Standardization of methods for sampling the distal airspace in mechanically ventilated patients using heat moisture exchange filter fluid.

Noninvasive sampling of the distal airspace in patients with acute respiratory distress syndrome (ARDS) has long eluded clinical and translational researchers. We recently reported that fluid collected from heat moisture exchange (HME) filters closely mirrors fluid directly aspirated from the distal airspace. In the current study, we sought to determine fluid yield from different HME types, optimal HME circuit dwell time, and reliability of HME fluid in reflecting the distal airspace. We studied fluid yield from four different filter types by loading increasing volumes of saline and measuring volumes of fluid recovered. We collected filters after 1, 2, and 4 h of dwell time for measurement of fluid volume and total protein from 13 subjects. After identifying 4 h as the optimal dwell time, we measured total protein and IgM in HME fluid from 42 subjects with ARDS and nine with hydrostatic pulmonary edema (HYDRO). We found that the fluid yield varies greatly by filter type. With timed sample collection, fluid recovery increased with increasing circuit dwell time with a median volume of 2.0 mL [interquartile range (IQR) 1.2-2.7] after 4 h. Total protein was higher in the 42 subjects with ARDS compared with nine with HYDRO [median 708 µg/mL (IQR 244-2017) vs. 364 µg/mL (IQR 136-578), P = 0.047], confirming that total protein concentration in HME is higher in ARDS compared with hydrostatic edema. These studies establish a standardized HME fluid collection protocol and confirm that HME fluid analysis is a novel noninvasive tool for the study of the distal airspace in ARDS.

Inflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primates.

Perinatal inflammatory stress is associated with early life morbidity and lifelong consequences for pulmonary health. Chorioamnionitis, an inflammatory condition affecting the placenta and fluid surrounding the developing fetus, affects 25 to 40% of preterm births. Severe chorioamnionitis with preterm birth is associated with significantly increased risk of pulmonary disease and secondary infections in childhood, suggesting that fetal inflammation may markedly alter the development of the lung. Here, we used intra-amniotic lipopolysaccharide (LPS) challenge to induce experimental chorioamnionitis in a prenatal rhesus macaque (Macaca mulatta) model that mirrors structural and temporal aspects of human lung development. Inflammatory injury directly disrupted the developing gas exchange surface of the primate lung, with extensive damage to alveolar structure, particularly the close association and coordinated differentiation of alveolar type 1 pneumocytes and specialized alveolar capillary endothelium. Single-cell RNA sequencing analysis defined a multicellular alveolar signaling niche driving alveologenesis that was extensively disrupted by perinatal inflammation, leading to a loss of gas exchange surface and alveolar simplification, with notable resemblance to chronic lung disease in newborns. Blockade of the inflammatory cytokines interleukin-1ß and tumor necrosis factor-α ameliorated LPS-induced inflammatory lung injury by blunting stromal responses to inflammation and modulating innate immune activation in myeloid cells, restoring structural integrity and key signaling networks in the developing alveolus. These data provide new insight into the pathophysiology of developmental lung injury and suggest that modulating inflammation is a promising therapeutic approach to prevent fetal consequences of chorioamnionitis.