Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis

To investigate the molecular events that may underpin dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we analyzed the expression patterns of beta-catenin on 20 IPF/UIP lung samples, together with two downstream target genes of Wnt signaling, cyclin-D1, and matrilysin. In 18 of 20 cases of IPF/UIP investigated on serial sections, nuclear beta-catenin immunoreactivity and abnormal levels of cyclin-D1 and matrilysin were demonstrated in proliferative bronchiolar lesions (basal-cell hyperplasia, squamous metaplasia, bronchiolization, honeycombing). The nature of these lesions was precisely defined using specific markers (DeltaN-p63, surfactant-protein-A, cytokeratin-5). Interestingly, nuclear beta-catenin accumulation was also demonstrated in fibroblast foci in most (16 of 20) IPF/UIP samples, often associated with bronchiolar lesions. Similar features were not observed in normal lung and other fibrosing pulmonary diseases (diffuse alveolar damage, organizing pneumonia, nonspecific interstitial pneumonia, desquamative interstitial pneumonia). Sequence analysis performed on DNA extracted from three samples of IPF/UIP did not reveal abnormalities affecting the beta-catenin gene. On the basis of these findings new models for IPF/UIP pathogenesis can be hypothesized, centered on the aberrant activation of Wnt/beta-catenin signaling, with eventual triggering of divergent epithelial regeneration at bronchiolo-alveolar junctions and epithelial-mesenchymal-transitions, leading to severe and irreversible remodeling of the pulmonary tissue.     

Evidence of type II pneumocyte apoptosis in the pathogenesis of idiopathic pulmonary fibrosis (IFP)/usual interstitial pneumonia (UIP)

BACKGROUND/AIMS: The pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), a chronic and incurable human respiratory disease, is not well established. This study was designed to investigate whether the apoptosis of type II pneumocytes could be the precipitating factor in the pathogenesis of IPF. METHODS: Nineteen specimens obtained by retrospective review of the medical and pathological records of 55 patients with IPF, four normal subjects, and 10 disease control lungs were analysed. The selected specimens had normal alveoli with intervening patchy scarring of the lung parenchyma, fulfilling the pathological criteria for UIP. To identify individual cells undergoing apoptosis in the normal alveoli, electron microscopy and in situ end labelling of fragmented DNA were performed on paraffin was embedded sections using digoxigenin-11-dUTP and the enzyme terminal deoxynucleotidyl transferase. RESULTS: Apoptosis was detected in the normal alveoli of 17 of the 19 patients with IPF/UIP and was absent in the controls. Electron microscopy demonstrated apoptotic changes in type II pneumocytes. These results indicate that apoptotic type II pneumocyte death occurs in normal alveoli of IPF/UIP and could be the principal cause of several events that account for the histological, clinical, and functional alterations seen in IPF/UIP. CONCLUSIONS: In conclusion, numerous type II pneumocytes from the normal alveoli of most patients with IPF/UIP actively undergo programmed cell death. This finding may shed new light on the pathogenesis of this disease, with implications mainly for the treatment of affected patients.     

Enhanced expression of interleukin-18 and its receptor in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP) is a major interstitial lung disease (ILD). Recently, we established a new mouse model for ILD in which daily administration of interleukin (IL)-18 with IL-2 induces lethal lung injury, suggesting that IL-18 is involved in the pathogenesis of ILD. Here, utilizing immunohistochemistry, we have analyzed IL-18 and IL-18 receptor (IL-18R) alpha expression in the lungs of 18 patients with IPF/UIP and 13 control subjects by using monoclonal anti-IL-18 antibodies and a new monoclonal antibody for IL-18Ralpha (H44). IL-18 was expressed in bronchoalveolar epithelium, alveolar macrophages, and the endothelium of small vessels in control subjects, and was abundantly expressed in the majority of pulmonary cells in patients with IPF. IL-18Ralpha was expressed in bronchoalveolar epithelium and alveolar macrophages in control subjects, and was strongly expressed in interstitial cells in patients with IPF, especially in the fibroblastic foci (FF). Interestingly, IL-18Ralpha expression was only weakly observed in areas showing established fibrosis. Semiquantitative analysis revealed that the histologic FF score was significantly correlated with the IL-18Ralpha expression level in FF lesions. Moreover, IL-18 levels in the serum and bronchoalveolar lavage fluid of patients with IPF were significantly higher than those in control subjects. Our findings suggest IL-18 and IL-18R are involved in the pathogenesis of IPF/UIP.     

Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia

Takemura T, Akashi T, Kamiya H, Ikushima S, Ando T, Oritsu M, Sawahata M & Ogura T
(2012) Histopathology
Pathological differentiation of chronic hypersensitivity pneumonitis from idiopathic pulmonary fibrosis/usual interstitial pneumonia Aims: To evaluate the histological characteristics differentiating chronic hypersensitivity pneumonitis (chronic HP) with a usual interstitial pneumonia (UIP)‐like pattern from idiopathic pulmonary fibrosis (IPF)/UIP. Methods and results: Surgical lung biopsy specimens from 22 patients with chronic HP diagnosed as having a UIP‐like pattern upon histological examination and 13 patients with IPF/UIP were examined and the incidences of bronchiolitis, perilobular fibrosis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, fibroblastic foci, honeycombing, granulomas, giant cells, lymphocytic alveolitis and lymphoid follicles were compared. Bronchiolitis, centrilobular fibrosis, bridging fibrosis, organizing pneumonia, granulomas, giant cells and lymphocytic alveolitis were significantly more frequent among patients with chronic HP than among patients with IPF (all P < 0.01). Conclusions: Centrilobular fibrosis, bridging fibrosis and organizing pneumonia, in addition to bronchiolitis, granulomas and giant cells, are characteristic features of chronic HP with a UIP‐like pattern. These features are therefore important in differentiating chronic HP from IPF/UIP, as management strategies differ for the two disorders.     

Pathogenetic mechanisms in usual interstitial pneumonia/idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, usually fatal, form of interstitial lung disease characterized by failure of alveolar re-epithelialization, persistence of fibroblasts/myofibroblasts, deposition of extracellular matrix, and distortion of lung architecture which ultimately results in respiratory failure. Clinical IPF is associated with a histopathological pattern of usual interstitial pneumonia (UIP) on surgical lung biopsy. Therapy for this disease with glucocorticoids and other immunomodulatory agents is largely ineffective and recent trials of newer anti-fibrotic agents have been disappointing. While the inciting event(s) leading to the initiation of scar formation in UIP remain unknown, recent advances in our understanding of the mechanisms underlying both normal and aberrant wound healing have shed some light on pathogenetic mechanisms that may play significant roles in this disease. Unlike other fibrotic diseases of the lung, such as those associated with collagen vascular disease, occupational exposure, or chemotherapeutic agents, UIP is not associated with a significant inflammatory response; rather, dysregulated epithelial-mesenchymal interactions predominate. Identification of pathways crucial to fibrogenesis might offer potentially novel therapeutic targets to slow or halt the progression of IPF. This review focuses on evolving concepts of cellular and molecular mechanisms in the pathogenesis of UIP/IPF.     

COX-2 is widely expressed in metaplastic epithelium in pulmonary fibrous disorders

Idiopathic usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF) and asbestosis represent progressive and often fatal pulmonary fibrous disorders, whereas cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), and respiratory bronchiolitis-interstitial lung disease (RB-ILD) usually are reversible or nonprogressive conditions. Prostaglandin E2 (PGE2) inhibits fibroblast proliferation and myofibroblast transition, its production depending on cyclooxygenase-2 (COX-2). In patients with UIP/IPF, levels of PGE2 and COX-2 are reduced in fibroblasts, and levels of PGE2 in bronchioalveolar lavage fluid may be lowered. We analyzed the immunohistochemical expression of COX-2 in UIP/IPF, asbestosis, COP, DIP, and RB-ILD. Our results show that the metaplastic epithelium in UIP/IPF, asbestosis, and COP is widely COX-2+, whereas COX-2 positivity is scant in DIP and RB-ILD. The mesenchymal cells remained negative. Our results suggest that irrespective of the underlying disease, lung injury that causes extensive fibrosis induces wide expression of COX-2 in the regenerating metaplastic epithelium.     

