Presence Of Pulmonary Fibrosis Research Articles

Prevalence and characteristics of newly diagnosed heart failure in patients with shortness of breath after coronavirus infection

Aim. To determine the prevalence and show the features of the development of newly diagnosed heart failure (HF) in patients with dyspnea after a coronavirus disease 2019 (COVID-19).Material and methods. This clinical prospective observational study was conducted during 2020-2022. The study consecutively included 368 outpatients with shortness of breath, who applied to the clinic. Depending on the presence of prior COVID-19, the patients were divided into 2 groups: the first group consisted of 205 patients with shortness of breath after COVID-19, the second group — 163 patients without prior COVID-19. All patients underwent a clinical examination within 3 days after presentation with an assessment of outpatient records and other medical documents for the differential diagnosis of dyspnea. The severity of dyspnea was determined using the Modified Medical Research Council Dyspnoea Scale (mMRC). The diagnosis of HF was verified in accordance with the 2020 Russian Society of Cardiology guidelines and in some cases reclassified in accordance with the 2021European Society of Cardiology guidelines. For further analysis, 2 subgroups of patients with HF were identified depending on the presence and absence of prior COVID-19. The subgroup analysis excluded patients with acute heart failure, acute illness, and conditions requiring hospitalization and/or intensive care.Results. Among 368 patients who presented to the clinic with dyspnea during 2020-2022, 205 patients (55,7%) had COVID-19. The average period of treatment after COVID-19 was 3,5 [1,5; 22,4] months. Patients after COVID-19 applied earlier after the onset of dyspnea, which is associated with higher mMRC score. The prevalence of HF among patients with shortness of breath after COVID-19 was significantly higher than in patients without this pathology in history, and amounted to 19,0% vs 9,8% (p=0,021). Prior COVID-19 increased the relative risk (RR) of HF in patients with shortness of breath by 1,7 times. RR for HF in systolic blood pressure >140 mm Hg increased by 1,9 times, while in diastolic blood pressure >90 mm Hg — by 1,9 times, with the development of a hypertensive crisis — by 28%, with a heart rate >80 bpm at rest — by 1,4 times, with the development of type 2 diabetes — by 31%, in the presence of pulmonary fibrosis — by 2,3 times. Patients with shortness of breath after COVID-19 had more severe HF, both according to clinical tests and according to the blood concentration of N-terminal pro-brain natriuretic peptide (NT-proBNP), mainly with the preserved ejection fraction (EF) with a higher prevalence of left atrial (LA) enlargement in combination with a decrease in right ventricular (RV) systolic function and its dilatation. In patients after COVID-19 in the presence of chronic kidney disease, the RR for HF increased by 4,5 times; in the presence of C-reactive protein >4 mg/l — by 1,6 times.Conclusion. Every fifth patient with shortness of breath 3,5 months after COVID-19 had more severe HF, both according to clinical tests and according to blood NT- proBNP concentration, mainly with preserved EF with a higher prevalence of LA increase in combination with a decrease in RV systolic function and its dilatation. The risk of HF is interrelated with the female sex and multiple comorbidities.

Prognostic Factors for Pulmonary Fibrosis Following Pneumonia in Patients with COVID-19: A Prospective Study

The frequency and clinical manifestation of lung fibrosis accompanied by coronavirus disease (COVID-19) are not well-established. We aimed to identify the factors attributed to post-COVID-19 fibrosis. This single-center prospective study included patients diagnosed with COVID-19 pneumonia from 12 April to 22 October 2021 in the Republic of Korea. The primary outcome was the presence of pulmonary fibrosis on a CT scan 3 months after discharge; the fibrosis risk was estimated by a multiple logistic regression. The mean patient age was 55.03 ± 12.32 (range 27–85) years; 65 (66.3%) were men and 33 (33.7%) were women. The age, Charlson Comorbidity Index, lactate dehydrogenase level, aspartate aminotransferase level, and Krebs von den Lungen-6 level were significantly higher and the albumin level and the saturation of the peripheral oxygen/fraction of inspired oxygen (SpO2/FiO2) ratio were significantly lower in the fibrosis group than in the non-fibrosis group; the need for initial oxygen support was also greater in the fibrosis group. An older age (adjusted odds ratio (AOR) 1.12; 95% confidence interval (CI) 1.03–1.21) and a lower initial SpO2/FiO2 ratio (AOR 7.17; 95% CI 1.72–29.91) were significant independent risk factors for pulmonary fibrosis after COVID-19 pneumonia. An older age and a low initial SpO2/FiO2 ratio were crucial in predicting pulmonary fibrosis after COVID-19 pneumonia.

