Tissue Resilience Research Articles

PDGFRα promotes organ resistance to immune-mediated damage

Abstract Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that exhibits great clinical heterogeneity. Development and clinical expression of autoimmune diseases is strongly influenced by genetic variants. The single nucleotide polymorphism (SNP) rs1364989, located close to PDGFRA, has been associated with the development of lupus nephritis through an unknown mechanism. Because PDGF, through its α and β receptors, regulates tissue response to inflammation, we hypothesized that rs1364989 could modulate the behavior of renal cells in the context of immune-mediated glomerulonephritis. To determine whether rs1364989 affects the expression of PDGFRα, we analyzed umbilical cord mesenchymal cells from carriers of risk and protective alleles. We observed that the presence of the risk allele was associated with reduced PDGFRα expression. Next, we analyzed whether inflammatory mediators could modulate PDGFRα expression in in vitro and in vivo settings. We documented that its levels increase during acute inflammation in a murine model of glomerulonephritis. In vitro, this effect could be reproduced by IL-17. Absence of PDGFRα increased kidney damage during immune complex-induced glomerulonephritis. An analogous effect was observed in joints of mice with collagen-induced arthritis. Our results demonstrate that the SLE-associated allele of rs1364989 reduces the expression of PDGFRα and that this receptor may activate a pathway that protects tissues in response to local inflammation. These findings highlight the importance of tissue resilience as a factor that can protect an organ from inflammatory damage in the setting of autoimmunity. This work was supported by the Consejo Nacional de Ciencia y Tecnología (CONACYT), Mexico

Probiotic consumption can modify the resilience of periodontal tissues in rats under experimental periodontitis.

This study evaluated the effects of systemic administration of Bifidobacterium animalis subsp. lactis HN019 (B. lactis HN019) on experimental periodontitis (EP) in rats. Thirty-two rats were allocated to groups C (control), C-HN019 (probiotic), EP (EP only), and EP-HN019 (EP+probiotic). From day 0, the animals of C-HN019 and EP-HN019 groups received B. lactis HN019 (1×109 CFU/ml) daily. On the 14th day, the animals of EP and EP-HN019 groups received silk ligature around mandibular molars. Animals were euthanized on the 28th day. Samples of oral biofilm, gingival tissues, blood serum, and mandible were obtained for microtomographic, histomorphometric, microbiological, and immunological analyses. Data were statistically analyzed (p<0.05). Group EP-HN019 presented significantly less alveolar bone loss when compared with Group EP in histomorphometric and microtomographic analyses. In gingival tissue and serum, Group EP-HN019 presented lower proinflammatory/anti-inflammatory cytokines ratios than Group EP. Group EP-HN019 showed higher expression of beta-defensins and less TRAP-positive cells than Group EP. Group EP presented higher gene expression of Ifng and lower gene expression of Foxp3 when compared with Group EP-HN019 in gingival tissue. In oral biofilm, EP-HN019 group presented a lower percentage of species similar to Fusobacterium periodonticum and a higher percentage of species similar to Actinomyces gereneseriae, Actinomyces israelli, and Streptococcus gordonii when compared with Group EP. There was a significant increase of B. lactis HN019 after administration of probiotic therapy in oral biofilm of Group EP-HN019. The consumption of B. lactis HN019 promotes a protective effect against alveolar bone loss by modifying local and systemic microbiological and immunoinflammatory parameters.

The extracellular matrix fibulin 7 maintains epidermal stem cell heterogeneity during skin aging.