Vascular dysfunction by myofibroblast activation in patients with idiopathic pulmonary fibrosis and prognostic significance

In this study, we demonstrated the importance of telomerase protein expression and determined the relationships among telomerase, endothelin-1 (ET-1) and myofibroblasts during early and late remodeling of parenchymal and vascular areas in usual interstitial pneumonia (UIP) using 27 surgical lung biopsies from patients with idiopathic pulmonary fibrosis (IPF). Telomerase+, myofibroblasts α-SMA+, smooth muscle cells caldesmon+, endothelium ET-1+ cellularity, and fibrosis severity were evaluated in 30 fields covering normal lung parenchyma, minimal fibrosis (fibroblastic foci), severe (mural) fibrosis, and vascular areas of UIP by the point-counting technique and a semiquantitative score. The impact of these markers was determined in pulmonary functional tests and follow-up until death from IPF. Telomerase and ET-1 expression was significantly increased in normal and vascular areas compared to areas of fibroblast foci. Telomerase and ET-1 expression was inversely correlated with minimal fibrosis in areas of fibroblast foci and directly associated with severe fibrosis in vascular areas. Telomerase activity in minimal fibrosis areas was directly associated with diffusing capacity of the lung for oxygen/alveolar volume and ET-1 expression and indirectly associated with diffusing capacity of the lungs for carbon monoxide and severe fibrosis in vascular areas. Cox proportional hazards regression revealed a low risk of death for females with minimal fibrosis displaying high telomerase and ET-1 expression in normal areas. Vascular dysfunction by telomerase/ET-1 expression was found earlier than vascular remodeling by myofibroblast activation in UIP with impact on IPF evolution, suggesting that strategies aimed at preventing the effect of these mediators may have a greater impact on patient outcome.     

Cell‐specific elevation of NRF2 and sulfiredoxin‐1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non‐specific interstitial pneumonia

Mazur W, Lindholm P, Vuorinen K, Myllärniemi M, Salmenkivi K, Kinnula VL. Cell‐specific elevation of NRF2 and sulfiredoxin‐1 as markers of oxidative stress in the lungs of idiopathic pulmonary fibrosis and non‐specific interstitial pneumonia. APMIS 2010; 118: 703–12. Human idiopathic pulmonary fibrosis (IPF) and non‐specific interstitial pneumonia (NSIP) have been proposed to be attributable to oxidative stress. The nuclear factor, erythroid derived 2, like protein (NRF2)–sulfiredoxin‐1 (SRX1) pathway was hypothesized to be associated with the pathogenesis of human pulmonary fibrosis. Several methods including digital morphometry were used in the assessment of the cell‐specific localization and expression of NRF2 and SRX1 and selected proteins linked to their activation/stability in human IPF/usual interstitial pneumonia (UIP) and NSIP lung. The proteins of the NRF2 pathway were localized in the hyperplastic alveolar epithelium and inflammatory cells in IPF and NSIP, but were absent in the fibroblastic foci characteristic of IPF. Morphometric evaluation revealed NRF2 and KEAP1 to be significantly elevated in the hyperplastic alveolar epithelium compared with the normal alveolar epithelium, and NRF2 was remarkably expressed in the nuclear compartment of the hyperplastic cells. SRX1 was expressed mainly in alveolar macrophages, and the number of SRX1‐positive macrophages/surface area was elevated in NSIP, a disease which contains more marked inflammatory reaction compared with the IPF/UIP lung. The expression of the NRF2 pathway in human IPF and NSIP is further evidence that the pathogenesis of human fibrotic lung diseases is oxidant‐mediated and originates from the alveolar epithelium.     

