hazard of death after adjusting for age, sex, smoking history, baseline FVC percent predicted, and baseline DLCO. In a similar study, Kinder and colleagues (23) evaluated the association of serum surfactant protein (SP)-A and SP-D levels with mortality in a prospective cohort of 82 patients with biopsy-proven IPF. SP-A and SP-D are secreted primarily by alveolar epithelial type II cells, and their plasma levels appear to increase early after injury of the alveolar epithelium. The authors found that serum SP-A levels obtained at the time of initial diagnosis are independently and strongly associated with death or lung transplant, particularly during the first year of follow-up. These studies indicate that models containing serum biomarkers in addition to clinical factors known to be associated with increased risk of mortality may have substantial predictive value for this disease.
Acute Exacerbations of IPF
Acute exacerbation represents a rapid and clinically significant deterioration of unidentifiable cause in a patient with underlying IPF (31). It is a catastrophic event with a poor survival rate, characterized by an unexplained and severe worsening of dyspnea and hypoxemia within 30 days. Upon exacerbation, HRCT reveals novel bilateral ground-glass abnormalities or consolidation superimposed on a background reticular or honeycomb pattern consistent with the usual interstitial pneumonia pattern. Histopathology shows a diffuse alveolar damage superimposed on underlying usual interstitial pneumonia. Two studies published in 2009 contributed to our understanding of the pathophysiology of this process and identified biomarkers that could allow an early diagnosis. Moeller and colleagues quantified the percent of circulating fibrocytes in 51 patients with stable IPF and seven patients during an episode of acute exacerbation (32). As controls, they evaluated 10 patients with acute respiratory distress syndrome (ARDS) and seven age-matched healthy subjects. Fibrocytes are circulating bone marrow–derived cells identified by the coexpression of mesenchymal markers (i.e., type I and III collagens) and hematopoietic markers (i.e., CD34, CD45). Circulating fibrocytes home to and extravasate into sites of tissue injury, upon which these cells differentiate into fibroblasts and
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myofibroblasts. Recent findings have also indicated that fibrocytes may contribute to the expansion of the mesenchymal cell population during the development of IPF. The study by Moeller and colleagues demonstrated a threefold increase in circulating fibrocytes in patients with stable IPF compared with healthy control subjects. But importantly, fibrocyte counts increased substantially (from less than 1% to an average of 15% of peripheral blood leukocytes) during episodes of acute exacerbation and returned to preexacerbation levels in patients who recovered. Fibrocytes did not correlate with clinical parameters of IPF but were predictive of higher mortality. Intriguingly, fibrocyte counts in patients with ARDS were not different from those of control subjects or patients with stable IPF despite the fact that they present diffuse lung damage and actively create a variety of repair signals. The results of this study suggest that the quantification of fibrocytes may be a potential tool as a biomarker, regardless of our understanding their biological (or pathological) properties in the lung microenvironment. To better understand the molecular mechanisms and to identify new potential biomarkers, Konishi and colleagues (33) analyzed global gene expression patterns in the lungs of patients with stable IPF and those undergoing acute exacerbations. Interestingly, compared with control samples, lungs from stable IPF or IPF with acute exacerbation exhibited similar gene expression signatures. However, direct comparison of stable IPF and IPF lungs with acute exacerbation led to the identification of 579 significantly differentially expressed genes. Among them were genes related to stress response, such as heat-shock proteins, b-defensins, or mitosis-related genes including histones and CCNA2. The b-defensins and CCNA2 were localized to the epithelium of acute exacerbation IPF lungs, where widespread areas of proliferation and apoptosis were detected, indicating that the central molecular events during acute exacerbation are localized to the alveolar epithelium. In addition, plasma levels of b-defensins were significantly higher in patients with acute exacerbation, suggesting that the identification of proteins originating from the lung epithelium have a potential use as biomarkers for evaluating patients with IPF during the course of acute exacerbation.
