A Review on Role of Transforming Growth Factor-?1 in Hemorrhage

Abstract

Haemorrhage, the escape of blood from the vascular system, remains a critical concern in global health due to its potential to rapidly compromise organ function and threaten life. Spanning a wide clinical spectrum from minor, self-limiting bleeding to acute, catastrophic blood loss haemorrhage plays a pivotal role in trauma care, surgical procedures, obstetric emergencies, and chronic disease complications. Central to the pathophysiology of haemorrhage is the disruption of vascular integrity, which triggers a complex physiological response aimed at restoring hemostasis. While the body possesses inherent compensatory mechanisms, these can be quickly overwhelmed in the face of severe or uncontrolled bleeding. This paper highlights the fundamental mechanisms, clinical implications, and global burden of haemorrhage, emphasizing the need for timely diagnosis, effective management, and context-sensitive intervention strategies. It also explores the disparity in outcomes across healthcare systems, particularly in low-resource settings where haemorrhage continues to be a leading cause of preventable death. Through a comprehensive examination of current practices and emerging innovations, this discussion reinforces the urgency of equipping healthcare professionals with the knowledge and tools necessary to recognize and control hemorrhagic events swiftly and effectively. Ultimately, reducing the global impact of haemorrhage depends on a combination of clinical expertise, systemic preparedness, and continued advancements in both technology and public health infrastructure.

