A systematic literature search was conducted from database inception to February 1, 2025, across PubMed, Embase, Web of Science, and the Cochrane Library. The search strategy combined keywords and MeSH terms for “aortic dissection, respiratory distress syndrome, acute lung injury, and hypoxia” (full syntax provided in Supplementary Material S1). Study selection followed a PRISMA-guided process (Supplementary Figure S1), with dual independent screening prioritizing clinical relevance and methodological quality.

The 2024 Global Definition of ARDS (11) is applied to current clinical management and recent studies. Historical studies are referenced using their original terminology [e.g., “acute lung injury (ALI)” from the 1994 American-European Consensus Conference [AECC] criteria], which was later superseded by the Berlin definition.

The SIR represents a critical pathological process in AAD patients (17–20), with the lungs serving as primary target organs through three distinct mechanisms. First, pulmonary capillaries filter circulatory metabolites, bioactive mediators, and particulate matter that accumulate during vascular injury. Second, neutrophil-endothelial interactions induce pulmonary microvascular endothelial cells (PMVECs) apoptosis and extracellular matrix degradation via proteolytic enzyme release, significantly increasing capillary permeability. Third, resident alveolar macrophages amplify local inflammation through pro-inflammatory cytokine cascades when activated by systemic triggers. During SIR, the excessive release of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) serves as a key mediator of pathological progression (21). These pro-inflammatory factors activate critical signaling pathways, such as nuclear factor kappa-B (NF-κB) (22), mitogen-activated protein kinase (MAPK) (23), Janus Kinase 2/signal transducer and activator of transcription 3 (24), leading to amplified pulmonary inflammation, injury to pulmonary vascular endothelial cells and alveolar type II epithelial cells (AT2 cells), enhanced vasoconstriction, and microthrombus formation. These synergistic pathological events collectively culminate in the development of ALI.

The SIR is also implicated in the development of AAD-inducedARDS. Experimental evidence from a canine AAD model demonstrates rapid progression of this pathophysiology (25). Within 2 h after the formation of aortic dissection, plasma endotoxin and cytokine levels including TNF-α, IL-6, and interleukin-10 (IL-10) showed significant elevation, progressing to peak concentrations by 6 h. This cytokine surge correlated with progressive hypoxemia (PaO₂ reduction from 2 to 6 h) and histological confirmation of alveolar edema, hemorrhage, alveolar rupture, alveolar septal broadening, and interstitial broadening. Clinical observations reinforce these experimental findings. AAD patients developing ALI exhibit significantly higher inflammatory markers than those without pulmonary complications [C-reactive protein (CRP) and/or white blood cell count; both P < 0.0] (7, 8, 15). Notably, CRP and IL-6 were identified as independent predictors of preoperative hypoxemia, suggesting their utility as early biomarkers (7). Critically, the severity of aortic injury itself, quantified by the percentage of the volume of false lumen to that of the aorta in the descending aorta (AAD%) demonstrated a stronger inverse correlation with PaO₂/FiO₂ (r = −0.604, P < 0.001) and was the sole independent predictor of oxygenation impairment (OR = 1.323, 95% CI = 1.035–1.691, P = 0.026). The positive association between AAD% and CRP (r = 0.545, P < 0.001) further supports aortic structural damage exacerbates systemic inflammation. These findings collectively suggest that ARDS in AAD appears to be closely correlated with the amount of aortic injury, possibly mediated by the magnitude of SIR associated with the aortic injury (6).

The imbalance of RAS homeostasis is involved in the development of ARDS. The activated angiotensin converting enzyme (ACE)-angiotensin (Ang) Ⅱ-Ang Ⅱ type 1 receptor (AT1-R) axis promotes the occurrence of ARDS by inducing an excessive inflammatory response, impairing alveolar barrier function, and triggering dysfunction in the coagulation. While the ACE2-Ang (1–7)-Mas axis induces a negative regulatory effect on the ACE-Ang II-AT1-R axis by degrading Ang II and generating Ang (1–7). Overactivated Ang II disrupts this balance.