Chronic Exposure to Electronic Cigarettes Induces Lung Oxidative Stress, Inflammation, Fibrosis, and Impaired DNA Repair

BackgroundElectronic cigarettes (e‐cig) have been marketed as a safer alternative to tobacco cigarette smoking (TCS). While there are far less toxic compounds in e‐cig vape (ECV) than in tobacco cigarette smoke, detectable levels of toxicants are still present. Multiple in vitro and short‐term in vivo studies on e‐cig‐induced lung cell damage have been reported; however, questions remain regarding the health effects of chronic e‐cig use on the lungs. Therefore, studies were performed in a chronic mouse exposure model to investigate the deleterious effects of long‐term ECV exposure on the lungs.MethodsC57/BL6 male mice were exposed for 2 hours/day, 5 days/week to either air (control group; 25 mice) or ECV generated from e‐cig liquid containing 24 mg/ml nicotine (e‐cig group; 25 mice) for 16 weeks. At the end of the exposure, animals were euthanized, lungs were lavaged, then the recovered bronchoalveolar lavage fluid (BALF) was prepared to assess the percentages of inflammatory cells in BALF. Fixed lung sections were also prepared and stained with hematoxylin and eosin (H & E) or Masson’s trichrome stain to assess the degree of lung inflammation and fibrosis; respectively. Superoxide radical generation was measured in frozen lung sections using DHE. Western blotting (WB) and immunofluorescence (IF) in lung tissue were used to detect the levels of nitrotyrosine, and the expression of the DNA repair enzymes XPC and OGG1.ResultsThe number of inflammatory cells present in the BALF, including neutrophils, macrophages, and eosinophils, was significantly higher in ECV‐exposed mice compared to that with air exposure. In the ECV‐exposed mice, H & E stained lung sections showed clear inflammatory infiltrates with lymphoid aggregates of lymphocytes, plasma cells and macrophages that stretch from the perivascular and peribronchiolar areas into adjacent septal adipose tissue. Masson’s trichrome stained slides showed increase in connective tissue around airways and bronchioles in e‐cig exposed mice, indicating the presence of pulmonary fibrosis. Using the fluorescence‐based superoxide probe DHE, significantly increased superoxide generation was observed in the lungs of ECV exposed mice, compared to control. This DHE‐derived fluorescence was largely quenched by preincubation with the SOD mimetic MnTBAP, confirming that the observed fluorescence was largely derived from superoxide. WB and IF showed elevated levels of nitrotyrosine. Reduced expression of the DNA damage repair proteins XPC and OGG1 were seen in lung tissue of the ECV exposed mice compared to the controls.ConclusionChronic ECV exposure induced lung inflammation, pulmonary fibrosis, and increased superoxide generation. ECV exposure increased oxidative stress and inflammation in the lungs while decreasing the levels of DNA damage repair proteins. These findings suggest that chronic e‐cig use can trigger oxidative stress with inflammatory lung damage and impaired DNA repair that together may predispose to neoplastic transformation and cancer onset.

Novel biomarker for pulmonary vascular disease in systemic sclerosis patients

In systemic sclerosis (SSc) patients, pulmonary arterial hypertension (PAH), which is preceded by pulmonary vascular disease (PVD), is one the of major causes of morbidity and mortality. Given the higher risk of PAH among anti-CENP antibodies (ACA)+ patients, we previously characterised a subset of ACA+ patients, based on a differential reactivity of their ACA with the phage clone (pc4.2)-expressing peptide 4.2 (p4.2). There was a considerably greater prevalence of a low diffusing lung capacity for carbon monoxide (DLCO), an expression of PVD, among patients with high anti-pc4.2 Ab levels. Here we examine whether a similar clinical subgroup can be identified within a larger cohort of ACA+ patients, using the synthetic p4.2. Clinical data and serum samples were collected from 134 ACA+ patients. Sera were screened for reactivity with p4.2 by indirect ELISA. Statistical analyses were performed to define any associations between anti-p4.2 Ab levels and PVD. Kendall's analysis showed that anti-p4.2 Ab were directly associated with both a reduced DLCO and the presence of pulmonary fibrosis (PF). These associations were confirmed by Fisher's exact test. At multivariate analysis, anti-p4.2 Ab was associated to DLCO<70, DLCO≤60, and PF. Moreover, multivariable analysis showed that only the association of anti-p4.2 Ab with DLCO<70, and not with DLCO≤60, was independent of PF. Anti-p4.2 Ab are able to identify SSc patients at high risk of developing PVD even in the absence of PF. Patients with high anti-p4.2 Ab levels should be strictly monitored for PVD onset and eventually PAH.

