Abstract
Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are among the most prevalent complications associated with cardiac surgery involving extracorporeal circulation (ECC), contributing to adverse outcomes and representing a significant impediment to successful cardiac surgical procedures. Vascular endothelial growth factor (VEGF) is implicated in the etiology of ALI/ARDS; however, its precise role remains a subject of debate due to the presence of somewhat contradictory findings in the literature, necessitating further investigation. To date, numerous studies have explored the role of VEGF in the pathophysiology of ALI/ARDS, with ongoing discussions regarding whether VEGF exerts a protective or detrimental effect. The genetic polymorphism of the VEGF gene is a significant factor in the development of ALI/ARDS. Research has indicated that the prevalence of the VEGF polymorphic gene is markedly higher in postoperative cardiac surgery patients who develop ALI/ARDS compared to the general population. Furthermore, the mortality rate among patients possessing the VEGF polymorphic gene is significantly elevated. Concurrently, it has been demonstrated that ARDS patients who are positive for the VEGF polymorphism exhibit a reduction in VEGF levels within alveolar lavage fluid, which correlates with an exacerbation of lung injury. The present paper provides a comprehensive review of the genetic polymorphisms of VEGF and their implications in the pathophysiological alterations observed in postoperative cardiac surgery patients with ALI/ARDS, thereby offering novel insights and evidence to further elucidate the mechanisms underlying ALI/ARDS.
Introduction
Acute lung injury (ALI) represents the initial phase of the spectrum leading to acute respiratory distress syndrome (ARDS) and is frequently encountered as a postoperative complication following open heart surgery. Despite advancements in medical care, ALI continues to be a significant complication post-extracorporeal circulation (ECC), posing a considerable impediment to patient recovery. ALI and ARDS ensuing from cardiopulmonary bypass are characterized by a disruption in the integrity of alveolar capillaries due to inflammatory responses, with the primary pathophysiological alterations being alveolar edema and a marked increase in vascular permeability in patients undergoing cardiac surgery. Clinically, these conditions manifest as severe hypoxemia, pulmonary edema, and the infiltration of neutrophils. , Although our comprehension of ALI/ARDS has evolved over the past decades, the mortality rate remains distressingly high, ranging from 17-23% in contemporary clinical practice. The precise etiology of ALI/ARDS remains to be fully elucidated; however, the majority of research indicates that inflammation-mediated injury to capillary endothelium and alveolar epithelial cells is the initial event and the pathological foundation of these conditions. Vascular endothelial growth factor (VEGF), a pivotal component of the inflammatory response, is highly significant in the etiology, progression, and prognosis of ALI/ARDS. ,
Vascular endothelial growth factor (VEGF) is a member of the platelet-derived growth factor family, characterized as a glycoprotein initially isolated and purified from the culture medium of bovine pituitary follicular stellate cells. VEGF is synthesized in a variety of organs, with the lung tissue exhibiting the highest concentration of this factor. Research to date has established that VEGF facilitates the proliferation of vascular endothelial cells, the formation of vascular support structures, an increase in vascular permeability, and the inhibition of apoptosis in tumor cells. These multifaceted functions are not only integral to sustaining normal physiological processes such as embryogenesis and osseous development but also undergo significant alterations in lung tissue and plasma during the pathogenesis and progression of ALI/ARDS. These changes in VEGF function are believed to exert a substantial influence on the trajectory and prognosis of lung injury, particularly in response to endogenous or exogenous stimuli that either upregulate or downregulate VEGF levels, as evidenced by findings from both human and animal studies. Consequently, VEGF is widely recognized for its pivotal role in the pathophysiology of ALI/ARDS. Nonetheless, the precise mechanisms underlying its actions in this context remain to be fully elucidated.
While a comprehensive scientometric analysis of the relationship between VEGF gene polymorphism and the development of ALI/ARDS has not yet been reported in the literature, the existing studies offer preliminary insights into this association. Scientometric analysis, which employs statistical methods and graphical representations, is an innovative and efficient means of exploring the structure and patterns within a specific subject area or field. This methodology enables the identification of key nodes and the extraction of significant data from the relevant literature (as depicted in Fig. 1 : A, B, C, D). This paper aims to synthesize the current understanding of VEGF gene polymorphism and the evolving treatment paradigms for ALI/ARDS, highlighting the significance of VEGF in the pathophysiological alterations associated with these conditions. By doing so, it seeks to contribute additional perspectives and empirical evidence to the ongoing investigation into the mechanisms of ALI/ARDS. The integration of scientometric techniques with the analysis of VEGF’s role in ALI/ARDS offers a novel perspective that may facilitate a deeper comprehension of the complex interplay between genetic factors and clinical outcomes in respiratory critical care.
Pathophysiological changes of ALI / ARDS
ALI is recognized as the precursor to ARDS and is a contributing factor in the development of multiple organ failure syndromes (MOFs). ALI is prevalent in the context of various clinical scenarios, including infections, shock, and severe trauma, posing a significant risk to patient life safety. Pathologically, ALI/ARDS can be categorized into distinct stages: an exudative phase characterized by neutrophil infiltration and increased endothelial permeability; the formation of hyaline membranes to varying degrees; and ultimately, the resolution phase following the fibroproliferative stage, which involves interstitial and fibrotic changes.
