The chemokine, CXCL10, and its cognate receptor, CXCR3, are important mediators of the pathobiology of lung fibrosis. Macrophages are a known source of CXCL10, but their specific source in the lung ...is poorly defined due to incomplete characterization of macrophage subpopulations. We recently developed a novel flow cytometric approach that discriminates resident alveolar macrophages from recruited exudative macrophages (ExMacs) after infectious lung injury. We hypothesized that ExMacs are present after noninfectious lung injury with bleomycin, and are a source of CXCL10. We found that ExMacs are recruited to the lung after injury, peaking at Day 7, then maintained through Day 28. ExMac recruitment was significantly reduced, but not abolished, in CCR2 null mice. ExMacs, but not alveolar macrophages, produce CXCL10, both constitutively and after stimulation with hyaluronan (HA) fragments. Interestingly, ExMac stimulation with LPS resulted in complete suppression of CXCL10. In contrast, ExMacs produced TNF-α and CXCL2/MIP-2 (Macrophage Inflammatory Protein-2) after stimulation with both HA and LPS. ExMacs were present in CXCR3 null mice after bleomycin, but produced minimal CXCL10. This impairment was overcome by administration of exogenous IFN-γ or IFN-γ with HA. Collectively, these data suggest that ExMacs are recruited and maintained in the lung after noninfectious lung injury, are a source of a variety of cytokines, but importantly, are essential for the production of antifibrotic CXCL10. Understanding the contribution of ExMacs to the pathobiology of lung injury and repair could lead to new treatment options for fibrosing lung diseases.
Recent studies have identified impaired type 2 alveolar epithelial cell (ATII) renewal in idiopathic pulmonary fibrosis (IPF) human organoids and severe fibrosis when ATII is defective in mice. ATIIs ...function as progenitor cells and require supportive signals from the surrounding mesenchymal cells. The mechanisms by which mesenchymal cells promote ATII progenitor functions in lung fibrosis are incompletely understood. We identified growth hormone receptor (GHR) is mainly expressed in mesenchymal cells, and its expression is substantially decreased in IPF lungs. Higher levels of
expression correlated with better lung function in patients with IPF. Profibrotic mesenchymal cells retarded ATII growth and were associated with suppressed vesicular
expression. Vesicles enriched with
promote ATII proliferation and diminished pulmonary fibrosis in mesenchymal
-deficient mice. Our findings demonstrate a previously unidentified mesenchymal paracrine signaling coordinated by
that is capable of supporting ATII progenitor cell renewal and limiting the severity of lung fibrosis.
Inhalation of ambient ozone alters populations of lung macrophages. However, the impact of altered lung macrophage populations on the pathobiology of ozone is poorly understood. We hypothesized that ...subpopulations of macrophages modulate the response to ozone. We exposed C57BL/6 mice to ozone (2 ppm × 3 h) or filtered air. At 24 h after exposure, the lungs were harvested and digested and the cells underwent flow cytometry. Analysis revealed a novel macrophage subset present in ozone-exposed mice, which were distinct from resident alveolar macrophages and identified by enhanced Gr-1(+) expression Gr-1 macrophages (Gr-1 Macs). Further analysis showed that Gr-1(+) Macs exhibited high expression of MARCO, CX3CR1, and NAD(P)H:quinone oxioreductase 1. Gr-1(+) Macs were present in the absence of CCR2, suggesting that they were not derived from a CCR2-dependent circulating intermediate. Using PKH26-PCL to label resident phagocytic cells, we demonstrated that Gr-1 Macs were derived from resident lung cells. This new subset was diminished in the absence of CX3CR1. Interestingly, CX3CR1-null mice exhibited enhanced responses to ozone, including increased airway hyperresponsiveness, exacerbated neutrophil influx, accumulation of 8-isoprostanes and protein carbonyls, and increased expression of cytokines (CXCL2, IL-1β, IL-6, CCL2, and TNF-α). Our results identify a novel subset of lung macrophages, which are derived from a resident intermediate, are dependent upon CX3CR1, and appear to protect the host from the biological response to ozone.
The molecular mechanisms of acute lung injury are incompletely understood. MicroRNAs (miRNAs) are crucial biological regulators that act by suppressing their target genes and are involved in a ...variety of pathophysiologic processes. miR-127 appears to be down-regulated during lung injury. We set out to investigate the role of miR-127 in lung injury and inflammation. Expression of miR-127 significantly reduced cytokine release by macrophages. Looking into the mechanisms of regulation of inflammation by miR-127, we found that IgG Fcγ Receptor I (FcγRI/CD64) was a target of miR-127, as evidenced by reduced CD64 protein expression in macrophages over-expressing miR-127. Furthermore, miR-127 significantly reduced the luciferase activity with a reporter construct containing the native 3′-UTR of CD64. Importantly, we demonstrated that miR-127 attenuated lung inflammation in an IgG immune complex (IgG IC) model in vivo. Collectively, these data show that miR-127 targets macrophage CD64 expression and promotes the reduction of lung inflammation. Understanding how miRNAs regulate lung inflammation may represent an attractive way to control inflammation induced by infectious or non-infectious lung injury.
