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Purinergic Signalling May 2024Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This... (Review)
Review
Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca levels. The P2X subtype receptors facilitate extracellular Ca influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y, P2Y, and P2Y receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.
PubMed: 38713328
DOI: 10.1007/s11302-024-10010-5 -
Physiology (Bethesda, Md.) Jul 2024Cystic fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the... (Review)
Review
Cystic fibrosis (CF) is an inherited disorder caused by a deleterious mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Given that the CFTR protein is a chloride channel expressed on a variety of cells throughout the human body, mutations in this gene impact several organs, particularly the lungs. For this very reason, research regarding CF disease and CFTR function has historically focused on the lung airway epithelium. Nevertheless, it was discovered more than two decades ago that CFTR is also expressed and functional on endothelial cells. Despite the great strides that have been made in understanding the role of CFTR in the airway epithelium, the role of CFTR in the endothelium remains unclear. Considering that the airway epithelium and endothelium work in tandem to allow gas exchange, it becomes very crucial to understand how a defective CFTR protein can impact the pulmonary vasculature and overall lung function. Fortunately, more recent research has been dedicated to elucidating the role of CFTR in the endothelium. As a result, several vascular dysfunctions associated with CF disease have come to light. Here, we summarize the current knowledge on pulmonary vascular dysfunctions in CF and discuss applicable therapies.
Topics: Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Animals; Lung; Endothelium, Vascular; Mutation; Pulmonary Circulation
PubMed: 38501963
DOI: 10.1152/physiol.00024.2023 -
Frontiers in Immunology 2023Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular...
Pulmonary fibrosis (PF) and pulmonary hypertension (PH) have common pathophysiological features, such as the significant remodeling of pulmonary parenchyma and vascular wall. There is no effective specific drug in clinical treatment for these two diseases, resulting in a worse prognosis and higher mortality. This study aimed to screen the common key genes and immune characteristics of PF and PH by means of bioinformatics to find new common therapeutic targets. Expression profiles are downloaded from the Gene Expression Database. Weighted gene co-expression network analysis is used to identify the co-expression modules related to PF and PH. We used the ClueGO software to enrich and analyze the common genes in PF and PH and obtained the protein-protein interaction (PPI) network. Then, the differential genes were screened out in another cohort of PF and PH, and the shared genes were crossed. Finally, RT-PCR verification and immune infiltration analysis were performed on the intersection genes. In the result, the positive correlation module with the highest correlation between PF and PH was determined, and it was found that lymphocyte activation is a common feature of the pathophysiology of PF and PH. Eight common characteristic genes ( and ) were gained. Immune infiltration showed that compared with the control group, resting CD4 memory T cells were upregulated in PF and PH. Combining the results of crossing characteristic genes in ImmPort database and RT-PCR, the important gene was obtained. Knocking down could significantly reduce the proliferation and apoptosis resistance in pulmonary microvascular endothelial cells, pulmonary smooth muscle cells, and fibroblasts induced by hypoxia, platelet-derived growth factor-BB (PDGF-BB), and transforming growth factor-β1 (TGF-β1), respectively. Our work identified the common biomarkers of PF and PH and provided a new candidate gene for the potential therapeutic targets of PF and PH in the future.
Topics: Humans; Pulmonary Fibrosis; Hypertension, Pulmonary; Endothelial Cells; Genes, Regulator; Computational Biology; Proteins
PubMed: 37731513
DOI: 10.3389/fimmu.2023.1197752 -
Diagnostics (Basel, Switzerland) Apr 2024A heart with a borderline ventricle refers to a situation where there is uncertainty about whether the left or right underdeveloped ventricle can effectively support the... (Review)
Review
A heart with a borderline ventricle refers to a situation where there is uncertainty about whether the left or right underdeveloped ventricle can effectively support the systemic or pulmonary circulation with appropriate filling pressures and sufficient physiological reserve. Pediatric cardiologists often deal with congenital heart diseases (CHDs) associated with various degrees of hypoplasia of the left or right ventricles. To date, no specific guidelines exist, and surgical management may be extremely variable in different centers and sometimes even in the same center at different times. Thus, the choice between the single-ventricle or biventricular approach is always controversial. The aim of this review is to better define when "small is too small and large is large enough" in order to help clinicians make the decision that could potentially affect the patient's entire life.
PubMed: 38667469
DOI: 10.3390/diagnostics14080823 -
Seminars in Respiratory and Critical... Dec 2023The clinical presentation of pulmonary hypertension (PH) is nonspecific, resulting in significant delays in its detection. In the majority of cases, PH is a marker of...