Increased Frequency of Activated Switched Memory B Cells and Its Association With the Presence of Pulmonary Fibrosis in Diffuse Cutaneous Systemic Sclerosis Patients.

Disease-associated, high-affinity pathological autoantibody production is a well-described consequence of immune dysregulation affecting B cells in systemic sclerosis (SSc), including the distribution of B-cell subsets. We have previously shown that the increased relative frequency of CD19+CD27+IgD− switched memory B cells is associated with the severe form of SSc. This study sought to analyze memory B cell subsets using an extended range of markers for further subdivision based on CD19, IgD, CD27, CD38 and CD95 phenotype, to define relationship between the alterations of memory B cell subsets and the clinical features of SSc. Peripheral blood samples were obtained from 21 SSc patients, including 14 diffuse (dcSSc) and 7 limited (lcSSc) cutaneous SSc patients, with disease duration of 2.7 ( ± 1.6) years. After purification of CD19+ B cells, multiparametric flow cytometry was performed and the frequencies of CD19+IgD−CD27−CD38+ double negative (DN) 1, CD19+IgDloCD27+CD38+ unswitched, CD19+IgD−CD27+CD38+CD95− resting switched and CD19+IgD−CD27+CD38−CD95+ activated switched memory (ASM) B cells were determined, and correlated with clinical features of SSc. The dcSSc patients had a higher frequency of ASM B cells (p = 0.028) compared to lcSSc patients. The percentage of ASM B cells was elevated in anti-Scl-70 (anti-topoisomerase I) antibody positive patients compared to negative patients (p = 0.016). Additionally, the frequency of ASM B cells was also increased in patients with pulmonary fibrosis (p = 0.003) suggesting that patients with severe form of SSc have higher ASM B cell ratios. Furthermore, the ratio of DN1 B cells was decreased (p = 0.029), while the level of anti-citrate synthase IgG natural autoantibody was elevated (p = 0.028) in patients with active disease. Our observations on the increase of ASM B cells in dcSSc and in patients with pulmonary fibrosis may point to the association of this alteration with the severe form of the disease. Functionally the correlation of ASM B cells as effector memory-plasma cell precursors with anti-topoisomerase I antibody positivity could reflect their contribution to pathological autoantibody production, whereas the decrease of memory precursor DN B cells and the increase of anti-citrate synthase IgG autoantibody may have potential significance in the assessment of disease activity.

IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142–2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.

A Link between Lung Injury and Inflammatory Myopathies: Making the Diagnosis

Pulmonary fibrosis associated with various connective tissue diseases often presents insidiously but can progress to rapid deterioration. Previous studies have shown that, in the patients with connective tissue diseases, the presence of pulmonary fibrosis has prognostic implications and therefore early detection may be essential in the management of these patients. Our case outlines the close association between pulmonary fibrosis and idiopathic polymyositis. We report the findings of a patient who presented with slow onset progressive exercise dyspnea followed by proximal muscle weakness and joint and skin changes.

Clinical value of surfactant protein D as a biomarker of pulmonary fibrosis in patients with scleroderma systematica in relation to the presence of gastroesophageal reflux

To study the role of serum surfactant protein D (SP-D) as a biomarker of lung injury in scleroderma systematica (SDS) in relation to the presence of gastroesophageal reflux (GER). Fifty-six patients (mean age 46±14 years) with diffuse and circumscribed SDS were examined and underwent pulmonary functional tests, X-ray and, if lung injury was present, high-resolution computed tomography of the lung, echocardiography, gastroduodenoscopy, and barium X-ray of the esophagus; an enzyme-linked immunosorbent assay was used to determine serum SP-D levels. SP-D concentrations significantly correlate with the presence of lung injury in SDS and are significantly higher in the presence of pulmonary fibrosis and the signs of frosted glass and honeycomb lung patterns. SP-D levels were higher in the patients with lung injury and SDS in the group of those with pulmonary fibrosis and GER than in the group of pulmonary fibrosis patients without the latter. Serum SP-D may be considered in a number of biomarkers for the severity of lung injury in SDS, including GER-associated lung injury.

