Bimodal fibrosis in a novel mouse model of bleomycin-induced usual interstitial pneumonia

Idiopathic pulmonary fibrosis is pathologically represented by usual interstitial pneumonia (UIP). Conventional bleomycin models used to study pathogenic mechanisms of pulmonary fibrosis display transient inflammation and fibrosis, so their relevance to UIP is limited. We developed a novel chronic induced-UIP (iUIP) model, inducing fibrosis in D1CC×D1BC transgenic mice by intra-tracheal instillation of bleomycin mixed with microbubbles followed by sonoporation (BMS). A bimodal fibrotic lung disease was observed over 14 wk, with an acute phase similar to nonspecific interstitial pneumonia (NSIP), followed by partial remission and a chronic fibrotic phase with honeycombing similar to UIP. In this secondary phase, we observed poor vascularization despite elevated PDGFRβ expression. γ2PF- and MMP7-positive epithelial cells, consistent with an invasive phenotype, were predominantly adjacent to fibrotic areas. Most invasive cells were Scgb1a1 and/or Krt5 positive. This iUIP mouse model displays key features of idiopathic pulmonary fibrosis and has identified potential mechanisms contributing to the onset of NSIP and progression to UIP. The model will provide a useful tool for the assessment of therapeutic interventions to oppose acute and chronic fibrosis.

GENETIC DISORDERS OF SURFACTANT PROTEINS

The literature review provides up-to-date information on rare interstitial lung diseases, manifesting both in children, starting from the neonatal period, and in adults, – genetic disorders of surfactant proteins B, C, ATP-binding cassette protein A3 (ABCA3), manifested by such histopathological patterns, as chronic pneumonitis of infants, pulmonary alveolar proteinosis, desquamative interstitial pneumonia , nonspecific interstitial pneumonia. Information on epidemiology, genetics, pathogenesis, clinical picture, diagnosis and differential diagnosis, treatment of these diseases is given.

High-Resolution CT Findings of Myositis-Related Interstitial Lung Disease

Myositis-related interstitial lung disease presents with a wide variety of lesions, ranging from chronic to acute. It can be divided into two main forms by the types of onsets, namely, chronic to subacute type showing nonspecific interstitial pneumonia (NSIP) or NSIP with an organizing pneumonia (OP)/ fibrosing OP (FOP) pattern and acute type showing acute lung injury (ALI) to diffuse alveolar damage (DAD) pattern. Anti-aminoacyl tRNA Synthetase antibody-positive cases mainly show an NSIP or FOP pattern, whereas anti-melanoma differentiation-associated gene 5 antibody-positive cases show ALI to DAD pattern. Bilateral consolidation with or without ground-glass opacification with lower lobe predominance is common as a major pattern in all types, but the distribution or extent is sometimes different. The early detection of findings that indicate a rapid progressive course is vital. Diffuse cranio-caudal distribution and multiple ground-glass opacifications with random distribution might indicate a poorer prognosis.

Ascending aorta aneurysm in scleroderma

Ascending aorta aneurysm in scleroderma can be ascribed to its macrovascular involvement which is very less elucidated. We here describe a 56-year-old female with rapidly progressive diffuse cutaneous scleroderma. She presented with skin thickening involving all four limbs, thorax and abdomen. She had other features like arthritis, Raynaud’s phenomena, dyspnoea, heaviness of chest, and dysphagia. On investigation, she was strongly positive for antinuclear antibody and Scl 70. Imaging revealed interstitial lung disease (nonspecific interstitial pneumonia pattern) and a fusiform dilatation of ascending aorta of 6.5 cm. Patient was offered surgical correction for aneurysm, for which she refused. To the best of our knowledge, our case report adds up to the few cases of ascending aorta aneurysm in scleroderma available in world literature.

S100A9/CD163 expression profiles in classical monocytes as biomarkers to discriminate idiopathic pulmonary fibrosis from idiopathic nonspecific interstitial pneumonia

Circulating monocytes have pathogenic relevance in idiopathic pulmonary fibrosis (IPF). Here, we determined whether the cell surface levels of two markers, pro-inflammatory-related S100A9 and anti-inflammatory-related CD163, expressed on CD14strongCD16− classical monocytes by flow cytometry could discriminate IPF from idiopathic nonspecific interstitial pneumonia (iNSIP). Twenty-five patients with IPF, 25 with iNSIP, and 20 healthy volunteers were prospectively enrolled in this study. The S100A9+CD163− cell percentages in classical monocytes showed a pronounced decrease on monocytes in iNSIP compared to that in IPF. In contrast, the percentages of S100A9−CD163+ cells were significantly higher in iNSIP patients than in IPF patients and healthy volunteers. In IPF patients, there was a trend toward a correlation between the percentage of S100A9+CD163− monocytes and the surfactant protein-D (SP-D) serum levels (r = 0.4158, [95% confidence interval (CI) − 0.02042–0.7191], p = 0.051). The individual percentages of S100A9+CD163− and S100A9−CD163+ cells were also independently associated with IPF through multivariate regression analysis. The unadjusted area under the receiver operating characteristic curve (ROC-AUC) to discriminate IPF from iNSIP was (ROC-AUC 0.802, 95% CI [0.687–0.928]), suggesting that these are better biomarkers than serum SP-D (p < 0.05). This preliminary study reports the first comparative characterization of monocyte phenotypes between IPF and iNSIP.

