Form Of Idiopathic Interstitial Pneumonia Research Articles

Idiopathic pulmonary fibrosis fibroblasts migrate and proliferate to CC chemokine ligand 21

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is the severest form of idiopathic interstitial pneumonia for which therapeutic targets are needed. Surgical lung biopsy specimens from IPF/UIP patients exhibit focal expression of CC chemokine receptor (CCR) 7, but the identity of these CCR7-positive cells is unknown. The purpose of the present study was to examine the functional and signalling significance of CCR7 expression of primary fibroblasts grown from IPF/UIP and normal surgical lung biopsy specimens. Primary fibroblasts were cultured from surgical lung biopsy specimens from IPF/UIP and normal patients. Fibroblasts treated with or without CC chemokine ligand (CCL) 21 were analysed for functional, transcriptional and proteomic differences using immunocytochemical analysis, gene arrays, Taqman real-time PCR, and migration, proliferation and Western blot assays. CCR7 was expressed by IPF/UIP fibroblasts, but not normal fibroblasts. IPF/UIP fibroblasts, but not normal fibroblasts, showed significant migratory and proliferative responses when exposed to CCL21, which were inhibited by pertussis toxin or neutralising antibodies to CCR7. Exposure of IPF/UIP fibroblasts to CCL21 altered the phosphorylation status of mitogen-activated protein kinase kinase 1/2, extracellular signal-regulated kinase 1/2 and ribosomal S6 kinase (90 kDa) in these cells; this was abrogated by pertussis toxin or CCR7-specific small interfering RNA. Together, these data demonstrate that CC chemokine ligand 21 modulates the functional properties of idiopathic pulmonary fibrosis/usual interstitial pneumonia fibroblasts, but not normal fibroblasts.

Idiopathic Interstitial Pneumonia: A Clinicopathological Perspective

Idiopathic interstitial pneumonia (IIP) represents a diverse group of lung disorders with variable prognoses and responses to therapy. As the name implies, the etiology is unknown. In the more severe forms of IIP, such as idiopathic pulmonary fibrosis and acute interstitial pneumonia, no effective therapies have been identified. In this perspective, the spatiotemporal variability in the histopathology of these disorders is discussed. It is proposed that common etiologies or injurious agents may produce variable histopathological "reactions" in the lung due to complex interactions between the host (genetic/epigenetic factors, age) and environmental factors. Accurate clinical and biological phenotyping may be necessary to stratify or group patients who are most likely to respond to specific modes of therapy.

THE COMBINATION OF INTERFERON GAMMA-1B AND PIRFENIDONE INHIBITS TRANSFORMING GROWTH FACTOR–BETA-INDUCED GENE INDUCTION IN CELLULAR MODELS OF LUNG FIBROSIS

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common and most aggressive form of idiopathic interstitial pneumonia. Transforming growth factor beta (TGF-β) has been shown to be a particularly important mediator of fibroblast proliferation and extracellular matrix (ECM) production in IPF lungs. Interferon gamma-1b (IFN-γ 1b) inhibits TGF-β-induced collagen synthesis by up-regulating SMAD7 expression and inducing formation of an inhibitory RFX5 complex on the collagen promoter region. We recently discovered that pirfenidone exerts antifibrotic effects by inhibiting p38 MAPK, an essential intracellular mediator of TGF-β-induced collagen synthesis. Given their distinctive modes of action against TGF-β-induced collagen expression, we wanted to determine whether the concomitant administration of IFN-γ 1b and pirfenidone would result in complementary or antagonistic effects against TGF-β-induced gene induction in human lung fibroblasts (HFL-1).

DEVELOPMENT OF A HIGH THROUGHPUT COLLAGEN ASSAY USING A CELLULAR MODEL OF IDIOPATHIC PULMONARY FIBROSIS

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is the most common form of idiopathic interstitial pneumonia. Numerous inflammatory and pro-fibrotic cytokines may contribute to the development of this disease. Among these, transforming growth factor beta (TGF-?) plays a significant role in collagen accumulation by inducing expression and suppressing degradation of collagens. Undesirable accumulation of collagens results in the development of numerous diseases, including pulmonary fibrosis. Previous techniques, which were time-consuming and expensive, were based on the evaluation of radio-labeled proline, quantification of hydroxyproline using high performance liquid chromatography, or precipitation of collagen using Sirius Red.