Ang II signaling is not only implicated in the pathogenesis of AAD (26), but also plays a pivotal role in driving lung injury associated with this condition (27). Clinical studies demonstrate significantly elevated serum levels of Ang II (28–31), matrix metalloproteinase-9 (MMP-9) (28), and monocyte chemoattractant protein-1 (MCP-1) (29) in AAD patients with ALI compared to controls and non-ALI AAD cases. Postmortem analyses of ALI-complicated AAD patients further reveal upregulated AT1-R, MCP-1 and MMP-9 expression in lung tissues, accompanied by PMVEC apoptosis, infiltration of MMP-9-expressing macrophages, and interstitial edema. Experimental models utilizing β-aminopropionitrile (BAPN)-induced aortic pathology with Ang II infusion recapitulate these features, showing aggravated lung injury with macrophage accumulation and MMP-9 overexpression compared to BAPN-only controls.

Mechanistic studies reveal Ang II drives lung injury through two parallel pathways: AT1-R-mediated macrophage recruitment (demonstrated by attenuated pulmonary infiltration following AT1-R blockade despite persistent MMP-9 elevation) and NF-κB-dependent upregulation of MCP-1 in PMVECs, which drives chemotaxis of MMP-9-expressing macrophages (28, 29). Macrophages recruited via these pathways exacerbate vascular permeability through MMP-9-mediated endothelial damage and neutrophil infiltration (32). Concurrently, upregulated MCP-1 induces PMVECs apoptosis via B-cell lymphoma-2 (Bcl-2)/BCL-associated X (Bax) imbalance and caspase-3 activation, further compromising pulmonary microvascular integrity (29). Although the aforementioned studies did not delineate the relative contributions of Ang II-AT1-R binding and MCP-1 elevation in driving MMP-9-expressing macrophages recruitment to the lungs, establishing MCP-1 and MMP-9 as key mediators of Ang II-driven lung injury during the preoperative phase of AAD supports their potential as early predictive biomarkers and therapeutic targets. In addition, Wu et al. found that the expression level of vascular endothelial cadherin (VE-cadherin) is closely related to the apoptosis and skeletal rearrangement of PMVECs induced by Ang II, while the dephosphorylation of Y685-VE-cadherin is involved in Ang Ⅱ-mediated pulmonary microvascular endothelial barrier injury (30, 33). These discoveries also sheds new light on the mechanisms and potential interventions for AAD-inducedARDS (Figure 1).

HMGB1 is a nuclear nonhistone protein with a potent pro-inflammatory effect, secreted from the nucleus to the extracellular environment through the non-classical or passive release under stress response (34). It binds to the receptor for advanced glycation end products (RAGE) and activates the MAPK signalling pathway. The phosphorylation of the downstream p38MAPK and the activation of NF-κB lead to the release of several pro-inflammatory factors (35). The activation of the HMGB1/RAGE signalling pathway is a pivotal link in the inflammatory cascade and a crucial mediator of lung injury induced by various factors (36, 37).

Elevated serum HMGB1 levels are associated with both AAD progression and the development of AAD-inducedARDS. At 24 h post-admission, plasma levels of HMGB1 and RAGE were significantly elevated in all AAD patients compared to controls (P < 0.05), with notably higher concentrations in the ALI subgroup than in the non-ALI (P < 0.05). During the 96-hour monitoring period, both groups exhibited a progressive increase in HMGB1/RAGE levels alongside a concurrent decline in PaO₂/FiO₂ ratios. The ALI patients consistently demonstrated more severe dysregulation in these parameters at all timepoints (P < 0.05). Spearman analysis revealed strong negative correlations between the PaO₂/FiO₂ ratio and both HMGB1 (r = −0.978) and RAGE (r = −0.944), while HMGB1 and RAGE themselves showed a strong positive correlation (P < 0.001 for all) (38). These findings suggest that dynamic monitoring of HMGB1/RAGE trajectories provides critical prognostic insights for ALI risk stratification in AAD. However, this study did not comprehensively investigate the mechanisms underlying the elevated HMGB1 levels observed in the ALI subgroup compared to non-ALI subjects. Beyond the fundamental pathological processes of AAD, additional pivotal factors may contribute to HMGB-drivenARDS. This hypothesis is supported by evidence showing HMGB1's involvement in alternative lung injury pathways triggered by distinct etiological mechanisms. For instance, intestinal I/R injury, a potential secondary complication of AAD, has been shown to induce necroptotic enterocyte-derived HMGB1 release, promoting lung injury through neutrophilic inflammation and neutrophil extracellular trap formation via the Toll-like receptor 4/myeloid differentiation factor 88 (TLR4/MyD88) signaling pathway (39). The coexistence of such multifactorial mechanisms underscores the complexity of HMGB-driven ARDS pathogenesis in AAD patients, necessitating a more holistic approach to fully elucidate these mechanisms.