Tissue stem cells (SCs) divide infrequently as a protective mechanism against internal and external stresses associated with aging. Here, we demonstrate that slow- and fast-cycling SCs in the mouse skin epidermis undergo distinct aging processes. Two years of lineage tracing reveals that Dlx1+ slow-cycling clones expand into the fast-cycling SC territory, while the number of Slc1a3+ fast-cycling clones gradually declines. Transcriptome analysis further indicate that the molecular properties of each SC population are altered with age. Mice lacking fibulin 7, an extracellular matrix (ECM) protein, show early impairments resembling epidermal SC aging, such as the loss of fast-cycling clones, delayed wound healing, and increased expression of inflammation- and differentiation-related genes. Fibulin 7 interacts with structural ECM and matricellular proteins, and the overexpression of fibulin 7 in primary keratinocytes results in slower proliferation and suppresses differentiation. These results suggest that fibulin 7 plays a crucial role in maintaining tissue resilience and epidermal SC heterogeneity during skin aging.

EXAMINATION OF VICTIMS OF SHARP TRAUMA

Clinical forensic medicine is one that can be applied appropriately to the section of medical practice whose scope involves the interaction between the law, the judiciary, and the police involving (generally) living people and the issuance of visum et repertum. In general, there are two types of visum et repertum, namely visum et repertum for living victims and visum et repertum for the dead. The making of visum et repertum intended as a substitute for evidence is unlikely to be present before the trial court in such circumstances. A wound is a damage to a part of the body in the form of a break in the integrity of the tissues that can occur due to mechanical hardness. The body has the resilience and elasticity of tissues based on the softness and strength of the skeleton, the strength of which exceeds the strength of the tissues Then the tissue will adjust to the existing pressure, then the event does not happen, then the event will occur injury or injury. Sharp or pointed weapons leave characteristic wounds on the body, depending on the type of weapon used. Examination and treatment of the victim of a male, aged 34 years, the general condition of the patient is good, the awareness of mentis compost has been carried out, as well as the examination of vital signs within normal limits. On examination, it was found that there was a cut on the chin to the left jaw due to sharp trauma. Based on the theory of the results of the examination and the discussion above, it is concluded that the victim experienced a sharp trauma. The wound is qualified as a moderate wound because it causes obstruction in carrying out his daily work as a factory worker in accordance with Article 351 of the Criminal Code.

Gearing up for battle: Harnessing adaptive T cell immunity against gram-negative pneumonia.

Pneumonia is one of the leading causes of morbidity and mortality worldwide and Gram-negative bacteria are a major cause of severe pneumonia. Despite advances in diagnosis and treatment, the rise of multidrug-resistant organisms and hypervirulent strains demonstrates that there will continue to be challenges with traditional treatment strategies using antibiotics. Hence, an alternative approach is to focus on the disease tolerance components that mediate immune resistance and enhance tissue resilience. Adaptive immunity plays a pivotal role in modulating these processes, thus affecting the incidence and severity of pneumonia. In this review, we focus on the adaptive T cell responses to pneumonia induced by Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. We highlight key factors in these responses that have potential for therapeutic targeting, as well as the gaps in current knowledge to be focused on in future work.

Fic-mediated AMPylation tempers the unfolded protein response during physiological stress

The proper balance of synthesis, folding, modification, and degradation of proteins, also known as protein homeostasis, is vital to cellular health and function. The unfolded protein response (UPR) is activated when the mechanisms maintaining protein homeostasis in the endoplasmic reticulum become overwhelmed. However, prolonged or strong UPR responses can result in elevated inflammation and cellular damage. Previously, we discovered that the enzyme filamentation induced by cyclic-AMP (Fic)can modulate the UPR response via posttranslational modification of binding immunoglobulin protein (BiP) by AMPylation during homeostasis and deAMPylation during stress. Loss of fic in Drosophila leads to vision defects and altered UPR activation in the fly eye. To investigate the importance of Fic-mediated AMPylation in a mammalian system, we generated a conditional null allele of Fic in mice and characterized the effect of Fic loss on the exocrine pancreas. Compared to controls, Fic-/- mice exhibit elevated serum markers for pancreatic dysfunction and display enhanced UPR signaling in the exocrine pancreas in response to physiological and pharmacological stress. In addition, both fic-/- flies and Fic-/- mice show reduced capacity to recover from damage by stress that triggers the UPR. These findings show that Fic-mediated AMPylation acts as a molecular rheostat that is required to temper the UPR response in the mammalian pancreas during physiological stress. Based on these findings, we propose that repeated physiological stress in differentiated tissues requires this rheostat for tissue resilience and continued function over the lifetime of an animal.