Inhalation of ambient ozone alters populations of lung macrophages. However, the impact of altered lung macrophage populations on the pathobiology of ozone is poorly understood. We hypothesized that ...sub-populations of macrophages modulate the response to ozone. We exposed C57BL/6 mice to ozone (2 ppm × 3h) or filtered air. 24 h after the exposure, the lungs were harvested and digested and the cells underwent flow cytometry. Analysis revealed a novel macrophage subset present in ozone exposed mice, which were distinct from resident alveolar macrophages (AM) and identified by enhanced Gr-1+ expression (Gr-1 Macs). Further analysis identified that Gr-1+ Macs exhibited high expression of MARCO, CX3CR1, and NQO1. Gr-1+ Macs were present in the absence of CCR2, suggesting that they were not derived from a CCR2-dependent circulating intermediate. Using PKH26-PCL to label resident phagocytic cells, we demonstrated that Gr-1 Macs were derived from resident lung cells. This new subset was diminished in the absence of CX3CR1. Interestingly, CX3CR1-null mice exhibited enhanced responses to ozone, including increased airway hyperresponsiveness (AHR), exacerbated neutrophil influx, accumulation of 8-isoprostanes and protein carbonyls, and increased expression of cytokines (CXCL2, IL-1β, IL-6, CCL2, and TNF-α). Our results identify a novel subset of lung macrophages, which are derived from a resident intermediate, dependent upon CX3CR1, and appear to protect the host from the biological response to ozone.
The chemokine, CXCL10, and its cognate receptor, CXCR3, are important mediators of the pathobiology of lung fibrosis. Macrophages are a known source of CXCL10, but their specific source in the lung ...is poorly defined due to incomplete characterization of macrophage subpopulations. We recently developed a novel flow cytometric approach that discriminates resident alveolar macrophages from recruited exudative macrophages (ExMacs) after infectious lung injury. We hypothesized that ExMacs are present after noninfectious lung injury with bleomycin, and are a source of CXCL10. We found that ExMacs are recruited to the lung after injury, peaking at Day 7, then maintained through Day 28. ExMac recruitment was significantly reduced, but not abolished, in CCR2 null mice. ExMacs, but not alveolar macrophages, produce CXCL10, both constitutively and after stimulation with hyaluronan (HA) fragments. Interestingly, ExMac stimulation with LPS resulted in complete suppression of CXCL10. In contrast, ExMacs produced TNF-α and CXCL2/MIP-2 (Macrophage Inflammatory Protein-2) after stimulation with both HA and LPS. ExMacs were present in CXCR3 null mice after bleomycin, but produced minimal CXCL10. This impairment was overcome by administration of exogenous IFN-γ or IFN-γ with HA. Collectively, these data suggest that ExMacs are recruited and maintained in the lung after noninfectious lung injury, are a source of a variety of cytokines, but importantly, are essential for the production of antifibrotic CXCL10. Understanding the contribution of ExMacs to the pathobiology of lung injury and repair could lead to new treatment options for fibrosing lung diseases.
•Effects of tartaric acid (TA) on performance of MOS cement have been studied.•XRD, SEM, EIS and MIP were used to examine effects of TA on MOS cement.•The main strength phase of MOS cement with TA is ...5Mg(OH)2·MgSO4·7H2O crystal phase.•TA can retard the hydration rate of MOS cement.•Adding TA can improve strength and decrease shrinkage of MOS cement.
Magnesium oxysulfate (MOS) cement has the advantages of light weight, low alkalinity, fire resistance, and good decorative value. Large-scale applications of MOS cement in civil engineering have been restricted by its low strength, which can be improved by adding some proper additives. Here, the effects of tartaric acid on the setting time, compressive strength, flexural strength, and deformation of MOS cement have been studied. Fourier transform infrared spectra, pH changes, hydration-heat release rate, and impedance have been observed to determine the effects of tartaric acid on the hydration process of MOS cement. To a certain extent, the addition of tartaric acid extends the setting time of MOS cement by improving the stability of the hydration film of active MgO in magnesium sulfate. X-ray diffraction, scanning electron microscopy, and mercury intrusion porosimetry were used to examine the hydration products and pore-size distribution of MOS cement. The analysis results indicate that the main reason for the high strength of MOS cement with tartaric acid is that the addition of tartaric acid can promote the formation of the needle-like high-strength phase of 5Mg(OH)2·MgSO4·7H2O and inhibit the formation and growth of the Mg(OH)2 crystal phase.
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