Clinical presentation of own idiopathic pulmonary fibrosis patients according to international consensus statement

Clinical presentation of idiopathic pulmonary fibrosis (IPF) restricted, according to current definition to usual interstitial pneumonia (UIP) was presented. 62 patients (39 males and 23 females) were assessed. The diagnosis of IPF/UIP has been based upon a combination of clinical, radiographic and physiologic features in majority of patients. Histologic confirmation from lung biopsy has been obtained in 16% of cases. Mean age of the patients was 64.4 +/- 8.0 years. Mean duration of symptoms was 20.1 +/- 14.1 months. The main symptom was exertional dyspnea. Crepitations were found in 98% of patients. Lung volumes were in normal range in substantial number of patients; TLC in 15 (24%) and FVC in 33 (53%) out of 62 patients. Disturbances of lung function concerned mainly gas exchange (DLCO diminished in 92% of cases) and lung compliance (diminished in all patients). Presentation of clinical, radiographic and physiologic features of IPF/UIP in a homogenous group of patients may be helpful in diagnosis of this common interstitial lung disease.     

Abnormal re-epithelialization and lung remodeling in idiopathic pulmonary fibrosis: the role of deltaN-p63

Products of the p63 gene, a recently described member of the p53 family, are constitutively expressed in the basal cells of human bronchi and bronchioli. The truncated isoforms of the p63 gene (deltaN-p63 proteins) counteract the apoptotic and cell cycle inhibitory functions of p53 after DNA damage, and this property is likely to be central in the cell renewal strategy of stratified epithelial tissues. To investigate the dysfunctional repair processes that characterize idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP), we immunohistochemically analyzed the expression of the transactivating and dominant-negative isoforms of the p63 gene on 16 tissue samples obtained from patients suffering from this disorder. In most IPF cases herein investigated, epithelial cells expressing deltaN-p63 were observed at sites of abnormal proliferation at the bronchiolo-alveolar junctions, characterized by epithelial hyperplasia, squamous metaplasia, bronchiolization, and abnormal p53 nuclear accumulation. Similar features were not observed in normal lung and in samples taken from other pulmonary diseases used as controls, including acute interstitial pneumonia, idiopathic bronchiolitis obliterans organizing pneumonia, nonspecific interstitial pneumonia, and desquamative interstitial pneumonia. On the basis of these findings, we can hypothesize a new model for UIP pathogenesis, involving a deregulated development of mesenchymal-epithelial interactions and abnormal proliferation of epithelial cells at the bronchiolo-alveolar junction after cell injury. In our view, the progressive loss of alveolar tissue and lung remodeling after injury in IPF/UIP is concomitantly produced by pneumocyte loss and alveolar collapse on one hand and by progressive bronchiolar proliferation and architectural distortion on the other.     

Effect of an immunotoxin to folate receptor �� on bleomycin-induced experimental pulmonary fibrosis

It has been suggested that alveolar and interstitial macrophages play a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) by producing proinflammatory and/or fibrogenic cytokines. We showed that inflammatory macrophages expressed folate receptor β (FRβ) while resident macrophages in normal tissues expressed no or low levels of FRβ. In the present study, we examined the distribution of FRβ‐expressing macrophages in the lungs of patients with usual idiopathic pulmonary fibrosis (UIP) and mice with bleomycin‐induced pulmonary fibrosis (PF) and tested whether the depletion of FRβ‐expressing macrophages could suppress bleomycin‐induced PF in mice. Immunostaining with anti‐human or ‐mouse FRβ monoclonal antibody (mAb) revealed that FRβ‐expressing macrophages were present predominantly in fibrotic areas of the lungs of patients with UIP and mice with bleomycin‐induced PF. Intranasal administration of a recombinant immunotoxin, consisting of immunoglobulin heavy and light chain Fv portions of an anti‐mouse FRβ mAb and truncated Pseudomonas exotoxin A, increased survival significantly and reduced levels of total hydroxyproline and fibrosis in bleomycin‐induced PF. In immunohistochemical analysis, decreased numbers of tumour necrosis factor‐α‐, chemokines CCL2‐ and CCL12‐producing cells were observed in the immunotoxin‐treated group. These findings suggest a pathogenic role of FRβ‐expressing macrophages in IPF. Thus, targeting FRβ‐expressing macrophages may be a promising treatment of IPF.     