Fluid structure interaction versus rigid-wall approach in the study of the symptomatic stenosed carotid artery: Importance of wall compliance and resilience of loose connective tissue.

The purpose of this paper is to demonstrate the importance of a compliant wall approach in modeling of non‐Newtonian and non‐physiological blood flows. A case study of a stenosed and symptomatic carotid bifurcation was considered to show the influence of the wall‐resilience assumption on the flow parameters obtained with numerical simulations. Patient‐specific data concerning the geometry and flow conditions were collected and used to carry out two‐way coupled fluid structure interaction simulations of the pulsatile blood flow through carotid artery. The wall compliance was considered separately as related to the wall‐elasticity and as associated with the reaction of the loose connective tissue surrounding the carotid bifurcation. The obtained hemodynamic parameters were compared to those which were found in rigid‐wall simulations. The difference between the results obtained for rigid‐wall and compliant‐wall approaches for the peak‐systolic area‐averaged wall shear stress achieved 35%, whereas the difference between the time‐averaged local vorticity and shear strain reached, respectively, 42% and 43%. The influence of the highly resilient wall on the monitored hemodynamic parameters was significant even if time‐averaged values are compared, which suggests that these metrics are considerably overestimated if the wall compliance is not considered. Moreover, the findings show that the mechanical response of the loose connective tissue cannot be neglected in blood flow simulations. Additionally, this study indicates that stiffening of the arterial wall due to atherosclerosis significantly rises hemodynamic parameters. This explains the therapeutic benefits of surgical removal of plaque lesions formed in the carotid bifurcation (endarterectomy).

Sodium silicate treatment promotes suberin poly phenolic and silicon deposition, and enhances hardness and brittleness at muskmelon wounds

Silicon can enhance plant resistance to biotic stress by directly inhibiting pathogens, forming physical barriers, and inducing the synthesis of defense compounds. However, no study is available on silicon on fruit wound healing. Here, we found that sodium silicate enhanced the activities of phenylalanine ammonia-lyase, 4-coumarate coenzyme A ligase, and cinnamate-4-hydroxylase, and elevated levels of cinnamic, ρ-coumaric, caffeic, ferulic, sinapic acids, and total phenols at fruit wounds. Sodium silicate accelerated the deposition of suberin poly phenolic and silicon at wounds, increased the hardness and brittleness and reduced their resilience of the healing tissues, which slowed weight loss by wounded fruit, and disease index in fruit subjected to Trichothecium roseum. Taken together, sodium silicate may promote wound healing in muskmelons by activating phenylpropanoid pathway, accelerating suberin poly phenolic and silicon deposition at wounds, and increasing the hardness and brittleness of healing tissues.

Preharvest multiple sprays with chitosan promotes the synthesis and deposition of lignin at wounds of harvested muskmelons

As an important elicitor, chitosan could activate the synthesis of lignin in many plants. However, no report is available on whether preharvest chitosan sprays affects the synthesis and deposition of lignin at wounds of harvested muskmelons. In the present study, the plants and fruit of muskmelons were multiple sprayed with 0.1% chitosan during fruit development. Here, we found that chitosan sprays increased the activities of 4-coumaric acid-coenzyme A ligase, cinnamyl-CoA reductase and cinnamyl alcohol dehydrogenase, and elevated the levels of p-coumaryl alcohol, coniferyl alcohol, sinapyl alcohol and lignin at wounds. Chitosan sprays enhanced H2O2 level and peroxidase activity, and accelerated the deposition of lignin at wounds. Moreover, chitosan sprays resulted in a higher hardness and lower resilience, springiness and cohesiveness of the healing tissues. Taken together, preharvest chitosan sprays accelerated the deposition of lignin at wounds of muskmelons by activating lignin metabolism, and increasing H2O2 content and peroxidase activity.

