Intrinsic BMP inhibitor Gremlin regulates alveolar epithelial type II cell proliferation and differentiation.

Type 1 alveolar epithelial cells (AT1s) and type 2 alveolar epithelial cells (AT2s) regulate the structural integrity and function of alveoli. AT1s mediate gas exchange, whereas AT2s serve multiple functions, including surfactant secretion and alveolar repair through proliferation and differentiation into AT1s as progenitors. However, mechanisms regulating AT2 proliferation and differentiation remain unclear. Here we demonstrate that Gremlin, an intrinsic inhibitor of bone morphogenetic protein (BMP), induces AT2 proliferation and differentiation. Transient overexpression of Gremlin in rat lungs by adenovirus vector delivery suppressed BMP signaling, induced proliferation of AT2s and the production of Bmp2, which in turn led to the recovery of BMP signaling and induced AT2 differentiation into AT1s. Bleomycin-induced lung injury upregulated Gremlin and showed a similar time course of biomarker expression comparable to the adenovirus model. TGF-ß and IL-1ß induced Gremlin expression in fibroblasts. Taken together, our findings implicate that Gremlin expression during lung injury leads to precisely timed inhibition of BMP signaling and activates AT2s, leading to alveolar repair.

Prevalence of Use and Perceived Effectiveness of Medical, Surgical, and Alternative Therapies for Endometriosis Pain in Canadians.

OBJECTIVES: To describe the use and perceived effectiveness of medical, surgical, and alternative therapies (e.g., diet, exercise, heat, cannabis, etc.) in managing endometriosis-associated pain in Canadians. METHODS: A cross-sectional online survey was distributed via The Endometriosis Network Canada (TENC) from February to March 2021. Canadians aged 18-50 years with diagnosed or suspected endometriosis were eligible to participate. RESULTS: A total of 434 survey responses were included, and 93.8% of respondents reported that they used at least 1 alternative therapy in the past 6 months for endometriosis-associated pain. Respondents used an array of medical (2.3/6 months), surgical (1.7/lifetime), and alternative therapies (6.9/6 months) to manage their pain, yet 61.9% of respondents did not feel it was adequately managed. The most common alternative therapies were heat, meditation/mindfulness/rest, and diet. CONCLUSION: Alternative therapies were commonly used by Canadians living with endometriosis to manage pain. Cannabis and heat were perceived as the most effective alternative therapies. Here, we gain a better understanding of alternative therapies that can provide an additional therapeutic avenue that clinicians and people living with endometriosis may wish to discuss and explore.

The female reproductive tract microbiotas, inflammation, and gynecological conditions.

The intricate interactions between the host cells, bacteria, and immune components that reside in the female reproductive tract (FRT) are essential in maintaining reproductive tract homeostasis. Much of our current knowledge surrounding the FRT microbiota relates to the vaginal microbiota, where 'health' has long been associated with low bacterial diversity and Lactobacillus dominance. This concept has recently been challenged as women can have a diverse vaginal microbial composition in the absence of symptomatic disease. The structures of the upper FRT (the endocervix, uterus, Fallopian tubes, and ovaries) have distinct, lower biomass microbiotas than the vagina; however, the existence of permanent microbiotas at these sites is disputed. During homeostasis, a balance exists between the FRT bacteria and the immune system that maintains immune quiescence. Alterations in the bacteria, immune system, or local environment may result in perturbances to the FRT microbiota, defined as dysbiosis. The inflammatory signature of a perturbed or "dysbiotic" FRT microbiota is characterized by elevated concentrations of pro-inflammatory cytokines in cervical and vaginal fluid. It appears that vaginal homeostasis can be disrupted by two different mechanisms: first, a shift toward increased bacterial diversity can trigger vaginal inflammation, and second, local immunity is altered in some manner, which disrupts the microbiota in response to an environmental change. FRT dysbiosis can have negative effects on reproductive health. This review will examine the increasing evidence for the involvement of the FRT microbiotas and inflammation in gynecologic conditions such as endometriosis, infertility, and endometrial and ovarian cancer; however, the precise mechanisms by which bacteria are involved in these conditions remains speculative at present. While only in their infancy, the use of antibiotics and probiotics to therapeutically alter the FRT microbiota is being studied and is discussed herein. Our current understanding of the intimate relationship between immunity and the FRT microbiota is in its early days, and more research is needed to deepen our mechanistic understanding of this relationship and to assess how our present knowledge can be harnessed to assist in diagnosis and treatment of gynecologic conditions.

Connective-Tissue Growth Factor Contributes to TGF-ß1-induced Lung Fibrosis.

Idiopathic pulmonary fibrosis is a fatal lung disease characterized by progressive and excessive accumulation of myofibroblasts and in the lung. Connective-tissue growth factor (CTGF) exacerbates pulmonary fibrosis in radiation-induced lung fibrosis, and in this study, we demonstrate upregulation of CTGF in a rat lung fibrosis model induced by an adenovirus vector encoding active TGF-ß1 (AdTGF-ß1). We show that CTGF is also upregulated in patients with idiopathic pulmonary fibrosis. Expression of CTGF was upregulated in vascular smooth muscle cells cultured from fibrotic lungs on Days 7 and 14 as well as endothelial cells sorted from fibrotic lungs on Days 14 and 28. These findings suggest contributions of different cells in maintaining the fibrotic phenotype during fibrogenesis. Treatment of fibroblasts with recombinant CTGF along with TGF-ß increases profibrotic markers in fibroblasts, confirming the synergistic effect of recombinant CTGF with TGF-ß in inducing pulmonary fibrosis. Also, the fibrotic extracellular matrix upregulated CTGF expression, compared with the normal extracellular matrix, suggesting that not only profibrotic mediators but also a profibrotic environment contributes to fibrogenesis. We also showed that pamrevlumab, a CTGF inhibitory antibody, partially attenuates fibrosis in the model. These results suggest that pamrevlumab could be an option for treatment of pulmonary fibrosis.