Extracellular superoxide dismutase has a highly specific localization in idiopathic pulmonary fibrosis/usual interstitial pneumonia

Aims : Recent studies suggest the importance of oxidant stress in the progression of pulmonary fibrosis. The aim of this study was to investigate extracellular superoxide dismutase (ECSOD), the major antioxidant enzyme of the extracellular matrix of human lung, in biopsy - proven idiopathic pulmonary fibrosis (IPF) related to usual interstitial pneumonia (UIP).
Methods and results : Fibrotic areas and fibroblastic foci in UIP lungs were notable for absence of ECSOD by immunohistochemistry. Western blotting showed significantly lowered immunoreactivity of ECSOD in fibrotic compared with non-fibrotic areas of the diseased lung. The only cell type that showed intense ECSOD positivity in UIP was the interstitial mast cell. In order to investigate the mechanism for ECSOD depletion in fibrotic areas, alveolar epithelial cells were exposed to tumour necrosis factor-α and transforming growth factor (TGF)-β₁; TGF-β suggested a trend towards decreased synthesis. Patients with UIP were also assessed to determine whether this disease is associated with a naturally occurring mutation in ECSOD (Arg²¹³Gly) which leads to a loss of tissue binding of ECSOD. No significant differences could be found in the allele or genotype frequencies of this polymorphism between 63 UIP patients and 61 control subjects.
Conclusion : Overall, consistent with several other antioxidant enzymes, ECSOD is very low in fibrotic areas of UIP, which may further increase the oxidant burden in this disease.     

Gremlin localization and expression levels partially differentiate idiopathic interstitial pneumonia severity and subtype

Idiopathic pulmonary fibrosis (IPF) (histopathology of usual interstitial pneumonia, UIP) and non-specific interstitial pneumonia (NSIP) are diseases characterized by loss of normal lung architecture and function. The differential diagnosis between IPF/UIP and NSIP may be difficult. The levels of bone morphogenetic protein (BMP)-4 antagonist gremlin are up-regulated in IPF/UIP. The present study was performed to clarify whether the localization or the mRNA expression of gremlin or BMP-4 could be used in the differential diagnosis or assessment of severity of IPF/UIP and NSIP. Gremlin and BMP-4 immunoreactivities were quantitated from 24 UIP and 12 NSIP lung specimens. Quantitative real-time polymerase chain reaction analyses were performed to compare gremlin and BMP-4 expression between UIP (n = 8) and NSIP (n = 5) biopsies. Immunohistochemical positivity and mRNA levels were correlated to lung function parameters. In IPF/UIP biopsies, gremlin was detected mainly in the thickened lung parenchyma, whereas in NSIP it was observed in the alveolar epithelium. BMP-4-positive (BMP-4+) cells were detected solely in the alveolar wall. The percentage of gremlin-positive area was higher in IPF/UIP (5.1 +/- 0.6) than in NSIP (1.8 +/- 0.7) (n = 36, p < 0.0001). Gremlin mRNA levels were higher in advanced UIP (p = 0.008) and NSIP (p = 0.007) biopsies than in the normal control lung. A negative correlation was found between the specific diffusion capacity corrected for alveolar volume (DLCO/VA) and gremlin mRNA levels (r = - 0.69, p = 0.007). The highest numbers of BMP-4+ cells were found in NSIP biopsies. BMP-4 mRNA levels correlated positively with forced vital capacity (r = 0.801, p < 0.0001) and diffusion capacity. Parenchymal gremlin immunoreactivity is thus suggestive of a UIP-type interstitial pneumonia. Gremlin expression levels correlating negatively and BMP-4 levels positively with disease severity support recent observations of a fibroprotective role for the BMPs.     

Idiopathic pulmonary fibrosis vs. pulmonary involvement of collagen vascular disease: HRCT findings.