During aortic intimal tear in AAD, blood directly contacts the aortic media's extracellular matrix, triggering a defense response. This results in the release of inflammatory cytokines by immune cells and endothelial cells, along with tissue factor (TF) from endothelial cells due to vascular injury. Excessive TF not only induces a great production of inflammatory factors by endothelial cells, but also initiates the extrinsic coagulation pathway, the latter inducing extensive thrombus formation in the false lumens, subsequently triggering hyperfibrinolysis (40). These processes may lead to pulmonary microthrombosis and alveolar fibrin deposition (41, 42). The excessive release of inflammatory factors further increases the secretion of TF by activating the NF-κB pathway, leading to the occurrence of the coagulation cascade (41, 43). Alveolar epithelial cells and alveolar macrophages (AMs) also activate the coagulation process in the alveoli by upregulating TF activity (44, 45). These intricate and intersecting mechanisms associated with TF are involved in the pathogenesis of AAD-induced lung injury (Figure 2). Gao et al. reported that significantly increased levels of TF (F = 133.67, P < 0.001; F = 68.14, P < 0.001) and tissue factors pathway inhibitor (TFPI) (F = 31.98, P < 0.001; F = 45.58, P < 0.001) in both serum and bronchoalveolar lavage fluid (BALF) among preoperative Stanford type-A aortic dissection (ST-AAD) patients with ALI compared to those without. Furthermore, a significant association exists between oxygenation impairment and levels of TF in both serum and BALF in preoperative AAD patients (40). Despite the elevation in TFPI concentration, it remains much lower than that of TF (about 1% of TF's concentration). This may deplete the TFPI pool in endothelial cells, leaving insufficient TFPI to neutralize TF and reverse its coagulation activation.

Plasminogen activator inhibitor-1 (PAI-1), the predominant fibrinolysis inhibitor through plasmin suppression, drives lung injury through various mechanisms including the following. PAI-1 promotes fibrin deposition and αIIbβ3 integrin-dependent platelet aggregation, forming prothrombotic niches (46, 47). Additionally, PAI-1 enhances pulmonary inflammation by regulating inflammatory signaling pathways such as MyD88/NF-κB activation and interleukin-1 receptor-associated kinase M/suppressor of cytokine signaling 1 suppression (48, 49). Moreover, elevated PAI-1 level is also associated with endothelial barrier dysfunction and the development of pulmonary edema (50). Preoperative ST-AAD patients with ALI have persistently higher levels of PAI-1 in serum and BALF compared to those without ALI (F = 213.88, P < 0.001; F = 107.95, P < 0.001). The concentration of PAI-1 in BALF is significantly higher than that in the serum. Moreover, a significant association is present between PAI-1 levels in BALF and oxygenation impairment among patients with ST-AAD (40). The aforementioned results uncovered a pertinent phenomenon: in ST-AAD patients, systemic hyperfibrinolysis coexists with the inhibition of fibrinolysis due to elevated levels of PAI-1. However, the impact of pulmonary PAI-1 on oxygenation is primarily mediated through its localized upregulation, as evidenced by two key findings: (1) Lung-derived PAI-1 from alveolar cells (including macrophages and epithelial cells) directly promotes fibrin deposition in pulmonary tissue (47, 51); (2) Targeted anticoagulation through inhaled heparin effectively reduces pulmonary fibrin formation and microvascular thrombosis (52, 53). This spatial specificity confirms the predominant role of local pulmonary mechanisms rather than systemic effects.

