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Many lung diseases are associated with dramatic changes in mechanical properties of the lung. Chest radiographs and computed tomography (CT) are the most common clinical methods for evaluating lung disease, but they are expensive, use radiation, and do not measure lung stiffness. Shear wave elastography (SWE) uses ultrasound radiation force (URF) to generate wave propagation in the tissue. However, URF should not be applied to the lung, because there are air and blood in the alveoli. Relatively high-intensity ultrasound can cause alveolar hemorrhage and lung injury. We have developed a noninvasive, and clinically feasible technology, lung ultrasound surface wave elastography (LUSWE), that is capable of measuring lung elastic properties with speed and accuracy. LUSWE uses a handheld shaker to generate a local small harmonic vibration on the chest surface. The resulting wave propagates through the intercostal muscle and propagates on the lung. The surface wave speed is noninvasively measured using an ultrasound technique. LUSWE is safe because diagnostic ultrasound is only used to detect the wave propagation along the lung duo to mechanical wave generation on the chest. LUSWE may be used to assess multiple lung disorders such as lung fibrosis or lung edema.

The evaluation of diffuse lung disease invariably involves chest computerized tomography (CT). The detailed information obtained is often equivalent to that from lung biopsies. It, however, involves exposure to ionising radiation which limits its repeated application in monitoring and follow up. Ultrasound techniques offer potentially safer/cheaper alternatives and lung ultrasound surface wave elastography (LUSWE) is a novel, noninvasive, and clinically feasible technique to quantify lung stiffness, an important biomechanical property that changes in diffuse fibrotic and infiltrative lung diseases. We have developed a sensitive, accurate and reproducible technique to measure changes in lung surface stiffness by using surface wave transmission speed and demonstrated its value in detecting and staging the degree of fibrosis in diffuse interstitial lung diseases, specifically idiopathic pulmonary fibrosis and progressive systemic sclerosis associated lung disease, as well as changes in heart failure. The technique consists of ultrasound detection of the propagation speed of a wave generated by the vibrations from an indenting shaker in multiple intercostal spaces to provide a representative assessment of both lungs. It offers the prospect of simple, radiation-free, repetitive assessment of changes in acute and chronic diffuse lung diseases with the potential for easy and rapid bedside use, all important considerations in clinical practice.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Abstract The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-γ and TNF stimulated lung macrophages to chronically release IL-1β, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

Aging‐related changes in lung mechanics of human subjects are characterized by a decrease in resistance and an increase in static compliance (decrease in elastic recoil). Together, these changes result in an increase in residual volume in the absence of an increase in total lung capacity. In C57BL/6x129 mice, it was reported that lung compliance increases with aging while elastic recoil pressure does not change. However, in these studies, “old” mice at 24 months of age were compared to “young” mice at 2 months of age, but at this younger age, alveologenesis is incomplete (completion does not occur until ~6 months of age). Accordingly, it remains to be established if the same aging‐related changes in lung mechanics are observed using fully developed adult C57BL/6x129 mice for comparison. To this end, we compared lung mechanics in C57BL/6x129 mice at 6 months (100% survival, n = 6), 18 months (90% survival, n = 6), and 24 months (75% survival, n = 6) of age. Respiratory system static mechanics (Resistance, R rs ; Compliance, C rs ; Elastance, E rs ) were assessed following tracheal intubation using the FlexiVent. There was a progressive aging‐related decrease in R rs (6 month, 0.47 ± 0.02; 18 month, 0.41 ± 0.02; 24 month, 0.35 ± 0.02 cmH 2 O.s/ml), an increase in C rs (6 month, 0.046 ± 0.002; 18 month, 0.052 ± 0.002; 24 month, 0.062 ± 0.002 ml/cmH 2 O), and a decrease in E rs (6 month, 21.73 ± 1.19; 18 month, 19.30 ± 0.87; 24 month, 16.62 ± 1.25 cmH 2 O/ml). Additionally, lungs were fixed following tracheal instillation of 4% paraformaldehyde at 25 cmH 2 O. Thereafter, lungs were dehydrated, paraffin embedded, sectioned (6 μm thick), and stained (hematoxylin and eosin). Using standard stereological approaches, lung sections were analyzed in a uniform systematic but random fashion to assess alveolar morphology (measurement of average distance between alveolar walls based on mean linear intercept, L m ). There was a progressive aging‐related increase in L m (6 month, 34 ± 2; 18 month, 40 ± 2; 24 month, 45 ± 2 μm) consistent with an aging‐related emphysematous‐like change in lung morphometry. Taken together, these results in appropriately aged C57BL/6x129 mice demonstrate an aging‐related change in lung mechanics and morphometry consistent with what is observed in aging humans. Therefore, the results of the present study confirm the use of rodent models for studying aging‐related changes in lung mechanics and morphometry. Support or Funding Information National Institute of Health grants R01‐AG044615 (CBM & GCS) and T32‐HL105355 (JEE).