The Efficacy of Photobiomodulation Therapy in Improving Tissue Resilience and Healing of Radiation Skin Damage

The increased precision, efficacy, and safety of radiation brachytherapy has tremendously improved its popularity in cancer care. However, an unfortunate side effect of this therapy involves localized skin damage and breakdown that are managed palliatively currently. This study was motivated by prior reports on the efficacy of photobiomodulation (PBM) therapy in improving tissue resilience and wound healing. We evaluated the efficacy of PBM therapy on 36 athymic mice with 125I seed (0.42 mCi) implantation over 60 days. PBM treatments were performed with either red (660 nm) or near-infrared (880 nm, NIR) LEDs irradiance of 40 mW/cm2, continuous wave, fluence of 20 J/cm2 once per week. Animals were evaluated every 7 days with digital imaging, laser Doppler flowmetry, thermal imaging, µPET-CT imaging using 18F-FDG, and histology. We observed that both PBM treatments—red and NIR—demonstrated significantly less incidence and severity and improved healing with skin radionecrosis. Radiation exposed tissues had improved functional parameters such as vascular perfusion, reduced inflammation, and metabolic derangement following PBM therapy. Histological analysis confirmed these observations with minimal damage and resolution in tissues exposed to radiation. To our knowledge, this is the first report on the successful use of PBM therapy for brachytherapy. The results from this study support future mechanistic lab studies and controlled human clinical studies to utilize this innovative therapy in managing side effects from radiation cancer treatments.

Laparoscopic sacral hysteropexy for pelvic organ prolapse in a patient affected by marfan syndrome: a case report.

Marfan Syndrome (MS) is a dominantly inherited connective tissue disorder with consequences on the strength and resilience of connective tissues that may predispose to Pelvic Organ Prolapse (POP). Literature lacks studies investigating POP surgery in patients affected by MS that might help surgical management decisions. The objective of this paper is to describe the surgical procedure of laparoscopic sacral hysteropexy (LSHP) in a 37 years old woman affected by MS with symptomatic POP. We performed a nerve-sparing laparoscopic sacral hysteropexy without complications and looked for anatomical and subjective outcomes. The patient completed The Female Sexual Distress Scale (FSDS), Pelvic Floor Disability Index (PFDI-20), and Wexner questionnaires preoperatively and postoperatively. The patient stated a complete resolution of all POP related symptoms and there was a total correction of the descensus. Furthermore, no perioperative and postoperative complications were noted. LSHP could be an effective and safe procedure for the treatment of POP in women affected by MS and this case report is the first to describe a reconstructive procedure in this category of patients. The literature lacks studies investigating POP surgery in women with MS, that might help surgeons, thus we present this case to describe surgical and functional outcomes in this patient category, underlying the higher risk of complications and relapses related to the weakness of connective tissue. This case report may represent the basis of future studies to confirm the safety, efficacy and feasibility of LSHP and sacral colpopexy in patients with MS.

Transcriptome dynamics in developing testes of domestic cats and impact of age on tissue resilience to cryopreservation

BackgroundFundamental knowledge of cellular and molecular mechanisms in developing testicular tissues is critical to better understand gonadal biology and responses to non-physiological conditions. The objective of our study was to (1) analyze transcriptome dynamics in developing testis of the domestic cat and (2) characterize age effects on the initial response of the tissue to vitrification. Tissues from adult and juvenile cats were processed for histology, DNA integrity, and RNA sequencing analyses before and after vitrification.ResultsTranscriptomic findings enabled to further characterize juvenile period, distinguishing between early and late juvenile tissues. Changes in gene expression and functional pathways were extensive from early to late juvenile to adult development stages. Additionally, tissues from juvenile animals were more resilient to vitrification compared to adult counterparts, with early juvenile sample responding the least to vitrification and late juvenile sample response being closest to adult tissues.ConclusionsThis is the first study reporting comprehensive datasets on transcriptomic dynamic coupled with structural analysis of the cat testis according to the age and exposure to cryopreservation. It provides a comprehensive network of functional terms and pathways that are affected by age in the domestic cat and are either enriched in adult or juvenile testicular tissues.