Characteristics of gastro-esophageal reflux in patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease with a median survival rate ranging from 2 to 3years from diagnosis. Recent data have illustrated the role of gastro-esophageal reflux (GER) in the pathogenesis and potential management of IPF patients. Although it is recognized that GER is increased among IPF patients, its prevalence and characteristics had been poorly defined. Patients and methodsForty patients were recruited; 20 with a diagnosis of IPF and the other, 20 with interstitial lung disease other than IPF (non IPF patients). All patients underwent pulmonary high-resolution computed tomography (HRCT) scan and impedance-pH monitoring while off antisecretory therapy. The presence of pulmonary fibrosis was assessed using validated HRCT scores. Reflux features included distal esophageal acid exposure, number of acid/weakly acidic reflux episodes and their proximal migration. ResultsSeventeen (85%) patients out of 20 with IPF had an abnormal distal acid exposure, compared with 7 (35%) out of 20 non IPF patients (p=0.003). Percentage total acid exposure time (AET) with pH<4 was significantly higher in IPF compared with non IPF patients (median (range) 10.1 (5.1–16.3) versus 3 (1.2–8.3), respectively; p<0.0001). In IPF patients the total (both acid and weakly acidic) numbers of reflux episodes [80 (45–99)], acid reflux [46 (25–57)] and weakly acidic reflux [35 (20–45)] were significantly higher than those of non IPF patients (45 (29–70), 28 (18–40) and 19 (10–30), respectively; p<0.0001). Also, more reflux episodes reached the proximal esophagus [54 (28–69)] in IPF patients than non-IPF patients [18 (8–32); p<0.0001]. In IPF patients there was a significant positive correlation between degree of pulmonary fibrosis (HRCT score) and total number of reflux episodes in both the distal (r2=0.57, p=0.008) and proximal (r2=0.61, p=0.004) esophagus. In contrast, in non IPF patients a non significant correlation was found between degree of pulmonary fibrosis and total number of reflux episodes in both the distal (r2=0.17, p=0.48) and proximal (r2=0.23, p=0.34) esophagus. ConclusionIPF patients have greater GER rate compared to non IPF ones. Not only acid reflux, but also weakly acidic reflux is significantly increased among IPF patients.

Smoking-associated fibrosis and pulmonary asbestosis

The diagnosis of pulmonary asbestosis is most often established based on clinical criteria and has both clinical and legal implications. Unfortunately, one of the confounding features in the diagnosis may be a history of cigarette abuse, which can produce interstitial opacities on chest imaging as well as diffusion defects on pulmonary function testing, criteria that are used in the diagnosis of pulmonary asbestosis. The objective of the present study was to evaluate the correlation of radiographically detected pulmonary fibrosis with fibrosis established histopathologically as attributable to asbestos, in a cohort referred for diagnosis of an asbestos-related malignancy in the context of litigation. We examined the slides of 186 cases with reported asbestos exposure, referred in consultation for asbestos-related malignancy and the presence of pulmonary fibrosis. Sixty-five cases had what was judged to be adequate tissue sampling for histopathologic evaluation of asbestosis as well as an existing radiologic assessment of pulmonary fibrosis by B-reader report. Of 24 cases judged to have asbestosis radiographically, which had sufficient tissue for pathologic examination, six showed asbestosis histopathologically. The remaining 18 cases (mean smoking history of 53 pack-years) showed interstitial fibrosis that was judged to be most consistent with smoking-associated pulmonary fibrosis. We conclude that the clinical diagnosis of mild asbestosis cannot be reliably distinguished from interstitial fibrosis in heavy smokers.

A3.25 systemic sclerosis patients exhibit an increased frequency of T cells and NK cells with effector/cytotoxic phenotype

BackgroundSystemic sclerosis (SSc) is an inflammatory and fibrotic disease characterised by inflammation, immune dysregulation and excessive extracellular matrix deposition. T cell and NK cell disturbance have already been described in...

