STAT1 employs myeloid cell-extrinsic mechanisms to regulate the neutrophil response and provide protection against invasive Klebsiella pneumoniae lung infection

Klebsiella pneumoniae (KP) is an extracellular Gram-negative bacterium that causes infections in the lower respiratory and urinary tracts and the bloodstream. STAT1 is a master transcription factor that acts to maintain T cell quiescence under homeostatic conditions. Although STAT1 helps defend against systemic spread of acute KP intrapulmonary infection, whether STAT1 regulation of T cell homeostasis impacts pulmonary host defense during acute bacterial infection and injury is less clear. Using a clinical KP respiratory isolate and a pneumonia mouse model, we found that STAT1 deficiency led to an early neutrophil-dominant transcriptional profile and neutrophil recruitment in the lung preceding widespread bacterial dissemination and lung injury development. Yet, myeloid cell STAT1 was dispensable for control of KP proliferation and dissemination, because myeloid cell-specific STAT1-deficient (LysMCre/WT;Stat1fl/fl) mice showed bacterial burden in the lung, liver, and kidney similar to that of their wild-type littermates. Surprisingly, IL-17-producing CD4+ T cells infiltrated Stat1-/- murine lungs early during KP infection. The increase in Th17 cells in the lung was not due to preexisting immunity against KP and was consistent with circulating rather than tissue-resident CD4+ T cells. However, blocking global IL-17 signaling with anti-IL-17RC administration led to increased proliferation and dissemination of KP, suggesting that IL-17 provided by other innate immune cells is essential in defense against KP. Contrastingly, depletion of CD4+ T cells reduced Stat1-/- murine lung bacterial burden, indicating that early CD4+ T cell activation in the setting of global STAT1 deficiency is pathogenic. Altogether, our findings suggest that STAT1 employs myeloid cell-extrinsic mechanisms to regulate neutrophil responses and provides protection against invasive KP by restricting nonspecific CD4+ T cell activation and immunopathology in the lung

The matricellular protein thrombospondin-1 in lung inflammation and injury

Matricellular proteins comprise a diverse group of molecular entities secreted into the extracellular space. They interact with the extracellular matrix (ECM), integrins, and other cell-surface receptors, and can alter matrix strength, cell attachment to the matrix, and cell-cell adhesion. A founding member of this group is thrombospondin-1 (TSP-1), a high molecular-mass homotrimeric glycoprotein. Given the importance of the matrix and ECM remodeling in the lung following injury, TSP-1 has been implicated in a number of lung pathologies. This review examines the role of TSP-1 as a damage controller in the context of lung inflammation, injury resolution, and repair in noninfectious and infectious models. This review also discusses the potential role of TSP-1 in human diseases as it relates to lung inflammation and injury.National Institutes of Health; Folios: R01 HL136143, P01HL114453, R01 HL142084, K24HL143285Millennium Science Initiative Program:Millennium Institute on Immunology and Immunotherapy; Folio: ICN09_016, ICN 2021_045; anterior P09/016-

Plausible role of INPP4A dysregulation in idiopathic pulmonary fibrosis

Abstract INPP4A has been shown to be involved in the regulation of cell proliferation and apoptosis of multiple cell types including fibroblasts. Previous reports from our group have demonstrated the role of inositol polyphosphate 4‐phosphatase Type I A (INPP4A) in these functions. Though existing evidences suggest a critical role for INPP4A in the maintenance of lung homeostasis, its role in chronic lung diseases is relatively under explored. In the current study, we made an attempt to understand the regulation of INPP4A in idiopathic pulmonary fibrosis (IPF). Through integration of relevant INPP4A gene expression data from public repositories with our results from in vitro experiments and mouse models, we show that INPP4A is altered in IPF. Interestingly, the direction of the change is dependent both on the disease stage and the region of the lung used. INPP4A was found to be upregulated when analyzed in lung sample representative of the whole lung, but was downregulated in the fibrotic regions of the lung. Similarly, INPP4A was found to be high, compared to controls, only in the early stage of the disease. Though the observed increase in INPP4A was found to be negatively correlated to physiological indices, FVC, and DLCO, of lung function, treatment with anti‐INPP4A antibody worsened the condition in bleomycin treated mice. These contrasting results taken together are suggestive of a nuanced regulation of INPP4A in IPF which is dependent on the disease stage, cellular state and extent of fibrosis in the lung region being analyzed

Oral Feeding of Cow Milk Containing A1 Variant of β Casein Induces Pulmonary Inflammation in Male Balb/c Mice

AbstractMilk is globally consumed as a rich source of protein and calcium. A major protein component of milk is casein, with β-casein having 2 major variants A1 and A2. Of these, A1 casein variant has been implicated as a potential etiological factor in several pathologies, but direct effect on lungs has not been studied. The objective of the present study was to evaluate the A1and A2 β casein variants of cow milk as factors causing allergic airway disease in murine model. Mice fed with A1A1 milk exhibited increased airway hyperresponsiveness with increasing concentration of bronchoconstrictor (methacholine), which was not observed in mice fed with A2A2 milk. Significantly elevated levels of IL-4 and IL-5 were found in bronchoalveolar lavage and serum of A1A1 variant fed mice. Increased IgE and IgG levels along with increased infiltration of lymphocytes and eosinophils, leading to peribronchial inflammation was also observed in A1A1 variant fed mice, although, no goblet cell hyperplasia or airway remodeling was observed. In contrast, A2A2 milk fed mice presented phenotype matching the control group, while A1A2 milk fed group presented an intermediate phenotype. In summary, our results show that A1 form of cow milk has a proinflammatory effect on the lung resulting in phenotype closely matching with the typical allergic asthma phenotype.</jats:p