The purpose of this study is to assess the differences of high-resolution CT (HRCT) findings in patients with idiopathic pulmonary fibrosis (IPF) and pulmonary involvement of collagen vascular disease (CVD). We analyzed the HRCT findings of 33 patients with IPF and 23 patients with CVD in terms of predominant pattern, site of involvement, mediastinal lymph node enlargement, pleural change, and pulmonary volume loss. The predominant HRCT pattern was honeycombing for IPF (58%), and ground-glass opacity for CVD (57%). Predominantly subpleural involvement was seen in 90% of IPF and 83% of CVD patients. Mediastinal lymph node enlargement was seen in 61% of the patients with IPF and 13% with CVD (p = 0.0004). Pleural thickening was seen in 97% of the patients with IPF and 35% with CVD and the severity of pleural thickening is statistically significant (p = 0.00001). Pleural effusion was seen in 6% of the patients with IPF and 26% with CVD (p = 0.0351). The hilar height ratio was more than 1.5 in 52% of the patients with IPF and 30% with CVD (p = 0.2620). Although HRCT findings of IPF and pulmonary involvement of CVD are similar and overlap considerably, but patients with IPF showed a tendency to more progressed fibrosis than patients with CVD.     

Asbestos bodies in pulmonary hilar lymph nodes

Asbestos bodies (AB) have long been recognized in light microscopic (LM) sections of pulmonary hilar lymph nodes (LN) from patients with asbestos-related diseases, but the presence of AB on LM has not been correlated with the lung AB burden. The purpose of the present study was to determine whether AB in histologic sections of LN are indicative of heavy lung asbestos burdens. Twenty cases (17 with asbestosis, 15 with carcinoma of the lung, and two with malignant pleural mesothelioma) with at least one AB on a hilar LN section were identified. Bleach digestion of lung tissue in 15 cases demonstrated a median of 24,000 AB/g by LM and 44,000 AB/g by scanning electron microscopy. Digestion of hilar nodes demonstrated 21,800, 15,500, and 3,200 AB/g by LM in three cases which had lung burdens of 22,000, 481,000, and 5470 AB/g, respectively. A fourth LN specimen contained 322,000 AB/g in a case with no lung available to digest. Mean AB lengths in the LN in three cases were 48, 45, and 27 microns. Fourteen control cases of men over 50 without known asbestos exposure or asbestos-related disease had no AB in LN sections even after staining for iron. Among fourteen patients with parietal pleural plaques and an elevated lung asbestos body content, AB were observed in iron-stained LN sections in only two cases. These two patients had 3240 and 610 AB/g lung tissue, respectively (normal range 0 to 20 AB/g). We conclude that the finding of AB on a histologic section of hilar LN is generally indicative of a heavy lung AB burden.(ABSTRACT TRUNCATED AT 250 WORDS)     

Heterogeneous proliferation of type II pneumocytes in usual interstitial pneumonia

AIMS: Heterogeneous alveolar fibrosis, the most specific pathological finding in idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP), enables differentiation of UIP from other interstitial pneumonias. Heterogeneous and mild alveolar injury may occur, and this will be a clue to clarifying the pathogenesis of UIP. METHODS: We examined nine lung biopsy specimens obtained from patients with IPF and five control specimens. We semi-quantitatively examined alveolar injury by measuring the density of type II pneumocytes. Serial 3 microm sections were stained with anti-Thomsen-Friedenreich (TF) antibody. We divided each UIP lesion into three areas: area near fibrosis (fibrous area), area with an apparently normal alveolar structure (normal area), and area between the fibrous and normal areas (intervening area). RESULTS: Immunostaining with anti-TF antibody stained the apical surface of type II pneumocytes and enabled us to recognise and count type II pneumocytes. The density of type II pneumocytes was increased in the fibrous area, and gradually decreased away from the fibrous lesion. The densities of type II pneumocytes in the above three areas were, respectively: 13.9+/-2.0, 7.2+/-1.6, and 9.5+/-1.6/mm alveolar length. The densities in the fibrous and intervening areas were significantly greater than those in the normal area and in control specimens (6.6+/-0.7/mm). CONCLUSIONS: If the density of type II pneumocytes indicates their degree of regeneration after alveolar injury, it reflects the severity of the pre-existing injury. This study confirms that heterogeneous and mild alveolar injury occurs in UIP.     

Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis

Cha S‐I, Chang C S, Kim E K, Lee J W, Matthay M A, Golden J A, Elicker B M, Jones K, Collard H R & Wolters P J (2012) Histopathology  61, 98–106 Lung mast cell density defines a subpopulation of patients with idiopathic pulmonary fibrosis Aims: The relationship of mast cells to the pathogenesis of lung fibrosis remains undefined despite recognition of their presence in the lungs of patients with pulmonary fibrosis. This study was performed to characterize the relationship of mast cells to fibrotic lung diseases. Methods and results: Lung tissues from patients with idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis (HP), systemic sclerosis (SSc)‐related interstitial lung disease (ILD) and normal individuals were subjected to chymase immunostaining and the mast cell density quantified. Eosinophils were quantified by immunostaining for eosinophil peroxidase. Changes in lung function were correlated with mast cell density. Lung tissue obtained from IPF patients had a higher density of chymase‐immunoreactive mast cells than that from patients with HP, SSc‐related ILD or normal lungs. IPF lung tissue had a higher density of eosinophils than normal lung. There was no correlation between mast cell density and eosinophil density in IPF lung. IPF patients with high mast cell density had a slower rate of decline in forced vital capacity (FVC) than IPF patients with low mast cell density. Conclusions: Mast cell density in IPF lungs is higher than in other fibrotic lung diseases and normal lungs. Increased mast cell density in IPF may predict slower disease progression.     

Lymph node pathology in pulmonary veno-occlusive disease and pulmonary capillary heamangiomatosis

To assess the histological bases of lymphadenomegaly, which has been reported as a frequent radiological finding in pulmonary veno-occlusive disease (PVOD), we have reviewed pulmonary and mediastinal lymph nodes resected during lung transplantations in 19 patients suffering from PVOD and related pulmonary capillary haemangiomatosis (PCH). Lymphatic congestion was common and was often obvious in subsegmental and segmental lymph nodes. Vascular transformation of the sinuses, intra-sinusal haemorrhage with erythrophagocytosis and lymphoid follicular hyperplasia were frequent especially in lobar, hilar and mediastinal lymph nodes. These lesions were very significantly less frequent in 33 cases of pulmonary hypertension unrelated to PVOD. Due to their thoracic location, these non-specific lesions could simulate other diagnoses such as Castleman disease or lymphangioleiomyomatosis. However, in the setting of pulmonary hypertension, they should suggest PVOD and PCH. They are probably secondary to venous congestion, veno-lymphatic shunts and angiogenetic factors associated with these diseases.     

Nonspecific interstitial pneumonia: pathologic features and clinical implications

Nonspecific interstitial pneumonia (NSIP) is a form of chronic interstitial pneumonia that should be separated from the other idiopathic interstitial pneumonias, including most importantly, usual interstitial pneumonia (UIP). Diagnosis is predicated on identification of characteristic findings in a surgical lung biopsy in the appropriate clinical and radiological context. Affected patients may have a variety of underlying or associated conditions, although most have a form of idiopathic lung disease associated with a more favorable prognosis than UIP/idiopathic pulmonary fibrosis (IPF). Keys to distinguishing NSIP from UIP include absence of heterogeneous lung involvement, architectural distortion in the form of fibrotic scarring and/or honeycomb change, and fibroblast foci in NSIP.     

Insulin-like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition

Idiopathic pulmonary fibrosis (IPF) is a fibrotic disease of unknown etiology that results in significant morbidity and mortality. The pathogenesis of IPF is not completely understood. Because recent studies have implicated insulin-like growth factor-I (IGF-I) in the pathogenesis of fibrosis, we examined the expression and function of insulin-like growth factor binding proteins (IGFBP)-3 and -5 in IPF. IGFBP-3 and -5 levels were increased in vivo in IPF lung tissues and in vitro in fibroblasts cultured from IPF lung. The IGFBPs secreted by IPF fibroblasts are functionally active and can bind IGF-I, and IGFBPs secreted by primary fibroblasts bind extracellular matrix components. Our results also suggest that IGFBPs may be involved in the initiation and/or perpetuation of fibrosis by virtue of their ability to induce the production of extracellular matrix components such as collagen type I and fibronectin in normal primary adult lung fibroblasts. Although transforming growth factor-beta increased IGFBP-3 production by primary fibroblasts in a time-dependent manner, IGFBP-5 levels were not increased by transforming growth factor-beta. Taken together, our results suggest that IGFBPs play an important role in the development of fibrosis in IPF.