Beyond Bronchiolitis Obliterans: In-Depth Histopathologic Characterization of Bronchiolitis Obliterans Syndrome after Lung Transplantation

Bronchiolitis obliterans syndrome (BOS) is considered an airway-centered disease, with bronchiolitis obliterans (BO) as pathologic hallmark. However, the histologic spectrum of pure clinical BOS remains poorly characterized. We provide the first in-depth histopathologic description of well-characterized BOS patients and patients without chronic lung allograft dysfunction (CLAD), defined according to the recent consensus guidelines. Explant lung tissue from 52 clinically-defined BOS and 26 non-CLAD patients (collected 1993–2018) was analyzed for histologic parameters, including but not limited to airway lesions, vasculopathy and fibrosis. In BOS, BO lesions were evident in 38 (73%) patients and varied from concentric sub-epithelial fibrotic BO to inflammatory BO, while 10/14 patients without BO displayed ‘vanishing airways’, defined by a discordance between arteries and airways. Chronic vascular abnormalities were detected in 22 (42%) patients. Ashcroft fibrosis scores revealed a median of 43% (IQR: 23–69) of normal lung parenchyma per patient; 26% (IQR: 18–37) of minimal alveolar fibrous thickening; and 11% (IQR: 4–18) of moderate alveolar thickening without architectural damage. Patchy areas of definite fibrotic damage to the lung structure (i.e., Ashcroft score ≥ 5) were present in 28 (54%) patients. Fibrosis was classified as bronchocentric (n = 21/28, 75%), paraseptal (n = 17/28, 61%) and subpleural (n = 15/28, 54%). In non-CLAD patients, BO lesions were absent, chronic vascular abnormalities present in 1 (4%) patient and mean Ashcroft scores were significantly lower compared to BOS (p = 0.0038) with 78% (IQR:64–88) normally preserved lung parenchyma. BOS explant lungs revealed evidence of various histopathologic findings, including vasculopathy and fibrotic changes, which may contribute to the pathophysiology of BOS.

Revisiting the role of pulmonary surfactant in chronic inflammatory lung diseases and environmental exposure

Pulmonary surfactant is a crucial and dynamic lung structure whose primary functions are to reduce alveolar surface tension and facilitate breathing. Though disruptions in surfactant homeostasis are typically thought of in the context of respiratory distress and premature infants, many lung diseases have been noted to have significant surfactant abnormalities. Nevertheless, preclinical and clinical studies of pulmonary disease too often overlook the potential contribution of surfactant alterations – whether in quantity, quality or composition – to disease pathogenesis and symptoms. In inflammatory lung diseases, whether these changes are cause or consequence remains a subject of debate. This review will outline 1) the importance of pulmonary surfactant in the maintenance of respiratory health, 2) the diseases associated with primary surfactant dysregulation, 3) the surfactant abnormalities observed in inflammatory pulmonary diseases and, finally, 4) the available research on the interplay between surfactant homeostasis and smoking-associated lung disease. From these published studies, we posit that changes in surfactant integrity and composition contribute more considerably to chronic inflammatory pulmonary diseases and that more work is required to determine the mechanisms underlying these alterations and their potential treatability.

3D Bioprinting Strategies, Challenges, and Opportunities to Model the Lung Tissue Microenvironment and Its Function

Human lungs are organs with an intricate hierarchical structure and complex composition; lungs also present heterogeneous mechanical properties that impose dynamic stress on different tissue components during the process of breathing. These physiological characteristics combined create a system that is challenging to model in vitro. Many efforts have been dedicated to develop reliable models that afford a better understanding of the structure of the lung and to study cell dynamics, disease evolution, and drug pharmacodynamics and pharmacokinetics in the lung. This review presents methodologies used to develop lung tissue models, highlighting their advantages and current limitations, focusing on 3D bioprinting as a promising set of technologies that can address current challenges. 3D bioprinting can be used to create 3D structures that are key to bridging the gap between current cell culture methods and living tissues. Thus, 3D bioprinting can produce lung tissue biomimetics that can be used to develop in vitro models and could eventually produce functional tissue for transplantation. Yet, printing functional synthetic tissues that recreate lung structure and function is still beyond the current capabilities of 3D bioprinting technology. Here, the current state of 3D bioprinting is described with a focus on key strategies that can be used to exploit the potential that this technology has to offer. Despite today’s limitations, results show that 3D bioprinting has unexplored potential that may be accessible by optimizing bioink composition and looking at the printing process through a holistic and creative lens.

Recent Advances in Fluorescence Imaging of Pulmonary Fibrosis in Animal Models

Pulmonary fibrosis (PF) is a lung disease that may cause impaired gas exchange and respiratory failure while being difficult to treat. Rapid, sensitive, and accurate detection of lung tissue and cell changes is essential for the effective diagnosis and treatment of PF. Currently, the commonly-used high-resolution computed tomography (HRCT) imaging has been challenging to distinguish early PF from other pathological processes in the lung structure. Magnetic resonance imaging (MRI) using hyperpolarized gases is hampered by the higher cost to become a routine diagnostic tool. As a result, the development of new PF imaging technologies may be a promising solution. Here, we summarize and discuss recent advances in fluorescence imaging as a talented optical technique for the diagnosis and evaluation of PF, including collagen imaging, oxidative stress, inflammation, and PF-related biomarkers. The design strategies of the probes for fluorescence imaging (including multimodal imaging) of PF are briefly described, which can provide new ideas for the future PF-related imaging research. It is hoped that this review will promote the translation of fluorescence imaging into a clinically usable assay in PF.

Tenascin-C: Friend or Foe in Lung Aging?

Lung aging is characterized by lung function impairment, ECM remodeling and airspace enlargement. Tenascin-C (TNC) is a large extracellular matrix (ECM) protein with paracrine and autocrine regulatory functions on cell migration, proliferation and differentiation. This matricellular protein is highly expressed during organogenesis and morphogenetic events like injury repair, inflammation or cancer. We previously showed that TNC deficiency affected lung development and pulmonary function, but little is known about its role during pulmonary aging. In order to answer this question, we characterized lung structure and physiology in 18 months old TNC-deficient and wild-type (WT) mice. Mice were mechanically ventilated with a basal and high tidal volume (HTV) ventilation protocol for functional analyses. Additional animals were used for histological, stereological and molecular biological analyses. We observed that old TNC-deficient mice exhibited larger lung volume, parenchymal volume, total airspace volume and septal surface area than WT, but similar mean linear intercept. This was accompanied by an increase in proliferation, but not apoptosis or autophagy markers expression throughout the lung parenchyma. Senescent cells were observed in epithelial cells of the conducting airways and in alveolar macrophages, but equally in both genotypes. Total collagen content was doubled in TNC KO lungs. However, basal and HTV ventilation revealed similar respiratory physiological parameters in both genotypes. Smooth muscle actin (α-SMA) analysis showed a faint increase in α-SMA positive cells in TNC-deficient lungs, but a marked increase in non-proliferative α-SMA + desmin + cells. Major TNC-related molecular pathways were not up- or down-regulated in TNC-deficient lungs as compared to WT; only minor changes in TLR4 and TGFβR3 mRNA expression were observed. In conclusion, TNC-deficient lungs at 18 months of age showed exaggerated features of the normal structural lung aging described to occur in mice between 12 and 18 months of age. Correlated to the increased pulmonary function parameters previously observed in young adult TNC-deficient lungs and described to occur in normal lung aging between 3 and 6 months of age, TNC might be an advantage in lung aging.