Abstract Background Impaired RV-PA coupling portends a poor prognosis in PAH, and right ventricular free wall strain/systolic pulmonary artery pressure (RVFWS/sPAP) has been reported as a measure of RV-PA coupling. Furthermore, increased RVFWS and right atrial area (RAA), as well as decreased pulmonary artery compliance (PAC) are associated with increased mortality risk in PAH. Seralutinib is a novel, small molecule kinase inhibitor that targets PDGFR, CSF1R, and c-KIT administered via dry powder inhaler. TORREY, a phase 2, double-blind, randomised, placebo-controlled study of inhaled seralutinib in patients with PAH (NCT04456998) met its primary endpoint, demonstrating a significant reduction in pulmonary vascular resistance (PVR) from baseline (BL) to Week 24 compared to placebo. In addition, seralutinib significantly decreased NT-proBNP. Purpose To test the hypothesis that seralutinib would improve RVFWS/sPAP and other measures of right heart function after 24 weeks of treatment compared to placebo in the TORREY study. Methods Eighty-six patients with WHO Group 1 PH (Functional Class II, III), ages ≥18 years, pulmonary vascular resistance ≥400 dyne*s/cm5, and on stable PAH standard of care therapy (the majority of whom were on double and triple therapy with approved PAH medications) were enrolled. Right heart catheterisation (RHC) and full echocardiography were performed at BL and Week 24 and at BL, Week 12, and Week 24, respectively; both were analysed in a blinded central laboratory. To calculate RVFWS/sPAP, the pulmonary artery systolic pressure from RHC was used. PAC was calculated from RHC data with the formula (SV/(PAS-PAD)). Statistical analysis was performed using ANCOVA. Results At Week 24, the change in RVFWS/sPAP was lower in the seralutinib group compared to placebo (Table). The changes in RVFWS and RAA were lower in the seralutinib group vs placebo at Week 12 and Week 24 (Table). Change in NT-proBNP correlated with change in RAA (r = 0.43). At Week 24, change in PAC was greater in the seralutinib group (-0.02 ± 0.085 placebo, 0.19 ± 0.089 seralutinib; LSMD 0.22 (0.104) p = 0.04). There was no effect of seralutinib on left ventricular ejection fraction. Conclusion Treatment with seralutinib was associated with a significant reduction of RVFWS/sPAP. In addition, significant differences in RVFWS itself, RAA, and PAC were observed. These treatment effects support improved RV-PA coupling and right heart function. In conjunction with concordant reductions in PVR and NT-proBNP, these data suggest potential favourable effects of seralutinib in PAH. Seralutinib is in clinical development as a potential new treatment option for patients with PAH.

Local production of growth factors within the airway with autocrine/paracrine effects can promote features of asthma. Here, we show that glial-derived neurotrophic factor (GDNF) is a procontractile and proremodeling factor that contributes to allergen-induced airway hyperreactivity and tissue remodeling in a mouse model of asthma. Blocking GDNF signaling attenuates allergen-induced airway hyperreactivity and remodeling, suggesting a novel approach to alleviating structural and functional changes in the asthmatic airway.

Chronic airway disease is a short- and long-term consequence of premature birth. Understanding effects of O2 exposure during the perinatal period is key to identify targetable mechanisms that initiate and sustain adverse airway changes. Our findings show a beneficial effect of exogenous H2S on developing mouse airway structure and function with notable sex differences. H2S donors alleviate effects of O2 on airway hyperreactivity, contractility, airway smooth muscle thickness, and extracellular matrix deposition.

Background/Objective Few studies have investigated associations between rheumatologic serology patterns and different interstitial lung disease (ILD) patterns. Methods We present novel findings of a historic cohort study (n = 454) with data collected from 2011 to 2021 within our hospital system. In this institutional review board–approved study, data regarding rheumatologic serologies and ILD patterns were noted based on chart review in patients with scleroderma. The Kruskal-Wallis rank sum and χ 2 tests were used for statistical analysis. Results Results showed a statistically significant association between anti-U1 snRNP with lymphoid interstitial pneumonia, which has not been previously described. Conclusions We demonstrated novel serologic associations with ILD patterns, which have important clinical implications. More robust and high-powered studies are needed to elucidate the role of serologic testing and their association with ILD phenotypes.