Konservasi Tanaman Lada (Piper Nigrum L.) Secara in Vitro

In vitro conservation of black pepper (Piper nigrum L.)Black pepper (Piper nigrum L.) is one of the economically im¬ potant spices. The major constraint in black pepper cultivation and conservation in ield is foot rot disease caused by Phytopthora capsici which could cause plants die. Conservation of black pepper germplasms as living collections in ield is risky due to pests and natural disaster. The experiment on in vitro cop ervation of black pepper var. LDL was conducted al the laboratory of Plant Genetic Resources and Breeding, Research Institute for Spice and Medicinal Crops (RISMC) Bogor from April 1998 to Maret 1999. Single node cuttings from sterile culture were used as explains. The explains were cultured on Murashige and Skoog (MS) medium on full and half strength concentration supplemented with paclobutrazol (paclo) (0, 1, 3 and 5 mg/1). The experiment was performed in a randomized complete block design arranged factorially with 10 replications. The result showed that the medium supplemented with paclo on both full MS and MS A medium could suppress vegetative growth until 12 months. There was no signiicant interaction between medium and paclo on shoot initiation. The effect was signiicant on shoot height, number of leaves and culture performances. Increasing paclo concen¬ tration caused higher suppression of plant growth. MS A medium supplemented with paclo 5 mg/1 showed the slowest growth with shool height 2.10 cm and number of leaves 9. Culture performance was fresh, with green leaves and vigorous. Advcntive shoots were able to regenerate on the medium supplemented with BA 0.3 mg/1. In vitro conservation of black pepper with paclo did not change plant regeneration ability. Therefore, this technique may be used as an altenative method for black pepper conservation

Additional file 6: of Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach

Association of SNPs varying between Prakriti with selection pressures such as climatic conditions, mode of subsistence, pathogen pressure and cultural practices (source: http://genapps2.uchicago.edu:8081/dbcline/ )

Additional file 5: of Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach

Allele frequency differences between Prakriti types and IE pool

Additional file 3: of Combined genetic effects of EGLN1 and VWF modulate thrombotic outcome in hypoxia revealed by Ayurgenomics approach

Total scores of protective alleles in combined genotypes of VWF and EGLN1 in high altitude and a genetically related low altitude population in India

Linoleic acid metabolite leads to steroid resistant asthma features partially through NF-κB

Abstract Studies have highlighted the role of nutritional and metabolic modulators in asthma pathobiology. Steroid resistance is an important clinical problem in asthma but lacks good experimental models. Linoleic acid, a polyunsaturated fatty acid, has been linked to asthma and glucocorticoid sensitivity. Its 12/15–lipoxygenase metabolite, 13-S-hydroxyoctadecadienoic acid (HODE) induces mitochondrial dysfunction, with severe airway obstruction and neutrophilic airway inflammation. Here we show that HODE administration leads to steroid unresponsiveness in an otherwise steroid responsive model of allergic airway inflammation (AAI). HODE treatment to allergic mice further increased airway hyperresponsiveness and goblet metaplasia. Treatment with dexamethasone was associated with increased neutrophilic inflammation in HODE treated allergic mice; unlike control allergic mice that showed resolution of inflammation. HODE induced loss of steroid sensitivity was associated with increased p-NFkB in mice and reduced GR-α transcript levels in cultured human bronchial epithelia. In summary, HODE modifies typical AAI to recapitulate many of the phenotypic features seen in severe steroid unresponsive asthma. We speculate that since HODE is a natural metabolite, it may be relevant to the increased asthma severity and steroid insensitivity in patients who are obese or consume high fat diets. Further characterization of HODE induced steroid insensitivity may clarify the mechanisms

Adhatoda Vasica: A Potential Ayurvedic Intervention Against COVID-19 Associated Impaired Immune Response and Hypoxia-Inflammation Phenotype

Abstract Background: The importance of hypoxia inducible factor-1 α (HIF-1α) stabilization in uncontrolled infection and inflammation is widely accepted. Several inhibitors of HIF signalling are in clinical trials for malignancy, ischemia and inflammatory diseases. Increased hypoxia is being reported to be an important modifier for several pathological features of COVID-19 such as impaired immunity, hyper-inflammation, thrombosis, lung injury and sepsis. Methods: In this study we tested the effect of whole aqueous extract Adhatoda Vasica (AV), that our group has shown to have anti-hypoxic and anti-inflammatory effects, on various outcomes of hypoxic response. Effects of AV were assessed in preclinical mouse models of pulmonary fibrosis, bacterial sepsis and siRNA induced hypoxia-thrombosis phenotype. Therapeutic relevance of AV in current pandemic were also examined through transcriptome and molecular docking analysis. Results: Oral administration AV extract attenuated the increased levels of airway inflammation, collagen content, transforming growth factor-b1 (TGF-b1), IL-6, HIF-1α and improved the overall survival rate in bleomycin treated and Cecum Ligation and Puncture (CLP) induced mice. AV treatment also rescued the prolyl hydroxylase domain 2 (phd2) siRNA induced HIF-1α and associated blood coagulation phenotypes in mice. Transcriptome analysis of lungs of AV treated naïve mice reveal downregulation of hypoxia, inflammation, TGF-b1 and angiogenesis and upregulation of adaptive immunity related genes. These genes and pathways show opposite expression in transcriptome of BALF and PBMCs of SARS-CoV2 infected patient. Molecular docking of AV constituents presents in extract reveal many molecules with low binding energy (≤ -8) to multiple SARS-CoV2 and host target proteins that are relevant in viral entry and replication. Conclusion: Our results provide a scientific rationale for this ayurvedic herbal medicine in ameliorating the hypoxia-hyperinflammation features which could be useful against SARS-CoV-2 infection.</jats:p