The early pathophysiological alterations in ALI/ARDS primarily involve the disruption of alveolar-capillary integrity, the impairment of alveolar surfactant function, and a marked increase in alveolar edema and vascular permeability. Concurrently, these changes activate the immune system and elicit an inflammatory response. The removal of metabolites further amplifies the inflammatory and immune responses, leading to alveolar edema, exacerbated local inflammatory reactions, increased permeability, the formation of hyaline membranes, and a significant deterioration in alveolar gas exchange function.
The severe perioperative pathophysiological changes associated with ALI/ARDS result in higher mortality and complication rates compared to non-cardiopulmonary bypass (CPB) cardiac surgery and other types of surgery. Approximately 20% of patients may experience cardiac and pulmonary dysfunction, 5% may develop acute renal failure, and nearly 60% may suffer from neurocognitive dysfunction. Although the precise mechanisms underlying ALI/ARDS are not fully understood, a general consensus has been reached on several key factors, including inflammatory responses, oxidative stress and redox imbalance, apoptosis, coagulation and fibrinolytic dysregulation, and genetic predispositions. The early pathological changes observed in patients with ALI/ARDS are graphically represented in Fig. 2 .
Ashbaugh and colleagues first articulated the concept of ALI and ARDS in 1967, and since then, the field has seen significant advancements in research. Despite these efforts, the clinical outcomes remain disheartening with high mortality rates associated with ALI/ARDS. The prevailing consensus among researchers is that the apoptosis of alveolar epithelial cells and pulmonary capillary endothelial cells, leading to increased permeability, is a central mechanism in the pathogenesis of ALI/ARDS. Pulmonary capillary endothelial cells form a monolayer lining the lumen of pulmonary capillaries and serve critical functions, including acting as a barrier, facilitating vasorelaxation, and participating in secretion processes. These cells are vital for the exchange of substances and for modulating local inflammatory responses through self-regulation.
The initial pathological changes in ALI/ARDS are attributed to increased permeability due to the dysfunction or apoptosis of the alveolar-capillary membrane (ACM). The primary causes of ACM dysfunction include:
1. Apoptotic Regulation : The apoptotic function of pulmonary capillary endothelial cells may be up-regulated due to various endogenous or exogenous stimuli, leading to premature apoptosis and insufficient endothelial cell reserves, which in turn results in pulmonary vascular endothelial dysfunction, increased permeability, and alveolar edema. Molecular markers indicative of ALI/ARDS have been identified during the apoptosis induced by double-stranded DNA exercises in pulmonary capillary endothelial cells.
2. Intracellular Calcium Imbalance : An increase in intracellular calcium can trigger the contraction of pulmonary capillary endothelial cells, leading to the disruption of intercellular junctions and increased permeability. The proposed mechanism involves the activation of Gq protein and phospholipase C upon stimulation, which then leads to the production of inositol triphosphate and diacylglycerol. This activates the ion-gated channel of the cell membrane, subsequently activating RhoA factor through protein kinase C. RhoA factor opens the cell membrane’s calcium channel, leading to increased intracellular calcium levels, activation of myosin light chain kinase, and ultimately, endothelial cell contraction and increased permeability.
3. Inflammatory Factors : Various inflammatory mediators, including VEGF and tumor necrosis factor α (TNF-α), influence ACM permeability through inflammatory reactions. VEGF, in particular, is known to affect endothelial permeability and plays a significant role in normal vascular development and in various pathologies, such as cancer, stroke, cardiovascular disease, retinal conditions, and conditions like COVID-19-associated pulmonary edema, sepsis, and acute lung injury. VEGF’s mechanism of increasing endothelial permeability involves the activation of tyrosine kinase and the subsequent production of inositol triphosphate and diacylglycerol upon binding to its receptor. The release of intracellular calcium ions increases intracellular calcium concentration, leading to enhanced vascular endothelial permeability.
VEGF is present in all adult organs and tissues, with the highest concentration found in lung tissue. The lung is the primary site for VEGF synthesis, and clinical studies have shown a significant increase in VEGF blood concentration in patients with ALI/ARDS. The peripheral blood monocytes of these patients have been shown to have an increased ability to secrete VEGF in vitro. The use of VEGF blockers has been observed to significantly reduce pulmonary vascular endothelial permeability, leading to the speculation that VEGF may play a crucial role in the development and progression of ALI/ARDS. , A comprehensive summary of the main literature included in this manuscript is presented in Table 1 .