Keywords

Introduction

Fig 1: Fibrosis and Inflammation In TGF- β 1

The TGF-β1 signalling pathway is initiated by the binding of TGF-β1 to type II and type I serine/threonine kinase receptors. Upon ligand binding, the receptors activate downstream mediators, primarily SMAD proteins. Receptor-regulated Smad’s (R-Smad’s) are classified into two subclasses: those activated by activin/TGF-β signalling pathways (ARSmads) and those activated by bone morphogenetic protein (BMP) signalling pathways (BRSmads). TGF-β1 is a member of the TGF-β superfamily, which includes more than 30 members with a broad range of biological activities [15]. This intricate signalling network allows TGF-β1 to elicit diverse effects on target cells, influencing gene expression, RNA processing, mRNA translation, and nuclear or cytoplasmic regulation [16].  Following the initial haemostatic response, an inflammatory reaction is triggered at the site of haemorrhage. This involves the recruitment of immune cells, such as neutrophils and macrophages, to clear debris, remove pathogens, and promote tissue repair [17]. A critical aspect of TGF-β1's role in haemorrhage is its involvement in fibrosis, the formation of scar tissue. While fibrosis is a natural part of the healing process, excessive or dysregulated fibrosis can lead to tissue dysfunction and long-term complications [18]. TGF-β1 can have both protective and detrimental effects in haemorrhage, depending on the context, cell type, and stage of the disease. This duality arises from the complex and multifaceted nature of TGF-β1 signalling. Further research is needed to elucidate the specific conditions under which TGF-β1 exerts its different effects and to identify the key factors that determine its role in haemorrhage. This research should focus on investigating the interactions between TGF-β1 and other signalling pathways, as well as the role of different cell types in mediating TGF-β1's effects. Understanding these nuances is critical for developing targeted therapies that selectively modulate TGF-β1 signalling to achieve beneficial outcomes by selectively modulating TGF-β1 signalling, it may be possible to harness its beneficial effects while minimizing its detrimental effects. This could involve using strategies that target specific components of the TGF-β1 signalling pathway or that modulate the activity of TGF-β1 in specific cell types [19]. Yasunori Miyamoto reported that the stab-wound traumatic brain injury (TBI) mouse model is a simple yet effective method used to study the localized effects of brain injury. TBI often results from physical trauma such as accidents or sports injuries, leading to primary damage like haemorrhage and secondary effects such as inflammation and neuronal loss. This model replicates penetrating brain injuries by inserting a needle through the skull into the mouse’s cerebral cortex. It requires no specialized equipment and causes only minimal behavioural changes in the animals, allowing researchers to focus on the injury site without systemic interference. The model is valuable for examining blood leakage, glial cell activation, and inflammatory cytokine production. It also provides a useful platform for testing potential treatments, including blood coagulants and anti-inflammatory drugs, making it a key tool in understanding TBI pathology and developing new therapies [20]. Hongying reported that the combination of calcium dobesilate and candesartan shows significant therapeutic effectiveness in treating proliferative diabetic retinopathy. In the study group, treatment efficacy was markedly higher than in the control group, with a total effective rate of 92.86% (p < 0.05). This group also exhibited a significantly smaller haemorrhage area and reduced macular thickness (p < 0.05). Best-corrected visual acuity improved notably, along with increased peak systolic and end-diastolic velocities (p < 0.05), indicating better retinal blood flow. Furthermore, levels of TGF-β1, VEGF, and IL-19 in the vitreous humor were significantly lower in the study group compared to controls (p < 0.05), suggesting reduced inflammation [21]. Dongying Ma reported that the chronic hydrocephalus is a frequent complication following aneurysmal subarachnoid haemorrhage (aSAH), but its underlying causes remain unclear. This study aimed to identify cerebrospinal fluid (CSF) biomarkers that could help predict the development of chronic hydrocephalus after aSAH. Researchers analysed CSF samples from 19 patients with chronic hydrocephalus and 44 aSAH patients without hydrocephalus. Using enzyme-linked immunosorbent assays (ELISA), they measured levels of several proteins involved in the TGF-β signalling pathway, including LRG, TGF-β, Smad proteins (Smad1, 4, 5, 8), Alk-1, Alk-5, P38, and TGFßRII. The study aimed to explore how these biomarkers are linked to the development of hydrocephalus, potentially offering new insights for early diagnosis and treatment [22]. Sai Sriram reported that the neuroinflammation plays a critical role in the development and progression of aneurysmal subarachnoid haemorrhage (aSAH). It can both contribute to aneurysm formation and rupture, and arise because of blood breakdown products after rupture. Persistent neuroinflammation has been linked to serious complications such as cerebral vasospasm and chronic hydrocephalus. This review explores the underlying mechanisms of aneurysm formation, the inflammatory response following rupture—including key cytokines involved—and the clinical impact of these processes. It also discusses emerging pre-clinical research and potential therapeutic strategies targeting neuroinflammation, offering valuable insights for both clinicians and researchers in advancing ash management [23]. Huimei Wen studied intracerebral haemorrhage (ICH) is a life-threatening type of stroke with no effective treatment currently available. This study highlights the potential of transforming growth factor-β1 (TGF-β1) as a therapeutic agent for ICH. The results show that TGF-β1, through the ALK-5 signalling pathway, helps protect the blood-brain barrier (BBB), reduces brain enema, and limits BBB damage. It also activates anti-inflammatory microglia and suppresses inflammatory responses, leading to improved long-term outcomes. These findings suggest that TGF-β1 could offer a promising approach for reducing brain injury and enhancing recovery in ICH patients [24]. This study identifies key immune-related biomarkers that can help predict the severity and early progression of haemorrhagic fever with renal syndrome (HFRS), a viral illness with high morbidity. By analysing serum samples from 26 patients, researchers found that high haemoglobin (HGB) levels and low urine output (UO) were associated with the acute phase of HFRS. Elevated levels of subpar and CXCL10 emerged as early-phase markers strongly linked to disease activity. In severe cases, IL-10 and CXCL10 were significantly increased, while TGF-β3 was decreased, suggesting a loss of anti-inflammatory protection. These biomarkers—especially subpar, IL-10, CXCL10, and TGF-β3—show strong potential in predicting disease severity. Additionally, reduced UO was correlated with higher levels of subpar, CXCL10, and TGF-β2, and lower levels of VEGF and TGF-β3, indicating a connection between kidney impairment and immune activation. Overall, this study highlights a promising biomarker panel that could guide early diagnosis, monitor progression, and inform treatment decisions in HFRS [25]. D Feng, Blood-Brain Barrier (BBB) injury worsens the prognosis of patients with subarachnoid haemorrhage (SAH), and matrix metalloproteinase-9 (MMP-9) plays a critical role in this damage. This study identifies reactive astrocytes as the primary source of increased MMP-9 production after SAH. The knockout of Ndrg2 in astrocytes reduced MMP-9 expression, mitigated BBB damage, and decreased Smad2/3 phosphorylation. NDRG2 in the cytoplasm binds to protein phosphatase PPM1A, inhibiting the dephosphorylation of Smad2/3. A novel peptide, TAT-QFNP12, that disrupts the NDRG2-PPM1A interaction, reduced MMP-9 production, and BBB