Surfactant protein C mutations in sporadic forms of idiopathic interstitial pneumonias

Interstitial pneumonias have recently been associated with mutations in the gene encoding surfactant protein C (SFTPC). In particular, SFTPC mutations have been reported in a number of familial forms of pulmonary fibrosis and in infants with interstitial lung diseases. The present study searched for SFTPC mutations in adult patients with sporadic idiopathic interstitial pneumonia. In total, 35 adult patients with sporadic idiopathic interstitial pneumonia and 50 healthy subjects were investigated for SFTPC mutations by direct DNA sequencing. Of the patients with sporadic idiopathic interstitial pneumonia, 25 suffered from idiopathic pulmonary fibrosis and 10 patients from nonspecific interstitial pneumonia. Only two frequent nonsynonymous variants, T138N and S186N, were detected. Allele frequencies of both variations as well as of other identified noncoding alterations did not differ significantly between the diverse patient groups and control subjects. In conclusion, mutations in the gene encoding surfactant protein C are not common in sporadic cases of idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia, suggesting that the mutated gene does not play an important role in the pathogenesis of these forms of idiopathic interstitial pneumonia.

Histologic Spectrum of Idiopathic Interstitial Pneumonias

Histopathologic classification plays a key role in separating multiple forms of idiopathic interstitial pneumonia into clinically meaningful categories with important differences in natural history, prognosis, and treatment. Microscopic criteria in diagnosis of these entities include the pattern and microanatomic distribution of inflammation, fibroblast proliferation, collagen deposition, and architectural remodeling. Usual interstitial pneumonia (UIP) defines idiopathic pulmonary fibrosis and is the most common of the idiopathic interstitial pneumonias. UIP has distinctive morphologic features that allow precise diagnosis in classical cases. Other forms of idiopathic interstitial pneumonia include desquamative interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, acute interstitial pneumonia, and nonspecific interstitial pneumonia. These latter categories differ from UIP in that the histopathologic findings do not, by themselves, allow specific diagnosis in most cases and require careful correlation with clinical and radiologic findings.

Transbronchial Biopsy in Usual Interstitial Pneumonia

Usual interstitial pneumonia (UIP) is a slowly progressive, usually fatal form of idiopathic interstitial pneumonia for which there is no effective treatment. Transbronchial biopsy (TBB) has been utilized only to exclude other diseases such as sarcoidosis, lymphangitic carcinoma, and infection, for example, but TBB is generally considered to have little role in confirming UIP. To determine whether diagnostic changes of UIP can be appreciated on TBB specimens. Retrospective analysis of TBB specimens from patients with proven UIP. Two study sites in the United States. Twenty-one patients with UIP confirmed by surgical lung biopsy and/or lung explant, and 1 patient with UIP confirmed by clinical and radiographic findings along with follow-up information. Adequate tissue for diagnosis was available in 18 cases; in 7 cases (32% overall), there were varying combinations of interstitial fibrosis in a patchwork pattern along with fibroblast foci and/or honeycomb change. These features were considered diagnostic of UIP. Interstitial fibrosis along with fibroblast foci or honeycomb change were seen in two other cases, but the fibrosis lacked a patchwork pattern, and these features were considered consistent with UIP. Nonspecific interstitial fibrosis alone was found in nine cases. In summary, characteristic histologic features of UIP can be identified on TBB specimens more often than previously appreciated. TBB may be more useful in confirming UIP than previously recognized.

高齢者呼吸器疾患の基礎と臨床の最前線 ２．特発性間質性肺炎の新規治療効果

Idiopathic pulmonary fibrosis (IPF), a chronic form of idiopathic interstitial pneumonia, has a poor prognosis with an average life expectancy of 3-4 years from the time of diagnosis. Although patients with IPF have been treated with steroids or immunosuppressants to control the inflammation that occurs earlier in the course of disease, these drugs have not improved the survival of patients with IPF. Recently, several clinical studies of antifibrotic drugs have been conducted in patients with IPF. In Japan, we demonstrated that pirfenidone prevents deterioration of pulmonary function and significantly decreases the incidence of acute exacerbation of IPF in a well-designed, placebo-controlled, double-blind, randomized study. We have also adopted a new system for evaluation of dynamic pulmonary function, which involves measuring the lowest SpO2 level during a 6-minute walk at a constant speed and assessing the pulmonary capacity of patients with IPF. In a study of patients with pulmonary fibrosis associated with Hermansky-Pudlak syndrome in the United States, pirfenidone slowed the decrease in %FVC in patients with a %FVC of >60%, but had no significant effects on patients with a %FVC of < or =60%. Large-scale clinical studies of INF-gamma in patients with IPF in North America and Europe have reported decreases in the mortality of patients with mild IPF with a FVC of >60%, although percentages of patients with disease status rated as 'exacerbated', 'unchanged' and 'improved' after treatment did not differ between the INF-gamma and placebo groups. This presentation reported important future strategies for the treatment of IPF.

Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis

Nonspecific interstitial pneumonia, a recently described form of idiopathic interstitial pneumonia, is characterized by uniform involvement of the alveolar septae with interstitial inflammation and variable amounts of fibrosis. Histological observations differentiate nonspecific interstitial pneumonia from usual interstitial pneumonia and clinically, patients with a nonspecific interstitial pneumonia pattern show better prognosis than those with usual interstitial pneumonia. We have genetically analyzed a family with a history of usual interstitial pneumonia. Most of the patients presented as adults and their biopsies showed a pattern consistent with usual interstitial pneumonia. However, three family members presented in early childhood and their biopsies revealed a nonspecific interstitial pneumonia pattern. The inheritance pattern of usual interstitial pneumonia is consistent with autosomal dominant inheritance with variable expression. DNA sequence analyses of the surfactant protein C gene in children with nonspecific interstitial pneumonia and adults with usual interstitial pneumonia exhibit a common heterozygous mutation located in exon 5. The mutation causes a Leu188 to Gln188 change in the carboxy-terminal region of prosurfactant protein C, possibly affecting peptide processing. These observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types.

Augmented pulmonary IL-4 and IL-13 receptor subunit expression in idiopathic interstitial pneumonia

Background: Some idiopathic interstitial pneumonias (IIPs) are characterised by fibroproliferation and deposition of extracellular matrix. Because efficacious treatment options are limited, research has been directed towards understanding the cytokine networks...

Interstitial lung diseases: characteristics at diagnosis and mortality risk assessment

As the diagnostic assessment of the different forms of interstitial lung disease (ILD) is similar, this study aims to compare age, sex, the functional and broncho-alveolar lavage fluid (BALF) findings at diagnosis between the different forms of ILDs. In addition we want to determine which of these variables determine survival. We evaluated 315 patients (176 males and 139 females) in whom the diagnosis was made of sarcoidosis ( n=87), ILD due to connective tissue disease ( n=56), hypersensitivity pneumonitis ( n=50), idiopathic pulmonary fibrosis (IPF) ( n=64), other forms of idiopathic interstitial pneumonia ( n=29) or ILD due to an undefined form of fibrosis ( n=29). We analysed the role on outcome of type of disease, gender, age at diagnosis, type of cells in BALF, FVC and DL CO. In a Kaplan–Meier analysis IPF has the worst outcome in comparison with other types of ILDs. A Cox regression analysis showed that type of ILD, FVC, age at diagnosis and % of macrophages in BALF predict outcome of patients affected by ILD.

Therapeutic Targeting of IL-4- and IL-13-Responsive Cells in Pulmonary Fibrosis

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia (UIP), can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Understanding the cytokine networks that may affect immune and structural cell activation and, hence, the progression of these fatal fibrotic diseases, has been a focus in our research. In this regard, we have examined the role of interleukin (IL)-4 and IL-13 and their respective receptor subunits in this process. Examination of clinical surgical lung biopsies (SLBs) showed that IIP is characterized by the abnormal, heightened expression of the receptor subunits that bind IL-4 and IL-13. Specifically, IL-4Ralpha and IL-13Ralpha2 (the high-affinity IL-13 receptor subunit) was present in greater abundance in SLBs and fibroblasts from IIP patients compared with normal patients, who exhibited no evidence of pulmonary fibrosis. These clinical findings prompted us to investigate whether the targeting of pulmonary cell types that were highly responsive to IL-4 and IL-13 was a viable therapeutic option in IIP. Using a chimeric protein comprised of human IL-13 and a truncated version of an exotoxin from Pseudomonas (abbreviated IL13-PE), we observed that IL13-PE selectively targeted human pulmonary fibroblasts grown from IIP SLBs, whereas it had a minimal effect on fibroblasts grown from biopsies from normal patients. In murine models characterized by abnormal airway or interstitial fibrotic responses, the intranasal administration of IL13-PE significantly attenuated the fibrotic response through the targeting of IL-4Ralpha- and IL-13Ralpha2-expressing pulmonary cells, including monocytes, macrophages, and pulmonary fibroblasts. Together, these data demonstrate that IL-4 and IL-13 are required for the initiation and maintenance of pulmonary fibrosis, and highlight the importance of further investigation of anti-fibrotic therapeutics that prevent the action of both cytokines during clinical pulmonary fibrosis.