| Studies | Year | Model | Type of study | Results | Conclusion |
|---|---|---|---|---|---|
| Chin-kuo lin | 2022 | Mice | RCT | VEGF expression in lung tissue positively correlated with the expression of Ki67, a cell proliferation marker, in alveolar epithelial cells. Monocytes are a cellular source of VEGF and the depletion of monocytes suppresses the post-VILI restoration of pulmonary VEGF. | Restoration of pulmonary VEGF by monocytes, which are mostly Ly6C +low , is associated with pulmonary epithelial proliferation. Lung-recruited monocytes and pulmonary VEGF may play crucial roles in post-VILI lung repair. |
| Li Wang | 2021 | Human | Basic research | VEGFR-2 phosphorylation is necessary for vascular permeability. VEGF/VEGFR-2 signaling results in JAK2- mediated activation of STAT3, which enables STAT3 to translocate to the nucleus and transcriptionally regulate genes involved in vascular barrier integrity, including ICAM-1 | VEGF/VEGFR-2/JAK2/STAT3 signaling regulates vascular barrier integrity, and inhibition of STAT3-dependent activity reduces VEGF induced vascular permeability. STAT3 may also regulate changes in genes that control vascular permeability in a VEGF-independent manner. |
| Peter Baluk | 2020 | Mice | RCT | Lymphangiogenesis is dependent on VEGF3 signaling, but not on VEGF2. VEGFC gene and protein expression increased specifically. Much of the lymphatic expansion was in the lung hilum around large airways, where VEGFC was secreted from CCSP-expressing epithelial cells; lymphatic expansion was less in the lung parenchyma. | Lymphatic growth is driven by VEGFC from macrophages through VEGFR3 signaling and is accompanied by extravasation of platelets and fibrinogen and influx of other immune cells. |
| Tzu-Hsiung Huang | 2019 | Mice | RCT | HTV-mechanical ventilation significantly increased the recruitment of COX-2, expressing Ly6C high , but not Ly6C low , monocytes. Celecoxib significantly diminished the recruitment of Ly6C high monocytes, attenuated the levels of VEGF and total protein in bronchoalveolar lavage fluid, and restored pulmonary oxygenation during VILI. | COX-2 activity is important in the recruitment of VEGF-secreting Ly6C high monocytes, which are involved in VILI pathogenesis, and indicate that the suppression of COX-2 activity might be a useful strategy in mitigating VILI. |
| Chin-Kuo Lin | 2019 | Mice | RCT | FE significantly increased pulmonary VEGF expression and MAPK phosphorylation. iNOS and IL-1β significantly increased after FE. Systemic administration of SU-1498, an antagonist of VEGF receptor 2 significantly attenuated the FE-induced inflammatory response and histological damage. | VEGF promotes angiogenesis and increases vascular permeability . VEGFR-2 blockade significantly attenuated pulmonary damage after FE via inhibition of MAPK phosphorylation, IL-1β release, and iNOS overproduction. |
| Ruihua Ma | 2018 | Mice | RCT | Telocytes can promote the proliferation of vascular endothelial cells under pathological conditions and appear to play a role in promoting the proliferation and repair of damaged blood vessels by increasing VEGF expression. | Telocytes could restore the proliferation of pulmonary vascular endothelial cells in vitro, potentially via the synthesis and secretion of VEGF. |
| Chung-Sheng Shi | 2016 | Mice | RCT | LPS+HTV significantly increased total proteins, TNF-α, IL-6, VEGF and mononuclear cells in the BALF. Clodronate liposomes were able to reduce pulmonary Ly6C +high monocytes, and VEGF and total protein in BALF, and restore PaO2/FiO2. | VEGF produced by pulmonary infiltrated Ly6C +high monocytes regulates vasculature permeability in a two-hit model of HTV-induced ALI. Ly6C+ high monocytes play an important role in the pathogenesis of VILI. |
| Junfeng Song | 2015 | Mice | Retrospective | VEGF reduced wet-to-dry ratio and pulmonary neutrophil infiltration in the VEGF group compared with the LPS group. VEGF increased the number of pulmonary vessels, and significantly increased the number of circulating EPC cells. Moreover, administration of VEGF decreased the percentage of apoptotic cells in the VEGF group. | VEGF may contribute to vascular endothelial repair and function as a protective factor against ALI. |
| Medford AR | 2009 | Human | RCT | VEGFR1, VEGFR2, and NRP-1 were expressed on both sides of the alveolar-capillary membrane in both normal and ARDS human lung tissue. ARDS, there was a significant upregulation of VEGFR1 and VEGFR2 versus normal and early ARDS (P˂0001). Neuropilin-1 was downregulated in early ARDS versus normal lung (P ˂ .05), with normalization in later ARDS (P ˂ .001). | VEGFR1, VEGFR2, and NRP-1 up-regulation occurs in human ARDS, providing evidence of further functional regulation of VEGF bioactivity viaVEGFR2 consistent with a protective role for VEGF in lung injury recovery. |
| Xue-Mei Ou | 2008 | Mice | RCT | Increased expressions of VEGF/VEGFR (Flk-1) were correlated to a larger number of micro-vessels and a higher score of pulmonary fibrosis. | SU5416, a VEGFR-2 inhibitor, reduces Bleomycin-induced pulmonary fibrosis. SU5416 also decreased VEGF/VEGFR-2 (Flk-1) expression and angiogenesis in the lung at early phase of bleomycin-induced pulmonary fibrosis |
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