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Plan Nacional de R+D+I [PI09/91074, PI13/02204, PI16/01606]; ISCIII-Subdireccion General de Evaluacion y el Fondo Europeo de Desarrollo Regional (FEDER); Fundacio Parc Tauli, Plan Avanza [TSI-020302-2008-38]; AEI/FEDER UE [RTC-2017-6193-1]

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.

Background. The STING protein is activated by the second messenger cGAMP to promote the innate immune response against infections. Beyond this role, a chronically overactive STING signaling has been described in several disorders. Patients with severe COVID-19 exhibit a hyper-inflammatory response (the cytokine storm) that is in part mediated by the cGAS-STING pathway. Several STING inhibitors may protect from severe COVID-19 by down-regulating several inflammatory cytokines. This pathway has been implicated in the establishment of an optimal antiviral vaccine response. STING agonists as adjuvants improved the IgG titers against the SARS-CoV-2 Spike protein vaccines. Methods. We investigated the association between two common functional STING1/TMEM173 polymorphisms (rs78233829 C>G/p.Gly230Ala and rs1131769C>T/p.His232Arg) and severe COVID-19 requiring hospitalization. A total of 801 non-vaccinated and 105 fully vaccinated (mRNA vaccine) patients, as well as 300 population controls, were genotyped. Frequencies between the groups were statistically compared. Results. There were no differences for the STING1 variant frequencies between non-vaccinated patients and controls. Vaccinated patients showed a significantly higher frequency of rs78233829 C (230Gly) compared to non-vaccinated patients (CC vs. CG + GG; p = 0.003; OR = 2.13; 1.29–3.50). The two STING1 variants were in strong linkage disequilibrium, with the rs78233829 C haplotypes being significantly more common in the vaccinated (p = 0.02; OR = 1.66; 95%CI = 1.01–2.55). We also studied the LTZFL1 rs67959919 G/A polymorphism that was significantly associated with severe COVID-19 (p < 0.001; OR = 1.83; 95%CI = 1.28–2.63). However, there were no differences between the non-vaccinated and vaccinated patients for this polymorphism. Conclusions. We report a significant association between common functional STING1 polymorphisms and the risk of developing severe COVID-19 among fully vaccinated patients.

Background: Human chromosome 3p21.31 variants introgressed from Neanderthals have been associated with a higher risk of developing a severe form of COVID-19. These Neanderthal DNA variants would regulate the expression of several genes, including LZTFL1 (implicated in the epithelial–mesenchymal transition) and proinflammatory chemokine receptors. Methods: We studied three introgressed haplotypes in patients who developed critical COVID-19 (N = 446; 82 deaths), less severe non-critical COVID-19 (N = 552), and population controls (N = 500) from the region of Asturias, Northern Spain. All the participants were genotyped for six single nucleotide polymorphisms that defined the three 3p21.31 haplotypes. Results: For the haplotype in the LZTFL1 gene, the total patients were significantly higher frequency carriers of the Neanderthal variant compared to controls (24% vs. 17%; p < 0.05, OR = 1.53, 95% CI = 1.16–2.01). Multiple logistic regression showed that critical COVID-19 was independently associated with male sex, hypertension, dyslipaemia, and the introgressed LZTFL1 haplotype (p = 0.006). The frequency of these introgressed genotypes did not differ between normotensives and normolipaemics in the two patient groups but was significantly increased among hypertensives (p = 0.003) and dyslipaemics (p = 0.001). Conclusions: In our population, the 3p21.31 haplotypes introgressed from Neanderthals were associated with increased risk of critical COVID-19, and the risk effect was higher among patients with hypertension and dyslipaemia.