The clinical presentation of pulmonary hypertension (PH) is nonspecific, resulting in significant delays in its detection. In the majority of cases, PH is a marker of the severity of other cardiopulmonary diseases. Differential diagnosis aimed at the early identification of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) who do require specific and complex therapies is as important as PH detection itself. Despite all efforts aimed at the noninvasive assessment of pulmonary arterial pressure, the formal confirmation of PH still requires catheterization of the right heart and pulmonary artery. The current document will give an overview of strategies aimed at the early diagnosis of PAH and CTEPH, while avoiding their overdiagnosis. It is not intended to be a replica of the recently published European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines on Diagnosis and Treatment of Pulmonary Hypertension, freely available at the Web sites of both societies. While promoting guidelines' recommendations, including those on new definitions of PH, we will try to bring them closer to everyday clinical practice, benefiting from our personal experience in managing patients with suspected PH.
Topics: Humans; Hypertension, Pulmonary; Pulmonary Artery; Risk Assessment; Chronic Disease
PubMed: 37487526
DOI: 10.1055/s-0043-1770116 -
Chest Sep 2023Right ventricular dysfunction in pulmonary hypertension (PH) contributes to reduced exercise capacity, morbidity, and mortality. Exercise can unmask right ventricular... (Review)
Review
TOPIC IMPORTANCE
Right ventricular dysfunction in pulmonary hypertension (PH) contributes to reduced exercise capacity, morbidity, and mortality. Exercise can unmask right ventricular dysfunction not apparent at rest, with negative implications for prognosis.
REVIEW FINDINGS
Among patients with pulmonary vascular disease, right ventricular afterload may increase during exercise out of proportion to increases observed among healthy individuals. Right ventricular contractility must increase to match the demands of increased afterload to maintain ventricular-arterial coupling (the relationship between contractility and afterload) and ultimately cardiac output. Impaired right ventricular contractile reserve leads to ventricular-arterial uncoupling, preventing cardiac output from increasing during exercise and limiting exercise capacity. Abnormal pulmonary vascular response to exercise can signify early pulmonary vascular disease and is associated with increased mortality. Impaired right ventricular contractile reserve similarly predicts poor outcomes, including reduced exercise capacity and death. Exercise provocation can be used to assess pulmonary vascular response to exercise and right ventricular contractile reserve. Noninvasive techniques (including cardiopulmonary exercise testing, transthoracic echocardiography, and cardiac MRI) as well as invasive techniques (including right heart catheterization and pressure-volume analysis) may be applied selectively to the screening, diagnosis, and risk stratification of patients with suspected or established PH. Further research is required to determine the role of exercise stress testing in the management of pulmonary vascular disease.
SUMMARY
This review describes the current understanding of clinical applications of exercise testing in the risk assessment of patients with suspected or established PH.
Topics: Humans; Hypertension, Pulmonary; Exercise Test; Ventricular Dysfunction, Right; Pulmonary Circulation; Risk Assessment; Ventricular Function, Right
PubMed: 37061028
DOI: 10.1016/j.chest.2023.04.013 -
AAPS PharmSciTech Jul 2023Idiopathic pulmonary fibrosis (IPF) is an ailment with no cure and a very high rate of progression that ultimately leads to death. The exact reason for this disease is... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is an ailment with no cure and a very high rate of progression that ultimately leads to death. The exact reason for this disease is still not acknowledged. Many underlying mechanisms of wound healing and various types of stimuli that trigger the pathogenesis of IPF continue to be intensively explored. The exact therapy for the reversal of this disease is not yet known and is constantly in progress. Existing treatments only slow down the process or mitigate the symptoms to enhance the patient's healthcare system. The only two Food and Drug Administration-approved oral medications include pirfenidone and nintedanib whose high dose and systemic circulation can have side effects to a greater extent. Further research on restorative and extra-curative therapies for IPF is necessary due to the absence of viable therapeutic choices. To assure minimum off-targeted site delivery and longer duration of action, techniques that offer a sustainable release of the drug, better bioavailability, and patient compliance can be used.The work is an overview of the main therapeutic targets and pertinent developing therapies for the management of IPF. This study is an attempt to focus on various drug delivery systems that are responsible for showing effectiveness in defense mechanisms against IPF.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Pyridones
PubMed: 37442839
DOI: 10.1208/s12249-023-02618-4