Tissue resilience: lessons from social resilience: Social sciences research on community resilience could inspire biology to understand homeostasis.

Molecular biology could find inspiration from social sciences and ecology research on how communities remain resilient in times of crisis to better understand tissue homeostasis and resilience.

The association between telomere length and ischemic stroke risk and phenotype

The chronological age of a person is a key determinant of etiology and prognosis in the setting of ischemic stroke. Telomere length, an indicator of biological aging, progressively shortens with every cell cycle. Herein, we determined telomere length from peripheral blood leukocytes by Southern blot analyses in a prospective cohort of ischemic stroke patients (n = 163) and equal number of non-stroke controls and evaluated its association with various ischemic stroke features including etiology, severity, and outcome. A shorter telomere length (i.e. lowest quartile; ≤ 5.5 kb) was significantly associated with ischemic stroke (OR 2.95, 95% CI 1.70–5.13). This significant relationship persisted for all stroke etiologies, except for other rare causes of stroke. No significant association was present between admission lesion volume and telomere length; however, patients with shorter telomeres had higher admission National Institutes of Health Stroke Scale scores when adjusted for chronological age, risk factors, etiology, and infarct volume (p = 0.046). On the other hand, chronological age, but not telomere length, was associated with unfavorable outcome (modified Rankin scale > 2) and mortality at 90 days follow-up. The association between shorter telomere length and more severe clinical phenotype at the time of admission, might reflect reduced resilience of cerebral tissue to ischemia as part of biological aging.

Cyclically stretched ACL fibroblasts emigrating from spheroids adapt their cytoskeleton and ligament-related expression profile

Mechanical stress of ligaments varies; hence, ligament fibroblasts must adapt their expression profile to novel mechanomilieus to ensure tissue resilience. Activation of the mechanoreceptors leads to a specific signal transduction, the so-called mechanotransduction. However, with regard to their natural three-dimensional (3D) microenvironment cell reaction to mechanical stimuli during emigrating from a 3D spheroid culture is still unclear. This study aims to provide a deeper understanding of the reaction profile of anterior cruciate ligament (ACL)-derived fibroblasts exposed to cyclic uniaxial strain in two-dimensional (2D) monolayer culture and during emigration from 3D spheroids with respect to cell survival, cell and cytoskeletal orientation, distribution, and expression profile. Monolayers and spheroids were cultured in crosslinked polydimethyl siloxane (PDMS) elastomeric chambers and uniaxially stretched (14% at 0.3 Hz) for 48 h. Cell vitality, their distribution, nuclear shape, stress fiber orientation, focal adhesions, proliferation, expression of ECM components such as sulfated glycosaminoglycans, collagen type I, decorin, tenascin C and cell–cell communication-related gap junctional connexin (CXN) 43, tendon-related markers Mohawk and tenomodulin (myodulin) were analyzed. In contrast to unstretched cells, stretched fibroblasts showed elongation of stress fibers, cell and cytoskeletal alignment perpendicular to strain direction, less rounded cell nuclei, increased numbers of focal adhesions, proliferation, amplified CXN43, and main ECM component expression in both cultures. The applied cyclic stretch protocol evoked an anabolic response and enhanced tendon-related marker expression in ACL-derived fibroblasts emigrating from 3D spheroids and seems also promising to support in future tissue formation in ACL scaffolds seeded in vitro with spheroids.