POS1435 CLINICAL CHARACTERIZATION AND PREDICTIVE FACTORS FOR PROGRESSION IN A COHORT OF ILD PATIENTS WITH FEATURES OF AUTOIMMUNITY: ARE IPAF CRITERIA SUFFICIENT?

Background:It is unknown whether patients with interstitial lung disease (ILD) and only some features of autoimmunity have a different natural history from those with a defined connective tissue disease (CTD-ILD). The classification criteria for “ILD with autoimmune features” (IPAF) may not be able to characterize all these patients, especially those with a usual interstitial pneumonia (UIP) pattern [1].Objectives:To determine clinical characteristics and predictive factors for progression in a cohort of ILD patients with features of autoimmunity, through the application of classification criteria for IPAF and specific CTD, whenever possible.Methods:We retrospectively selected a cohort of consecutive patients with ILD as onset manifestation and features of autoimmunity (at least 1 autoantibody and/or 1 clinical sign/symptom), evaluated by our multidisciplinary unit from March 2009 to March 2020. All the final diagnoses were revised according to the latest CTD and IPAF criteria. Patients were followed up for 33 (16.5-69.5) months.Results:Of the 101 patients enrolled (67.4±10.9 yrs, F/M ratio 65/36), 53 (52.5%) and 37 (36.6%) respectively satisfied the CTD and IPAF criteria. Eleven patients (10.9%) did not satisfy IPAF criteria because of only 1 item (clinical or serologic) within the IPAF domains and a UIP pattern; we defined this group as “autoimmune” UIP (AI-UIP). All the 8 patients initially classified as undifferentiated CTD had sufficient IPAF criteria. Among the IPAF patients (68.2±10.1 years, F/M ratio 20/17), the most common findings were: Nonspecific interstitial pneumonia pattern (56.8%), antinuclear antibodies positivity (43.2%) and arthritis (24.3%). The combination of a positive morphologic and serologic domain was the most common to reach the diagnosis (48.6%). Some IPAF patients had features not included in IPAF criteria, such as non-anti-synthetase myositis-specific antibodies (21.6%), objective sicca syndrome (13.5%) and anti-myeloperoxidase antibodies (2.7%). Over a median of 17 months, 2 IPAF patients (5.4%) developed a definite UIP pattern, while 4 (10.8%) a specific CTD. Comparing the IPAF, CTD-ILD and AI-UIP groups, no statistically significant differences were found in the mean age, sex distribution, smoking habits and mean duration of the disease. However, IPAF patients had a significantly higher prevalence of arterial hypertension and left-sided heart failure and a lower predominance of UIP pattern as expected (10.8% vs. 32.1% vs. 100%, p<0.01). Although no differences were found at the diagnosis, at 1 year the proportion of IPAF patients with radiological progression of the fibrosis and/or functional deterioration (defined by a decline in FVC of ≥ 10% and/or DLCO of ≥ 15% predicted) was lower to that of CTD-ILD and AI-UIP (17.1% vs. 31.4% vs. 63.6%, p 0.01). Fewer IPAF patients needed oxygen support (8.6% vs. 31.4% vs. 36.4, p 0.02). Considering the overall 101 patients, having an IPAF and a UIP pattern respectively predicted a slower (OR: 0.37, p 0.04) and a faster (OR: 3.56, p 0.01) ILD progression at the multivariate analysis.Conclusion:In our cohort, IPAF criteria were useful to identify a subset of patients with a slower ILD progression and a possible evolution to CTD (10-15% of cases) [2]. These criteria do not characterize all the patients with a UIP pattern and limited features of autoimmunity, which seem to have a worse prognosis, independently from the final diagnosis. Further studies are needed to clarify if the prognosis of AI-UIP is different from that of idiopathic pulmonary fibrosis.References:[1]Graney, et al. Ann Am Thorac Soc 2019;16(5):525-33.[2]Sebastiani, et al. Biomedicines 2021,9,17.Disclosure of Interests:None declared