Notably, this prospective study is primarily limited by its small sample size, single-center design, and the lack of BALF data at specific timepoints, which may have omitted valuable insights. Consequently, while the findings of this study provided evidence suggesting an association between elevated TF and PAI-1 levels and AAD-induced ARDS, their prognostic value remains to be validated in larger, multi-center cohorts.

Qin et al. (54) found that AAD canine models possess increased mean platelet volume (MPV)/platelet count and platelet size distribution width, indicating the presence of activated platelet. They performed the dynamic monitoring of both platelet activation levels and systemic inflammatory markers, identifying the simultaneous onset of platelet activation and systemic inflammation. Furthermore, activated platelets are involved in the occurrence of post-dissection inflammation (55). Patients with AAD also show a decreased platelet count (56, 57). Patients with a shorter duration of disease onset show a lower platelet count upon admission, especially within 3 days. Following aortic intimal injury, platelets are the first responders adhering to disrupted endothelial surfaces, with subsequent leukocyte recruitment contributing to false lumen thrombosis (58, 59). This process leads to subsequent consumption of platelets. Activated platelets mediate thrombo-inflammation through dual modulation of coagulation cascades and inflammatory signaling, establishing a self-perpetuating pathological milieu characteristic of aortic dissection progression.

Clinical studies suggest platelet hyperactivation post-AAD may contribute to hypoxemia and ALI. A single-center, prospective cohort study revealed that, compared with the low MPV/platelet count group, patients in the high MPV/platelet count group had a significantly higher risk of hypoxemia (all P < 0.05) (59). Pan et al. (60) revealed an increase in platelet-mediated thromboxane B2 (TXB2) production and corresponding changes in the prostaglandin I2 (PGI2)/TXB2 ratio in patients with AAD who develop ALI. Moreover, the imbalance in the above ratio is an independent risk factor associated with preoperative ALI in AAD. Platelets undergo activation after the initiation of AAD and subsequently release thromboxane A2 (TXA2), while TXB2 serves as the stable metabolite of TXA2. The production of TXA2 induces platelet aggregation and vasoconstriction, whereas PGI2 works in the opposite manner. Therefore, the excessively activated platelets after AAD onset may enhance coagulation by releasing TXA2, thereby contributing to lung injury. Notably, activated platelets are involved in the procoagulant process through various mechanisms, with TXA2 being just one of them. Whether additional procoagulant mechanisms mediated by platelet activation contribute to the development of AAD-induced ARDS requires further investigation.

In addition, activated platelets exacerbate lung inflammation by interacting with endothelial cells, and immune cells [such as polymorphonuclear leukocytes (PMNs) and monocytes] via pro-inflammatory mediators (61, 62), thereby amplifying alveolar-capillary barrier damage and vascular permeability (63). When platelet counts decrease, the loss of platelet-derived protective signals impairs endothelial barrier integrity, leading to fluid and protein leakage in both pulmonary and systemic microvasculature (64). Although platelet-mediated mechanisms of pulmonary inflammatory injury have been well documented in lung injury induced by multiple etiologies (65, 66), there is currently not enough evidence (preclinical or clinical) demonstrating their direct involvement in AAD-induced ARDS. In addition, due to methodological constraints (e.g., studies combining surgically/non-surgically managed patients with undocumented hypoxemia timelines) (59), current clinical evidence linking activated platelets to AAD-induced ARDS requires further identification.

Organ hypoperfusion occurs when an aortic dissection involves branch arteries. The rigorous blood pressure control measures are aimed at preventing further deterioration of aortic dissection, potentially exacerbating tissue and/or organ malperfusion in patients with chronic hypertension who have adapted to the state of hyper-perfusion. The systemic hypoperfusion associated with AAD, particularly when the dissection involves critical vascular branches including the celiac artery, superior mesenteric artery, and inferior mesenteric artery, contributes to the development of intestinal I/R injury (67).