Interactions Between Genes From Aging Pathways Significantly Influence Risk of Alzheimer’s Disease

Age is major risk factor for AD; however, relationships between aging and AD are not well understood. Decline in physiological resilience is universal feature of human aging that may also play role in AD. Aging-related pathways (such as IGF-I/P53/mTOR-mediated) that are involved in tissue resilience work in concert to decide outcomes of cell responses to stress/damage, such as survival, apoptosis, autophagy, etc. We hypothesized that interplay among genes in these pathways may influence AD risk as result of epistasis (GxG). We estimated effects of pairwise epistasis between SNPs in 53 genes from respective pathways on AD risk in the LLFS compared with other data (HRS, CHS, LOADFS). We found significant (fdr<0.05) GxG effects on AD risk in older adults across datasets. The SNP rs11765954 in CDK6 gene was involved in top GxG effects on AD in all datasets, when paired with SNPs in BCL2 and PPARGC1A. The CDK6 role in AD could be pleiotropic, depending on its activity in neurons: CDK6 expression is needed for DNA repair and neuronal survival; however, CDK6 overexpression may lead to the cell cycle reentry in postmitotic neurons resulting in apoptosis, which may contribute to neurodegeneration. CDK6 was earlier found to interfere with BCL2 effects on apoptosis, and with PPARGC1A effects on energy metabolism, which might contribute to observed GxG between these genes. We conclude that interactions among genes from biologically connected aging pathways may significantly influence AD risk. Uncovering such GxG effects has a potential to yield new genetic targets for AD prevention/treatment.

Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner

We previously demonstrated that exposing mouse dams to metformin during gestation results in increased beta-cell mass at birth and increased beta-cell insulin secretion in adult male offspring. Given these favorable changes after a gestational maternal metformin exposure, we wanted to understand the long-term metabolic impact on offspring after exposing dams to metformin during the postnatal window. The newborn period provides a feasible clinical window for intervention and is important for beta-cell proliferation and metabolic tissue development. Using a C57BL/6 model, we administered metformin to dams from the day of birth to postnatal day 21. We monitored maternal health and offspring growth during the lactation window, as well as adult glucose homeostasis through in vivo testing. At necropsy we assessed pancreas and adipocyte morphology using histological and immunofluorescent staining techniques. We found that metformin exposure programmed male and female offspring to be leaner with a higher proportion of small adipocytes in the gonadal white adipose tissue (GWAT). Male, but not female, offspring had an improvement in glucose tolerance as young adults concordant with a mild increase in insulin secretion in response to glucose in vivo. These data demonstrate long-term metabolic programming of offspring associated with maternal exposure to metformin during lactation.

Pro- and Anti-Inflammatory Responses in Severe COVID-19-Induced Acute Respiratory Distress Syndrome-An Observational Pilot Study.

ObjectivesThe severity of Coronavirus Disease 2019 (COVID-19) is largely determined by the immune response. First studies indicate altered lymphocyte counts and function. However, interactions of pro- and anti-inflammatory mechanisms remain elusive. In the current study we characterized the immune responses in patients suffering from severe COVID-19-induced acute respiratory distress syndrome (ARDS).MethodsThis was a single-center retrospective study in patients admitted to the intensive care unit (ICU) with confirmed COVID-19 between March 14th and May 28th 2020 (n = 39). Longitudinal data were collected within routine clinical care, including flow-cytometry of lymphocyte subsets, cytokine analysis and growth differentiation factor 15 (GDF-15). Antibody responses against the receptor binding domain (RBD) of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein were analyzed.ResultsAll patients suffered from severe ARDS, 30.8% died. Interleukin (IL)-6 was massively elevated at every time-point. The anti-inflammatory cytokine IL-10 was concomitantly upregulated with IL-6. The cellular response was characterized by lymphocytopenia with low counts of CD8+ T cells, natural killer (NK) and naïve T helper cells. CD8+ T and NK cells recovered after 8 to 14 days. The B cell system was largely unimpeded. This coincided with a slight increase in anti-SARS-CoV-2-Spike-RBD immunoglobulin (Ig) G and a decrease in anti-SARS-CoV-2-Spike-RBD IgM. GDF-15 levels were elevated throughout ICU treatment.ConclusionsMassively elevated levels of IL-6 and a delayed cytotoxic immune defense characterized severe COVID-19-induced ARDS. The B cell response and antibody production were largely unimpeded. No obvious imbalance of pro- and anti-inflammatory mechanisms was observed, with elevated GDF-15 levels suggesting increased tissue resilience.