Therapeutic attenuation of pulmonary fibrosis via targeting of IL-4- and IL-13-responsive cells.

Severe forms of idiopathic interstitial pneumonia (IIP), such as usual interstitial pneumonia, can be impervious to modern steroid and immunosuppressive treatment regimens, thereby emphasizing the need for novel effective therapies. Consequently, research attention has been directed toward understanding the cytokine networks that may affect fibroblast activation and, hence, the progression of certain IIPs. This led us to investigate whether the specific targeting of resident lung cells responsive to IL-4 and IL-13 exerted a therapeutic effect in an experimental model of IIP, namely the bleomycin-induced model of pulmonary fibrosis. IL-4, IL-13, and their corresponding receptor subunits, IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2, were maximally expressed at the mRNA and protein levels in whole lung samples on day 21 or 28 after an intratracheal bleomycin challenge. The intranasal administration of an IL-13 immunotoxin chimeric molecule (IL13-PE) from days 21-28, but not for 1-wk periods at earlier times, after bleomycin challenge had a significant therapeutic effect on histological and biochemical parameters of bleomycin-induced pulmonary fibrosis compared with the control group. The intranasal IL13-PE therapy significantly reduced the numbers of IL-4 and IL-13 receptor-positive mononuclear cells and macrophages and the levels of profibrotic cytokine and chemokine in the lungs of bleomycin-challenged mice on day 28. Thus, this study demonstrates that IL-4- and/or IL-13-binding cells are required for the maintenance of pulmonary fibrosis induced by bleomycin and highlights the importance of further investigation of antifibrotic therapeutics that target these cells during pulmonary fibrosis.

Centrilobular Fibrosis: A Novel Histological Pattern of Idiopathic Interstitial Pneumonia

The classification of idiopathic interstitial pneumonias (IIP) is still under debate. In this context, we observed in some of our patients with a clinical and radiological diagnosis of IIP a different histological picture with an aggressive centrilobular scarring centered in the bronchiolar epithelia, but involving the surrounding parenchyma, which underwent extensive remodeling. We hypothesized that this pattern is a form of IIP that could be separated out histologically from the previously described patterns, in particular from usual interstitial pneumonia (UIP) and non-specific interstitial pneumonia (NSIP). Forty-nine patients with clinical and radiological diagnosis of IIP and open-lung biopsies were retrospectively selected from 1982 to 1998. The biopsies were reviewed according to the following criteria: derangement of lobular architecture, temporal homogeneity and subpleural or bronchocentric distribution of the lesions, fibroblast foci, bronchial epithelium necrosis and regeneration, exposure of the basal membrane, squamous metaplasia, basophilic intraluminal contents, and foreign bodies within the remodeling airspaces. Three groups were found: UIP (24 patients), NSIP (13), and a third that we named centrilobular fibrosis (CLF) (12). All histological parameters were significantly different among the three groups (p < 0.001). CLF is a specific, homogeneous, and recognizable histological pattern of IIP, and can be isolated from UIP and NSIP.

Nonspecific Interstitial Pneumonia/Fibrosis

Sixty-four cases of interstitial pneumonia were identified that could not be classified into one of three main categories of idiopathic interstitial pneumonia. These cases, descriptively termed nonspecific interstitial pneumonia/fibrosis, were characterized by varying proportions of interstitial inflammation and fibrosis that appeared to be occurring over a single time span (i.e., the process was temporally uniform.) The most common presenting complaint was dyspnea for several months, and chest radiographs usually showed bilateral interstitial infiltrates. The prognosis was good with only five deaths due to progressive respiratory disease in 48 patients with known follow-up (11%). No deaths occurred in patients whose biopsies showed pure inflammation and no fibrosis. Nonspecific interstitial pneumonia must be separated from the three main forms of idiopathic interstitial pneumonia because of better prognosis and different treatment options. It should not be considered a specific disease, however, because it may have varying etiologies including underlying connective tissue diseases, organic dust or other exposures, and prior acute lung injury; less often, it may reflect a nonrepresentative biopsy of another process.