This study aimed to assess the prevalence and time course of asynchronies during mechanical ventilation (MV). Prospective, noninterventional observational study of 50 patients admitted to intensive care unit (ICU) beds equipped with Better Care™ software throughout MV. The software distinguished ventilatory modes and detected ineffective inspiratory efforts during expiration (IEE), double-triggering, aborted inspirations, and short and prolonged cycling to compute the asynchrony index (AI) for each hour. We analyzed 7,027 h of MV comprising 8,731,981 breaths. Asynchronies were detected in all patients and in all ventilator modes. The median AI was 3.41 % [IQR 1.95–5.77]; the most common asynchrony overall and in each mode was IEE [2.38 % (IQR 1.36–3.61)]. Asynchronies were less frequent from 12 pm to 6 am [1.69 % (IQR 0.47–4.78)]. In the hours where more than 90 % of breaths were machine-triggered, the median AI decreased, but asynchronies were still present. When we compared patients with AI > 10 vs AI ≤ 10 %, we found similar reintubation and tracheostomy rates but higher ICU and hospital mortality and a trend toward longer duration of MV in patients with an AI above the cutoff. Asynchronies are common throughout MV, occurring in all MV modes, and more frequently during the daytime. Further studies should determine whether asynchronies are a marker for or a cause of mortality.

Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a “multidimensional entity” characterized by four “domains” that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are 1) histological evidence of tissue injury, 2) alteration of the alveolar–capillary barrier, 3) presence of an inflammatory response, and 4) physiologic dysfunction. For each domain, we present “relevant measurements,” defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as “experimental ALI.” Finally, we propose that a time criterion defining “acute” in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.

Fibrogenesis is part of a normal protective response to tissue injury that can become irreversible and progressive, leading to fatal diseases. Senescent cells are a main driver of fibrotic diseases through their secretome, known as senescence-associated secretory phenotype (SASP). Here, we report that cellular senescence, and multiple types of fibrotic diseases in mice and humans are characterized by the accumulation of iron. We show that vascular and hemolytic injuries are efficient in triggering iron accumulation, which in turn can cause senescence and promote fibrosis. Notably, we find that senescent cells persistently accumulate iron, even when the surge of extracellular iron has subdued. Indeed, under normal conditions of extracellular iron, cells exposed to different types of senescence-inducing insults accumulate abundant ferritin-bound iron, mostly within lysosomes, and present high levels of labile iron, which fuels the generation of reactive oxygen species and the SASP. Finally, we demonstrate that detection of iron by magnetic resonance imaging might allow non-invasive assessment of fibrotic burden in the kidneys of mice and in patients with renal fibrosis. Our findings suggest that iron accumulation plays a central role in senescence and fibrosis, even when the initiating events may be independent of iron, and identify iron metabolism as a potential therapeutic target for senescence-associated diseases.

The inflection points of the pressure–volume curve have been used for setting mechanical ventilation in patients with acute lung injury. However, the lung status at these points has never been specifically addressed. In 12 patients with early lung injury we traced both limbs of the pressure–volume curve by means of a stepwise change in airway pressure, and a computed tomography (CT) scan slice was obtained for every pressure level. Although aeration (increase in normally aerated lung) and recruitment (decrease in nonaerated lung) were parallel and continuous along the pressure axis during inflation, loss of aeration and derecruitment were only significant at pressures below the point of maximum curvature on the deflation limb of the pressure–volume curve. This point was related to a higher amount of normally aerated tissue and a lower amount of nonaerated tissue when compared with the lower inflection point on both limbs of the curve. Aeration at the inflection points was similar in lung injury from pulmonary or extrapulmonary origin. There were no significant changes in hyperinflated lung tissue. These results support the use of the deflation limb of the pressure–volume curve for positive end-expiratory pressure setting in patients with acute lung injury.

Matrix metalloproteinases (MMPs) may have pro and antifibrotic roles within the lungs, due to its ability to modulate collagen turnover and immune mediators. MMP-8 is a collagenase that also cleaves a number of cytokines and chemokines. To evaluate its relevance in lung fibrosis, wildtype and Mmp8^−/− mice were treated with either intratracheal bleomycin or saline, and lungs were harvested at different time points. Fibrosis, collagen, collagenases, gelatinases, TGFβ and IL-10 were measured in lung tissue. Mmp8^−/− mice developed less fibrosis than their wildtype counterparts. This was related to an increase in lung inflammatory cells, MMP-9 and IL-10 levels in these mutant animals. In vitro experiments showed that MMP-8 cleaves murine and human IL-10, and tissue from knockout animals showed decreased IL-10 processing. Additionally, lung fibroblasts from these mice were cultured in the presence of bleomycin and collagen, IL-10 and STAT3 activation (downstream signal in response to IL-10) measured by western blotting. In cell cultures, bleomycin increased collagen synthesis only in wildtype mice. Fibroblasts from knockout mice did not show increased collagen synthesis, but increased levels of unprocessed IL-10 and STAT3 phosphorylation. Blockade of IL-10 reverted this phenotype, increasing collagen in cultures. According to these results, we conclude that the absence of MMP-8 has an antifibrotic effect by increasing IL-10 and propose that this metalloprotease could be a relevant modulator of IL-10 metabolism in vivo.