Limper, Andrew H.

Age-associated T RM cell malfunction supports chronic lung inflammation and tissue fibrosis after respiratory viral infection.

ObjectivesThe aim of this study was to assess bleomycin‐induced pulmonary fibrosis on ex vivo mouse lungs using ultrasound image grading and texture analysis.MethodsExcised mouse lungs were divided into 3 groups: control, mild fibrosis, and severe fibrosis based on the monitored indicators of health. B‐mode ultrasound images were obtained via scanning the mouse lungs ex vivo. The surface smoothness, echo density, and angle of lesions or the lung margin were graded, and the imaging contrast, correlation, homogeneity, and entropy were assessed via texture analysis.ResultsThe grades of surface smoothness, echo density, and angle were statistically higher for the severe fibrosis group compared with those of the control and mild fibrosis groups (P < .05). In addition, statistically significant differences in the contrast, correlation, and homogeneity between mild and severe fibrosis groups were observed (P < .05).ConclusionsThe results obtained in this study suggest that ultrasound image grading and texture analysis are valuable and meaningful methods for assessing pulmonary fibrosis in a bleomycin mouse model.

Pneumocystis jirovecii , the opportunistic fungus that causes Pneumocystis pneumonia (PCP) in humans, is a significant contributor to morbidity and mortality in immunocompromised patients. Given the profound deleterious inflammatory effects of the major β-glucan cell wall carbohydrate constituents of Pneumocystis through Dectin-1 engagement and downstream caspase recruitment domain-containing protein 9 (CARD9) immune activation, we sought to determine whether the pharmacodynamic activity of the known CARD9 inhibitor BRD5529 might have a therapeutic effect on macrophage innate immune signaling and subsequent downstream anti-inflammatory activity.

Abstract In the current work we show that the profibrotic actions of TGF‐β are mediated, at least in part, through a metabolic maladaptation in glutamine metabolism and how the inhibition of glutaminase 1 (GLS1) reverses pulmonary fibrosis. GLS1 was found to be highly expressed in fibrotic vs normal lung fibroblasts and the expression of profibrotic targets, cell migration, and soft agar colony formation stimulated by TGF‐β required GLS1 activity. Moreover, knockdown of SMAD2 or SMAD3 as well as inhibition of PI3K, mTORC2, and PDGFR abrogated the induction of GLS1 by TGF‐β. We further demonstrated that the NAD‐dependent protein deacetylase, SIRT7, and the FOXO4 transcription factor acted as endogenous brakes for GLS1 expression, which are inhibited by TGF‐β. Lastly, administration of the GLS1 inhibitor CB‐839 attenuated bleomycin‐induced pulmonary fibrosis. Our study points to an exciting and unexplored connection between epigenetic and transcriptional processes that regulate glutamine metabolism and fibrotic development in a TGF‐β‐dependent manner.

AbstractBackgroundPneumocystis major surface glycoprotein (Msg) is a 120-kD surface protein complex on the organism with importance in adhesion and immune recognition. In this study, we show that Msg significantly impairs tumor necrosis factor (TNF)-α secretion by macrophages induced by Saccharomyces cerevisiae and Pneumocystis carinii (Pc) β-glucans.MethodsMajor surface glycoprotein was shown to greatly reduce β-glucan-induced Dectin-1 immunoreceptor tyrosine-based activating motif (ITAM) phosphorylation. Major surface glycoprotein also down regulated Dectin-1 receptor messenger ribonucleic acid (mRNA) expression in the macrophages. It is interesting that Msg incubation with macrophages resulted in significant mRNA upregulation of both C-type lectin receptors (CLR) Mincle and MCL in Msg protein presence alone but to even greater amounts in the presence of Pc β-glucan.ResultsThe silencing of MCL and Mincle resulted in TNF-α secretions similar to that of macrophages treated with Pneumocystis β-glucan alone, which is suggestive of an inhibitory role for these 2 CLRs in Msg-suppressive effects on host cell immune response.ConclusionsTaken together, these data indicate that the Pneumocystis Msg surface protein complex can act to suppress host macrophage inflammatory responses to the proinflammatory β -glucan components of the organisms.