disruption. This research highlights the NDRG2-PPM1A signalling pathway as a crucial mediator of MMP-9 production and suggests a new therapeutic approach for protecting the BBB after SAH [26]. Mesenchymal stem cell-derived extracellular vehicles (EVs) have shown promising therapeutic effects in brain injuries. In a porcine model of traumatic brain injury (TBI) combined with haemorrhagic shock (HS), EV treatment significantly reduced brain lesion size, inflammation, and improved neurological outcomes. This study suggests that EVs promote neuroprotection and recovery by modulating the brain’s transcriptome—specifically by suppressing inflammatory pathways and enhancing genes involved in neurogenesis and neuroplasticity. These molecular changes likely underlie the observed healing effects, highlighting EVs as a potential treatment for severe brain injuries studied by Bambakidis [27].Georgios Galaris reported Hereditary Haemorrhagic Telangiectasia type 1 (HHT1) is caused by ENDOGLIN mutations, leading to low endoglin levels in blood vessels. Although the mutation is present throughout the body, only some organs are affected. This study found that organs with naturally low endoglin levels, like the skin, are more prone to disease. A critical threshold of endoglin is needed for normal blood vessel function, supporting therapies that boost endoglin as a potential treatment for HHT1[28]. IfeanyiO Iwuchukwu reported that the surgical treatment for intracerebral haemorrhage (ICH) remains debated, as its benefits are not yet clearly established. One key challenge is identifying which patients might truly benefit from surgery based on molecular and clinical factors. This study aimed to understand the molecular differences between patients who had favourable (mRS 0–3) and unfavourable (mRS 4–6) outcomes after surgical intervention. Researchers focused on changes in gene expression related to inflammation and cell survival over time. The study found that both proinflammatory and anti-inflammatory genes were actively expressed and showed significant changes across different time points. Notably, TNF (tumour necrosis factor), a proinflammatory cytokine, was significantly upregulated at later stages in patients with poor outcomes (mRS 4–6), while its expression remained unchanged in those with better recovery (mRS 0–3). These findings suggest that molecular markers like TNF may play a role in determining surgical outcomes. Future research will aim to explore how such gene expression patterns can guide patient selection and improve decision-making in the surgical management of ICH [29]. Intraventricular haemorrhage (IVH), a serious complication of preterm birth, often leads to hydrocephalus, brain injury, and altered expression of aquaporin channels (AQP1 and AQP4), which regulate cerebrospinal fluid flow. This study investigated the therapeutic potential of human cord blood-derived unrestricted somatic stem cells (USSCs) in a rabbit model of IVH. USSCs were injected into the ventricles 18 hours after IVH induction and resulted in significantly reduced ventricular enlargement and improved brain structure at 7 and 14 days. USSC treatment restored the expression of AQP1 and AQP4, reduced inflammation, preserved the ependymal wall, and normalized levels of TGF-β, CTGF, MMP-9, and the anti-inflammatory cytokine IL-10. These findings suggest that USSCs may offer a promising therapy to counteract the damaging effects of IVH in premature infants by reducing inflammation, restoring fluid regulation, and limiting hydrocephalus studied by D Purohit [30]. Lu-Ting Kuo reported hydrocephalus is a frequent and serious complication of aneurysmal subarachnoid haemorrhage (aSAH), contributing to poor neurological outcomes. This review outlines the key molecular and cellular mechanisms involved in its development, including disrupted cerebrospinal fluid (CSF) flow, blockage of arachnoid granulations by blood products, and ventricular adhesions. Molecular factors such as the activation of the TGF-β/SMAD pathway, upregulation of tenascin-C, CSF hypersecretion due to inflammation, and systemic immune responses play important roles in chronic hydrocephalus after aSAH. The review also evaluates predictive factors for shunt dependency and compares surgical clipping with endovascular coiling. Additionally, the effectiveness of treatments like external ventricular drainage, endoscopic clot removal, fibrinolysis, and third ventriculostomy is discussed to help guide optimal management strategies [31]. Kenan Rajjoub reported intraventricular haemorrhage (IVH) is a severe neurosurgical condition with high morbidity and mortality, often resulting from various causes. It typically presents with neurological symptoms such as altered mental status, seizures, headaches, and reduced Glasgow Coma Scale (GCS) scores. The standard approach involves using an external ventricular drain (EVD) to relieve pressure and remove blood clots. However, these drains frequently become clogged, requiring repeated replacements, which adds to the patient's risk and treatment complexity. This case highlights the use of DRIFT therapy (Drainage, Irrigation, and Fibrinolytics) with the Uroflow® irrigating catheter in a patient with severe IVH following aneurysmal subarachnoid haemorrhage. The technique allowed continuous clot removal and CSF circulation, offering a promising alternative to traditional EVD management [32]. Keigo Tamakoshi studied and investigated the impact of early treadmill exercise on brain recovery following intracerebral haemorrhage (ICH) in rats. Animals were divided into groups receiving no exercise, early exercise starting on day 2, or late exercise starting on day 9 after ICH. Early exercise significantly improved motor function, preserved cortical thickness, increased neuronal survival, and enhanced dendritic length and complexity compared to late or no exercise. Additionally, early exercise reduced the expression of the inflammatory marker IL-1β. These findings suggest that early physical activity after ICH may promote recovery by reducing neuroinflammation and preventing neuronal damage and brain atrophy [33]. Chao Jiang explored immune cell changes in the hematoma and blood of patients with acute intracerebral haemorrhage (ICH) and how these changes relate to recovery. Blood and hematoma fluid samples were collected from 35 ICH patients within 30 hours of symptom onset and compared with samples from 55 healthy controls. Flow cytometry and ELISA analysis showed that ICH patients had higher levels of granulocytes, regulatory T cells, Th17 cells, and dendritic cells, but lower levels of lymphocytes and both M1- and M2-like macrophages in peripheral blood compared to healthy individuals. Inflammatory cytokines including IL-6, IL-17, IL-23, TNF-α, IL-4, IL-10, and TGF-β were also elevated in ICH patients. White blood cell counts in the hematoma increased over time (12–30 hours), while peripheral Th cell percentages decreased. Importantly, higher IL-10 levels and lower M1-like macrophage presence in the hematoma were independently linked to better outcomes at 90 days, suggesting a protective, anti-inflammatory role. These findings highlight that immune cells within the hematoma actively contribute to the early inflammatory response in ICH and may influence long-term prognosis, emphasizing the potential of targeting immune responses to improve outcomes [34]. Carmelo Bernabeu reported that the Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder caused by mutations in ENG, ACVRL1, or SMAD4, leading to telangiectasis and arteriovenous malformations (AVMs) in organs like the skin, lungs, liver, and brain. While gene mutations are present throughout the body, vascular lesions appear only in certain areas, suggesting a “second-hit” mechanism. Possible triggers include mechanical trauma, inflammation, light exposure, vascular injury, angiogenic signals, shear stress, modifier genes, and somatic mutations in the remaining healthy allele. This review highlights these secondary factors and the mechanisms by which they may contribute to lesion development in HHT [35].