THE THERAPEUTIC CHALLENGE Clinical Trials
IPF is a progressive and lethal disease, and current therapies are largely ineffective. Last year, King and colleagues demonstrated that IFNg-1b had no effect on survival in patients with IPF and mild-to-moderate impairment of pulmonary function in the largest randomized controlled clinical trial (826 patients) performed in this disease (34). Similarly, a previous study performed with bosentan (BUILD1), a dual endothelin receptor antagonist, showed no effect, although a nonsignificant trend to delayedtime-to-death or disease progression was observed (35), and a second clinical trial is ongoing (BUILD3). Likewise, an exploratory study in patients with clinically progressive IPF was performed with etanercept, a recombinant soluble human tumor necrosis factor (TNF)-a receptor, which binds and neutralizes TNF activity (36). No differences were found in the predefined endpoints, although a nonsignificant reduction in disease progression was seen in several functional parameters and quality-oflife endpoints among subjects receiving etanercept (36). Finally, a multicentered, double-blind, placebo-controlled phase III clinical trial was conducted in Japanese patients to determine the efficacy and safety of pirfenidone, a novel antifibrotic agent. Pirfenidone is an orally active, small-molecule drug that is reported to exert antifibrotic, antiinflammatory, and antioxidant
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activities. Pirfenidone inhibits collagen synthesis, the production of multiple proinflammatory cytokines, and fibroblast proliferation and stimulation. Results of this study showed that, although pirfenidone did not induce an improvement of patients with IPF, it may decrease the rate of decline in vital capacity and increase the progression-free survival time at least over 52 weeks (37). Important Findings in Other DPLD
Granulomatous lung disorders. Hypersensitivity pneumonitis (HP) is a T-cell–mediated alveolitis with a marked Th1 response. The molecular mechanisms involved in the pathogenesis of the disease have not been fully elucidated. In this context, Joshi and colleagues (38) have shown that IL-17 is prominently expressed in experimental HP. IL-17 has multiple effects on immune and nonimmune cells and up-regulates the expression of a number of proinflammatory cytokines and chemokines. Importantly, neutralization of IL-17 with a polyclonal antibody provided a major therapeutic effect. These data indicate an important role of IL-17 during HP progression and suggest a therapy for relief from this disease. Sarcoidosis is other important and complex granulomatous inflammation affecting the lung. Crouser and colleagues (39) examined the gene expression profile of lung tissues obtained from patients with sarcoidosis. Their most relevant finding was the identification of highly interactive gene networks, which regulate the expression of granuloma-promoting signaling proteins (such as STAT1), Th1-type inflammatory cytokines (such as IL-7 or IL-15), or proteolytic enzymes (MMP-12 and ADAM-like, decysin 1 [ADAMDEC1], a recently discovered member of the metalloproteinase family) that are operating within the lung compartment of patients with sarcoidosis. Interestingly, increased MMP-12 and ADAMDEC1 gene and protein expression in BAL samples were associated with more advanced disease (39). One specific and clinically separate subgroup of patients with sarcoidosis is represented by Lo¨fgren’s syndrome, which has been associated with HLA-DRB1*03. Grunewald and colleagues investigated whether this human leukocyte antigen type influenced the clinical behavior in a large cohort of patients with this syndrome (40). In their study, patients with Lo¨fgren’s syndrome exibited a different disease course, depending on whether they were DRB1*03 positive or not. Almost every DRB1*03-positive patient recovered within 2 years, whereas this occurred only in half of the DRB1*03-negative patients. Although the granulomatous reaction is usually associated with a Th1-type response, accumulating evidence supports that a sustained challenge can polarize the cytokine environment toward a Th2-like phenotype. The mechanisms involved in this switch remain unclear. Ito and colleagues investigated the contribution of Toll-like receptor-9 (TLR9) to the initiation and maintenance of a Th2-dependent lung granulomatous response (41). The authors demonstrated that TLR9-deficient mice developed larger granulomas with increased collagen deposition, associated with a selective abrogation in IFN-g (Th1 cytokine) production, an enhanced Th2 (IL-4, IL-5, and IL-13) cytokine profile, and an increased M2 macrophage phenotype in the lung. Furthermore, the authors demonstrated that the adoptive transfer of bone marrow–derived dendritic cells isolated from wild-type mice, but not from TLR9deficient mice, can restore the granulomatous response in TLR92/2 to a wild-type phenotype. These findings indicate that TLR9 plays a key role in the polarization to a Th2-type lung granulomatous inflammation. Miscellaneous DPLD. Patients with systemic sclerosis (SSc) frequently develop interstitial lung disease. However, the pathogenic mechanisms and the factors that may enhance this pathologic reaction in the lungs are unclear. In this context,
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Savarino and colleagues explored the presence of gastroesophageal reflux (GER) in patients with SSc with and without ILD (42). Patients with SSc and ILD had lower esophageal contraction amplitudes, a higher frequency of GER episodes (both acid and nonacid), and a higher frequency of reflux episodes reaching the proximal esophagus. These findings suggest that patients with SSc with ILD have more extensive esophageal involvement and severe GER, which may contribute to the development or severity of the lung disease. In another interesting study involving patients with SSc without significant lung fibrosis, left heart dysfunction, and manifest pulmonary arterial hypertension, it was found that the presence of mean pulmonary arterial pressure and resistance in the upper normal range at rest or with moderate exercise is associated with decreased exercise capacity and may indicate early pulmonary vasculopathy (43). Hermansky-Pudlak syndrome type 1 (HPS-1) is a rare autosomal recessive disease characterized by defective biogenesis of lysosome-related organelles. Patients with HPS-1 may develop a progressive fibrotic lung disease, although the mechanisms involved are unclear. Rouhani and colleagues found that lung inflammation and alveolar macrophage activation in HPS-1 are associated with high lung concentrations of cytokines and chemokines but normal levels of TGF-b1 (44). Their findings also indicate that alveolar macrophages appear to be the main source of the pathogenic mediators and, thus, may contribute to a self-perpetuating proinflammatory cycle in the HPS-1 lung.
CONCLUSIONS The above cited studies in this and other journals, published largely over the last year, have contributed to important advances in our understanding of DPLD. These advances have translated to novel diagnostic ideas and potential predictors of outcome but not yet into novel therapeutic benefits. Although this remains the biggest challenge, the authors are hopeful that future updates in this journal will have the distinct pleasure to report those findings in detail. Conflict of Interest Statement: O.E. has received research grants from Ergonex Pharma ($50,001–$100,000) and the Helmholtz Society (over $100,000). M.S. has received consultancy fees from Boehringer Ingelheim ($5001–$10,000).
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