Autophagy has emerged as a key regulator of the inflammatory response. To examine the role of autophagy in the development of organ dysfunction during endotoxemia, wild-type and autophagy-deficient ( Atg4b -null) mice were challenged with lipopolysaccharide. Animals lacking Atg4b showed increased mortality after endotoxemia. Among the different organs studied, only the lungs showed significant differences between genotypes, with increased damage in mutant animals. Autophagy was activated in lungs from wild-type, LPS-treated mice. Similarly, human bronchial cells show an increased autophagy when exposed to serum from septic patients. We found an increased inflammatory response (increased neutrophilic infiltration, higher levels of Il6 , Il12p40 , and Cxcl2 ) in the lungs from knockout mice and identified perinuclear sequestration of the anti-inflammatory transcription factor ATF3 as the putative mechanism responsible for the differences between genotypes. Finally, induction of autophagy by starvation before LPS exposure resulted in a dampened pulmonary response to LPS in wild-type, but not knockout, mice. Similar results were found in human bronchial cells exposed to LPS. Our results demonstrate the central role of autophagy in the regulation of the lung response to endotoxemia and sepsis and its potential modulation by nutrition. Key messages Endotoxemia and sepsis trigger autophagy in lung tissue. Defective autophagy increases mortality and lung inflammation after endotoxemia. Impairment of autophagy results is perinuclear ATF3 sequestration. Starvation ameliorates lung injury by an autophagy-dependent mechanism.

Background Overstretching of lung parenchyma may lead to injury, especially during mechanical ventilation. To date, there are no specific biomarkers of lung stretch, but transcriptomic signatures have not been explored. Our objective was to identify stretch-specific signatures using micro-RNA and gene expression. Methods Data on micro-RNA and RNA expression in response to stretch in experimental models were systematically pooled. Signatures were identified as those micro-RNAs or genes with differential expression in samples from stretched cells or tissues, and optimized using a greedy algorithm. Expression data was used to calculate transcriptomic scores. The accuracy of these scores was validated in animal models of lung injury, ex vivo mechanically ventilated human lungs, and bronchoalveolar lavage fluid (BALF, n  = 7) and in serum samples ( n  = 31) of mechanically ventilated patients. Results Six micro-RNAs (mir-383, mir-877, mir-130b; mir-146b, mir-181b, and mir-26b) were differentially expressed in stretched cell cultures ( n  = 24). Amongst the genes regulated by these micro-RNAs, a 451-gene signature was identified in vitro ( n  = 106) and refined using data from animal models ( n  = 143) to obtain a 6-gene signature (Lims1, Atp6v1c1, Dedd, Bclb7, Ppp1r2 and F3). Transcriptomic scores were significantly higher in samples submitted to stretch or injurious mechanical ventilation. The microRNA and RNA signatures were validated in human tissue, BALF and serum, with areas under the ROC curve between 0.7 and 1 to identify lung overdistention. Conclusions Lung cell stretch induces the expression of specific micro-RNA and genes. The potential of these signatures to identify lung stretch in a clinical setting must be explored.

Purpose This study aimed to assess the prevalence and time course of asynchronies during mechanical ventilation (MV). Methods 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. Results 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. Conclusions 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.

Supported by a grant from Instituto de Salud Carlos III (Plan Estatal de I+D+I 2013-2016, PI16/01614, FEDER funds). C.H. is the recipient of a grant from Instituto de Salud Carlos III (Contratos Sara Borrell, CD16/00033). Instituto de Investigación Sanitaria del Principado de Asturias is supported by Fundación FINBA. Instituto Universitario de Oncología del Principado de Asturias is supported by Fundación Bancaria Caja de Ahorros de Asturias.

Supported by Instituto de Salud Carlos III (FIS-PI07/0597 and FIS-PI10/0606). AGL is the recipient of a grant from Universidad de Oviedo (UNOV-09-pf). AA and ILA are the recipients of grants from Instituto Universitario de Oncología del Principado de Asturias (IUOPA). EBS is the recipient of a grant from FICYT (COF-11-40). GMA is the recipient of a grant from Instituto de Salud Carlos III (Intensificación de la Actividad Investigadora-INT 11/14).