Temporal profile of lipopolysaccharide-induced airway inflammation in rats

Polymorphonuclear neutrophils are thought to play a critical role in the pathogenesis of respiratory conditions in diseases such as chronic obstructive pulmonary disease (COPD), adult respiratory distress syndrome (ARDS) and idiopathic pulmonary fibrosis. In these diseases, the recruitment and activation of neutrophils is known to contribute to observed dysfunctional symptoms, which include increased airway reactivity, presence of pulmonary fibrosis and mucus hypersecretion. These symptoms are exacerbated by increases in pulmonary cytokines, including tumor necrosis factor-alpha (TNF-) and cytokine-induced neutrophil chemoattractants (CINC-1 and CINC-3).

Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients

The aim of the study was to characterise gastro-oesophageal reflux (GOR) in idiopathic pulmonary fibrosis (IPF). 40 consecutive IPF patients underwent pulmonary high-resolution computed tomography (HRCT) scan and impedance-pH monitoring while off antisecretory therapy. The presence of pulmonary fibrosis was assessed using validated HRCT scores. Reflux features included distal oesophageal acid exposure, number of acid/weakly acidic reflux episodes and their proximal migration. 40 consecutive patients with interstitial lung disease other than IPF (non-IPF patients) and 50 healthy volunteers were also enrolled. IPF patients had significantly higher (p<0.01) oesophageal acid exposure (median (interquartile range (IQR)) 9.25 (4.7-15.4)% versus 3.3 (1.4-7.4)% versus 0.7 (0.2-4.2)%, number of acid (median (IQR) 45 (23-55) versus 32 (19-44) versus 18 (10-31)), weakly acidic (median (IQR) 34 (19-43) versus 21 (11-33) versus 18 (15-28)) and proximal reflux (median (IQR) 51 (26.5-65.5) versus 20 (9.5-34.5) versus 9 (5-20)) events compared to non-IPF patients and healthy volunteers, respectively. Pulmonary fibrosis HRCT scores correlated well with reflux episodes in both the distal (r(2)=0.567) and proximal (r(2)=0.6323) oesophagus. Patients with IPF had more bile acids and pepsin (p<0.03) in bronchoalveolar lavage fluid (BALF) (62% and 67%, respectively) and saliva (61% and 68%, respectively) than non-IPF patients (25% and 25% in BALF, and 33% and 36%, respectively, in saliva) and controls (0% and 0% in BALF and saliva, respectively). Acid GOR is common in IPF, but weakly acidic GOR may also occur. Patients with IPF had a risk of pulmonary aspiration of gastric contents. Outcome studies with intense antireflux therapy are needed.

New insight on the Xq28 association with systemic sclerosis

ObjectiveTo evaluate whether the systemic sclerosis (SSc)-associated IRAK1 non-synonymous single-nucleotide polymorphism rs1059702 is responsible for the Xq28 association with SSc or whether there are other independent signals in the nearby...

A7.14 IRF5Polymorphisms in Systemic Sclerosis

<h3>Introduction</h3> The transcription factor interferon regulatory factor 5 (IRF-5) plays a key role in the Toll-like receptor signalling pathway, and activation of the type I interferon response. As well as being associated with a number of other rheumatological diseases, including systemic lupus erythematosus and rheumatoid arthritis, <i>IRF5</i> has been identified as a candidate gene for systemic sclerosis (SSc) in a number of genome wide association studies. Although this finding has been replicated in several different studies, there has been variation in the single nucleotide polymorphisms (SNPs) tested, thereby making it difficult to determine which <i>IRF5</i> SNP(s) may be playing a role in susceptibility to SSc. We therefore tested a number of <i>IRF5</i> SNPs in a UK based population with the aim of elucidating the true causal variant(s). <h3>Materials and Methods</h3> To investigate involvement of this gene in susceptibility to SSc, UK Caucasian patients and controls (SSc n = 465, controls n = 416) were genotyped using commercially available TaqMan assays. The <i>IRF5</i> SNPs Rs4728142, Rs2004640, Rs10954213, and Rs10488631, previously reported to be associated with SSc, were selected for investigation. The presence of pulmonary fibrosis was defined as a forced vital capacity &lt;75% and/or the presence of fibrosis on chest imaging. <h3>Results</h3> The allele frequencies of each of the four <i>IRF5</i> SNPs were not significantly different (using Bonferroni correction for multiple testing) in the healthy controls and patients with SSc (Rs4728142: 0.52/0.50, Rs2004640: 0.56/0.60, Rs10954213: 0.37/0.35, Rs10488631: 0.12/0.14). There was also no significant difference found for any of the SNPs when the SSc patients were subdivided according to disease type (limited/diffuse), presence of pulmonary fibrosis, or auto-antibody type. <h3>Conclusions</h3> In contrast to previously published studies we did not detect a significant difference in allele frequency between patients with SSc and healthy control individuals for any of the four <i>IRF5</i> SNPs tested. However, due to the modest cohort sizes available, this study has limited power and therefore may have been unable to detect allele frequency differences with small effects. This study therefore will be repeated with larger cohorts in order to validate these results.