CONCLUSION: Haemorrhage remains a significant clinical challenge, with diverse types and management strategies. The role of TGF-β1 in haemorrhage highlights the complexity of the inflammatory and healing processes involved. Future research should focus on elucidating the specific mechanisms of TGF-β1 action, developing targeted therapies, and improving clinical outcomes for patients experiencing haemorrhage. By addressing the challenges and leveraging emerging trends in haemorrhage management, healthcare providers can enhance patient care and reduce morbidity and mortality associated with this critical condition’s-β1 emerges as a pivotal cytokine orchestrating multiple phases of haemorrhage response, influencing everything from initial clot formation to subsequent tissue remodelling. Its role in promoting haemostasis, regulating inflammation, and stimulating collagen synthesis highlights its complex involvement in wound healing. However, the profibrotic effects of TGF-β1 can also contribute to adverse outcomes like scar formation. Given its multifaceted actions, TGF-β1 presents a compelling, yet challenging, therapeutic target. Further research is essential to fully elucidate the context-dependent effects of TGF-β1 in haemorrhage and to develop targeted strategies that can harness its beneficial aspects while mitigating potential risks. Understanding the precise mechanisms by which TGF-β1 mediates its diverse effects could pave the way for novel interventions aimed at optimizing. The findings from this review highlight the complexity of haemorrhage management and the critical role of TGF-β1 in the pathophysiology of bleeding. A comprehensive understanding of haemorrhage types, severity grading, and the molecular mechanisms involved is essential for developing effective therapeutic strategies. By addressing the challenges and leveraging emerging trends in haemorrhage management, healthcare providers can improve patient care and reduce morbidity and mortality associated with this critical condition. Continued research into TGF-β1 and its role in haemorrhage will be vital for advancing our understanding and treatment of this significant clinical issue.

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