Predictors and Functional Outcomes of Fast, Intermediate, and Slow Progression Among Patients With Acute Ischemic Stroke.

We aimed to delineate the determinants of the initial speed of infarct progression and the association of speed of infarct progression (SIP) with procedural and functional outcomes. From a prospectively maintained stroke center registry, consecutive anterior circulation ischemic stroke patients with large artery occlusion, National Institutes of Health Stroke Scale score ≥4, and multimodal vessel, ischemic core, and tissue-at-risk imaging within 24 hours of onset were included. Initial SIP was calculated as ischemic core volume at first imaging divided by the time from stroke onset to imaging. Among the 88 patients, SIP was median 2.2 cc/h (interquartile range, 0-8.7), ranging most widely within the first 6 hours after onset. Faster SIP was positively independently associated with a low collateral score (odds ratio [OR], 3.30 [95% CI, 1.25-10.49]) and arrival by emergency medical services (OR, 3.34 [95% CI, 1.06-10.49]) and negatively associated with prior ischemic stroke (OR, 0.12 [95% CI, 0.03-0.50]) and coronary artery disease (OR, 0.32 [95% CI, 0.10-1.00]). Among the 67 patients who underwent endovascular thrombectomy, slower SIP was associated with a shift to reduced levels of disability at discharge (OR, 3.26 [95% CI, 1.02-10.45]), increased substantial reperfusion by thrombectomy (OR, 8.30 [95% CI, 0.97-70.87]), and reduced radiological hemorrhagic transformation (OR, 0.34 [95% CI, 0.12-0.94]). Slower SIP is associated with a high collateral score, prior ischemic stroke, and coronary artery disease, supporting roles for both collateral robustness and ischemic preconditioning in fostering tissue resilience to ischemia. Among patients undergoing endovascular thrombectomy, the speed of infarct progression is a major determinant of clinical outcome.

Influenza A Virus Pre-Infection Exacerbates Pseudomonas aeruginosa-Mediated Lung Damage Through Increased MMP-9 Expression, Decreased Elafin Production and Tissue Resilience.

Individuals with impaired immune responses, such as ventilated and cystic fibrosis patients are often infected with Pseudomonas aeruginosa (P.a) bacteria, and a co-infection with the Influenza virus (IAV) is often present. It has been known for many years that infection with IAV predisposes the host to secondary bacterial infections (such as Streptococcus pneumoniae or Staphylococcus aureus), and there is an abundance of mechanistic studies, including those studying the role of desensitization of TLR signaling, type I IFN- mediated impairment of neutrophil chemokines and antimicrobial production, attenuation of IL1β production etc., showing this. However, little is known about the mechanistic events underlying the potential deleterious synergy between Influenza and P.a co-infections. We demonstrate here in vitro in epithelial cells and in vivo in three independent models (two involving mice given IAV +/– P.a, and one involving mice given IAV +/– IL-1β) that IAV promotes secondary P.a-mediated lung disease or augmented IL-1β-mediated inflammation. We show that IAV-P.a-mediated deleterious responses includes increased matrix metalloprotease (MMP) activity, and MMP-9 in particular, and that the use of the MMP inhibitor improves lung resilience. Furthermore, we show that IAV post-transcriptionally inhibits the antimicrobial/anti-protease molecule elafin/trappin-2, which we have shown previously to be anti-inflammatory and to protect the host against maladaptive neutrophilic inflammation in P.a infections. Our work highlights the capacity of IAV to promote further P.a-mediated lung damage, not necessarily through its interference with host resistance to the bacterium, but by down-regulating tissue resilience to lung inflammation instead. Our study therefore suggests that restoring tissue resilience in clinical settings where IAV/P.a co-exists could prove a fruitful strategy.