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The respiratory system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Pulmonary hypertension is defined as a mean pulmonary arterial pressure of greater than 25 mm Hg at rest. There are a number of underlying causes, and the WHO classifies pulmonary hypertension into 5 groups. 1. Pulmonary arterial hypertension (PAH) (including familial, drug/toxin and connective tissue disorder (CTD) related, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis) 2. Pulmonary hypertension due to left heart failure (congenital and acquired) 3. Pulmonary hypertension secondary to chronic hypoxia and/or parenchymal lung disease, 4. Chronic thromboembolic pulmonary hypertension and 5. Pulmonary hypertension due to blood and other disorders. Common to many of these causes is chronic vasoconstriction, luminal obstruction, damage and/or remodelling of the pulmonary vasculature (Figure 8.28). In some cases there is a genetic component with mutations in certain genes causing or increasing the likelihood of developing PAH. Some familial cases are associated with mutations in Bone Morphogenic Protein Receptor 2 (BMPR2). These show incomplete penetrance, with only 10%–20% of family members with the mutation developing disease. The exact pathogenesis is unclear, but the BMP-BMPR2 signal pathway is important in cell apoptosis, proliferation, and differentiation. It is thought mutations in this gene result in vascular remodelling in small vessels leading to increased pulmonary arterial pressure. Cases of hereditary PAH are rare and over 350 mutations in the BMPR2 gene have been identified. Other genes less commonly associated with hereditary PAH include BMPR1B, CAV1, KCNK3, SMAD9 and TBX4. Gene mutations are also seen in some sporadic cases of PAH. Prolonged rises in pulmonary arterial or venous pressure produces morphological vascular changes, which often include thickening of the media and intima. Patients present late in the course of disease with chronic worsening dyspnoea, fatigue, and reduced exercise tolerance. The mortality is high with the development of right sided heart failure (cor pulmonale) and secondary infection, and 80% of patients die within 5 years.
Differential expression of BMP/SMAD signaling and ovarian-associated genes in the granulosa cells of FecB introgressed GMM sheep
Published in Systems Biology in Reproductive Medicine, 2020
Satish Kumar, Pradeep Kumar Rajput, Sangharatna V. Bahire, Basanti Jyotsana, Vijay Kumar, Davendra Kumar
It is well established that a single point mutation in the BMPRIB receptor (A746G) is associated with the hyper-prolificacy of the Booroola Merino and the Garole ewes (Mulsant et al. 2001; Souza et al. 2001; Wilson et al. 2001; Kumar et al. 2006). It has been found that BMPR1B mutation causes partial inactivation of the protein, therefore, BMPRIB might not have sufficient receptor activity for binding of its ligand molecules for proper BMP-signaling pathway (Mulsant et al. 2001). In the present study, the expression of BMPR1B and BMPRII were not-significantly higher (P > 0.05) in the GCs of non-carrier GMM than that of homozygous carrier GMM ewes. In other studies, no significant difference was reported in the expression of BMPR1B gene among three FecB genotypes (FecBBB, FecBB+, FecB++) of small tailed Han sheep (Tang et al. 2019). While in contrast, other workers have found the expression of BMPRIB and BMPRII higher in antral follicles of the high fecundity sheep than that of low fecundity sheep (Xu et al. 2010). Similarly, Regan et al. (2015) also demonstrated the up-regulation of the BMPR1B transcripts in GCs of homozygous Booroola ewes. Similar observations were also reported in the antral follicles of the homozygous Garole ewes (Goyal et al. 2017). It is inferred from the above discussion that the FecB mutation in BMPR1B may cause alteration in the binding site of its ligand molecules; therefore it might not be sufficiently potentiated to interact with BMPRII protein in close proximity; hence BMPRII is possibly not enough to phosphorylate the BMPR1B. Therefore, BMP signaling cascade would be disrupted in homozygous carrier ewes; henceforth it may cause higher ovulation rate in homozygous carrier ewes by an unknown mechanism.
Bone morphogenetic protein signaling in breast cancer progression
Published in Growth Factors, 2019
Lap Hing Chi, Allan D. Burrows, Robin L. Anderson
Conflicting prognostic value of BMPs and their receptors has been reported in different patient cohorts (Table 1). In some studies, patients with higher expression of BMP4 target genes (Shee et al. 2019), BMP5 (Romagnoli et al. 2012), BMP10 (L. Ye et al. 2010) or BMPRIB (Bokobza et al. 2009; Dai et al. 2015) had decreased risk of bone metastasis, and improved recurrence-free survival and overall survival. In contrast, other studies have reported increased risk of overall recurrence associated with high BMP4 (Alarmo et al. 2013), high BMP7 and bone metastasis (Alarmo et al. 2008), or high BMPRIB and poor overall survival (Helms et al. 2005; Pickup, Hover, Guo, et al. 2015). Direct contradictory data arise from analysis of BMP4, with Shee et al. (2019) analyzing four large transcriptomic data sets for expression of BMP4 associated genes and finding that a high BMP4 signature is associated with good outcome. On the other hand, Alarmo et al. (2013) assessed BMP4 itself at the protein level in 314 breast cancer cases with known outcome to find moderate diffuse staining in 14% of cases and strong granular staining in 23% of cases. Samples with granular staining displayed a lower proliferative index but these patients were more likely to suffer from a relapse. However, overall survival was not statistically different compared to the patients whose tumors did not display BMP4 protein (Alarmo et al. 2013). Thus, the two analyses used different techniques – transcript data and a gene signature compared to analysis of the protein levels of BMP4 itself. The transcript analysis cannot discriminate the organization and localization of BMP4 protein in the cell, but a BMP4 signature is likely to be a more powerful measure of the whole signaling pathway. The other contradictory analyses are from measurement of BMPR1B, where Dai et al. (2015) immunostained 357 breast cancer cases with clinical outcome data to conclude that low BMPR1B was associated with reduced progression-free survival and overall survival. However, Helms et al. (2005) reported that low BMPR1B was associated with improved overall survival in an analysis of 132 tumors by immunohistochemistry. Since both groups analyzed protein levels, differences may have arisen from the use of different anti-BMPR1B antibodies and the need for a 1:5 dilution of the antibody in Helms et al. (2005) study raises a concern about its specificity. Given the inconsistent findings that are potentially caused by different methodologies and varying sample sizes, further mechanistic studies are needed to investigate the effect of BMP signaling on breast cancer metastasis.