Pulmonary blood volume indexed to lung volume is reduced in newly diagnosed systemic sclerosis compared to normals--a prospective clinical cardiovascular magnetic resonance study addressing pulmonary vascular changes.

BackgroundPulmonary involvement, manifested as pulmonary arterial hypertension or pulmonary fibrosis, is the most common cause of death in systemic sclerosis (SSc). We aimed to explore the feasibility of detecting early pulmonary involvement in SSc using recently developed non-invasive quantitative measures of pulmonary physiology using cardiovascular magnetic resonance (CMR).MethodsTwenty-seven SSc patients (9 men, 57 ± 13 years) and 10 healthy controls (3 men, 54 ± 9 years) underwent CMR to determine the pulmonary blood volume (PBV) and the PBV variation (PBVV) throughout the cardiac cycle. Patients underwent Doppler echocardiography, high-resolution computed tomography (HRCT), and pulmonary function testing by spirometry. Comparisons were performed using the unpaired t-test and linear regression analysis was performed with Pearson’s correlation coefficient (r).ResultsCompared to healthy controls, the PBV indexed to lung volume (PBVI) was lower in patients (16 ± 4 vs 20 ± 5%, p < 0.05). There was no difference in PBV (466 ± 87 vs 471 ± 122 mL, p = 0.91) or PBVV/stroke volume (45 ± 10 vs 40 ± 6%, p = 0.09). There were no significant correlations between PBVI and pulmonary artery pressure estimated by Doppler (p = 0.08) the lung’s diffusion capacity for carbon monoxide (DLCO) (p = 0.09), vital capacity (p = 0.45), or pulmonary fibrosis by HRCT (p = 0.74).ConclusionsThis study is the first to measure the PBV in humans using CMR. Compared to healthy controls, newly diagnosed SSc patients have a reduced amount of blood in the pulmonary vasculature (PBVI) but unchanged pulmonary vascular distensibility (PBVV/stroke volume). PBVI is unrelated to DLCO, pulmonary artery pressure, vital capacity, and the presence of pulmonary fibrosis. PBVI may be a novel parameter reflecting vascular lung involvement in early-stage SSc, and these findings may be consistent with pathophysiological changes of the pulmonary vasculature.

High DNA Oxidative Damage in Systemic Sclerosis

Several lines of evidence suggest that the generation of reactive oxygen species (ROS) is of major importance in the pathogenesis of SSc. Protein and lipid damage have previously been demonstrated, but scarce data are available on oxidative damage to DNA. In patients with SSc, we evaluated levels of 8-hydroxy-2'-deoxyguanosine (8-oxodG), the main validated biomarker of endogenous oxidative damage to DNA, compared to levels of F2-isoprostane, a product of free radical-mediated peroxidation of arachidonic acid. Urinary levels of 8-oxodG and 8-isoprostaglandin-F(2α) (8-iso-PGF(2α)) were determined by competitive ELISA method in consecutive SSc patients and controls matched for age and sex. We included 80 unrelated SSc patients (72 women, mean age 56 ± 11 yrs) and 39 controls (33 women, mean age 64 ± 8 yrs). Urinary levels of 8-oxodG/creat and 8-iso-PGF(2α)/creat in SSc patients were found to be higher than in controls (6.5 ng/mg vs 3.7 ng/mg, p = 0.0001; and 11.4 ng/mg vs 4.2 ng/mg, p < 0.0001). In multivariate analysis, 8-oxodG levels were associated with the presence of pulmonary fibrosis on computerized tomography scan, decreased forced vital capacity, and decreased DLCO/alveolar volume. In patients with the diffuse cutaneous subset, a modified Rodnan skin score > 14 was independently associated with 8-oxodG levels. In SSc, 8-oxodG and 8-iso-PGF(2α) values were correlated (r = 0.32; p = 0.005). Our study confirmed marked oxidative stress in SSc. We also found increased values of 8-oxodG in SSc patients and a relevant association with a fibrotic phenotype. The predictive value of this marker and its potential influence on fibrotic disturbances remain to be determined.

Collaborative Radiologic and Histopathologic Assessment of Fibrotic Lung Disease

The idiopathic interstitial pneumonias (IIPs) are a seemingly disconnected collection of diseases usually associated with the presence of pulmonary fibrosis. Categorization of the IIPs continues to be problematic despite recent attempts to refine the diagnostic criteria and suggests that rather than separate diseases, these pneumonias represent a spectrum of injury and abnormal repair of the alveolar wall. Although the initiating injury or injuries are unknown, the IIPs share a restricted number of final common abnormal pathways that lead to volume loss and lung distortion. The pathways include (a) alveolar collapse, (b) incorporation of fibroblastic material into alveolar walls, and (c) cigarette smoke-related inflammation and fibrosis. A collaborative diagnostic process in which data from radiologic and histologic assessments are combined allows a more reliable identification of the predominant pathways leading to pulmonary fibrosis. This approach has implications for therapy and the future direction of research.

Is Dysfunction of Caveolin-1 a Link Between Systemic Sclerosis and Breast Cancer, Opening a Window on Both Etiologies?

Epidemiological and institutional studies have demonstrated an association between systemic sclerosis (SSc) and breast cancer. For example, breast cancer is one of the most common cancers seen in SSc patients, whereas a higher rate of cutaneous scleroderma appeared in a group in which SSc followed breast cancer diagnosis. Additionally, sex hormones and genetic factors within the estrogen receptor (ER) influence the development of SSc and breast cancer. An older age at diagnosis of SSc, lack of antinuclear antibody positivity and the presence of pulmonary fibrosis are shown to be associated with the development of breast cancer in SSc patients. On the other hand, increased mammographic densities that may be caused by SSc are an important risk factor for breast cancer development. Despite the evidence that SSc and breast cancer are epidemiologically linked, the cause of this correlation is unclear. Caveolin-1 (Cav-1) is a negative regulator that inhibits the basal activity of several pro-proliferative and oncogenic proteins. Cav-1 regulated TGF-beta/Smad signaling appears to participate in the pathogenesis of breast cancer and tissue fibrosis in SSc. Thus, it is proposed that Cav-1 regulated TGF-beta/Smad signaling via Cav-1 scaffolding domain (CSD) may play a key role in the link between SSc and breast cancer by suppressing TGF-beta-mediated phosphorylation of Smad. Future studies of Cav-1 regulated TGF-beta/Smad signaling may lead to novel insights into the link between SSc and breast cancer and may also lead to new strategies for the management of these two fatal diseases.

Prevalence and outcome of pulmonary fibrosis in microscopic polyangiitis

We sought to determine the type of pulmonary involvement in microscopic polyangiitis (MPA), primarily focusing on pulmonary fibrosis (PF), its prevalence, temporal relationship with other disease manifestations and outcome. 33 patients (16 males) with biopsy proven perinuclear anti-neutrophilic cytoplasmic antibody-positive MPA (age 63.5 yrs) participated in the study. Pulmonary involvement was assessed using standard methods, including radiographic imaging (chest radiographs and high-resolution computed tomography), pulmonary function testing, bronchoscopy and bronchoalveolar lavage, and, if indicated, lung biopsy. All-cause mortality was analysed by the Kaplan-Meier method and was compared between MPA patients with and without PF. At the time of diagnosis, renal involvement was detected in all patients, with renal biopsies being consistent with segmental necrotising glomerulonephritis in all patients. The most common respiratory symptom was haemoptysis, which was found in nine (27%) patients. PF was present in 12 (36%) patients at the time of diagnosis, whereas one patient developed PF while on therapy approximately 10 yrs after disease diagnosis. In seven patients with PF, respiratory symptoms related to fibrosis preceded other disease manifestations by a median (range) period of 13 (5-120) months. Patients were followed up for a period of 38+/-30 months. Presence of PF was associated with increased mortality (p = 0.02), with six deaths occurring in the fibrotic group and one in the nonfibrotic group. In the fibrotic group most deaths were related to PF. PF occurs frequently in MPA, may precede other disease manifestations by a variable length of time and has a poor prognosis.