Intestinal I/R initiates systemic and lung injury through interconnected pathways. First, disruption of the intestinal mucosal barrier facilitates bacterial/endotoxin translocation into systemic circulation, activating the TLR4/NF-κB pathway to amplify systemic inflammation (68, 69). Concurrently, intestinal I/R downregulates N-Myc downstream-regulated gene 2 in pulmonary endothelial cells, exacerbating apoptosis and NF-κB-driven inflammatory cascades (70). The gut-lung axis further contributes via microbiota dysbiosis and succinate imbalance. Elevated levels of succinate accumulates in the lungs, promoting M1-polarization of AMs through succinate receptor 1-mediated activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/hypoxia-inducible factor 1-alpha (HIF-1α) pathway, thereby aggravating lung injury (71). Second, mesenteric lymph transports pro-inflammatory mediators like eicosanoids (leukotriene B4, TXB2) and cytokines, upregulating endothelial E-selectin and boosting leukocyte adhesion. TXB2 also triggers platelet aggregation and vasoconstriction, worsening pulmonary microvascular permeability and edema (72, 73). These mediators also activate systemic NF-κB signaling, upregulating neutrophil CD11b expression and cytokine production, ultimately driving neutrophil infiltration and microvascular dysfunction (74). Emerging evidence suggests ferroptosis of AT2 cells, mediated by NF-E2-related factor 2 signalling, contributes to intestinal I/R-induced lung injury in vivo (75). Collectively, the aforementioned mechanisms ultimately contribute to the development of systemic inflammatory response syndrome and lung injury through the synergistic effects of persistent inflammation, microthrombosis, vascular leakage, and cell death (Figure 3).

While the mechanisms of intestinal I/R injury contributing to lung injuryhave been elucidated in animal models and in vitro studies, these findings have yet to be further validated in experimental AAD models or more clinical mechanistic investigations. Previous studies have suggested an association between aortic dissection involving the celiac trunk/mesenteric arteries and preoperative hypoxemia (7), potentially mediated by gut-originated inflammation. Furthermore, emerging researches have demonstrated that intestinal barrier dysfunction occurring subsequent to AAD is implicated in SIR and lung injury providing preliminary insights into the interplay mechanism between gut and lung injuries following AAD (68, 76, 77). However, the scientific validity and methodological rigor of the aforementioned study design and its conclusions warrant critical scrutiny. Notable limitations include the absence of controlled exclusion of confounding factors (e.g., systemic hypoperfusion, direct gastrointestinal vascular compromise by dissection) and incomplete assessment of I/R injury biomarkers (e.g., oxidative stress markers, lactate, creatine kinase, lactate dehydrogenase). Consequently, the temporal relationships and pathophysiological interplay among SIR, intestinal injury, and lung injury following AAD require further mechanistic exploration.

Currently, there are no specific biomarkers recommended for the early identification and diagnosis of AAD-induced ARDS. Based on the latest guidelines for ARDS, a diagnosis of AAD-induced ARDS should be considered when the following conditions are met: (1) Precipitated by AAD onset; (2) Acute onset or worsening of hypoxemic respiratory failure within 1 week of AAD onset; (3) Using the PaO₂/FiO₂ ≤ 300 mmHg or pulse oximetry SpO₂/FiO₂ ≤ 315 to identify hypoxemia; (4) Pulmonary edema is not primarily attributable to either cardiogenic factors (e.g., from left ventricular dysfunction or aortic regurgitation) or fluid overload; and hypoxemia/gas exchange abnormalities are not primarily attributable to atelectasis; (5) Bilateral infiltrates on chest radiography and computed tomography or bilateral B lines and/or consolidations on ultrasound. (6) Exclusion criteria were ARDS induced by other causes, and exacerbation of chronic lung diseases (10, 11).

Apart from diagnostic criteria, various monitoring methods are essential for clinical assessment, including respiratory status (respiratory rate and depth), pulse oximetry and/or arterial blood gas analysis (PaO₂/FiO₂ or SpO₂/FiO₂ ratios), computed tomography angiography and non-contrast chest CT (demonstrating the “dual signs” of aortic dissection and ground-glass opacities), and cardiopulmonary ultrasound (assessing cardiac structure/function and pulmonary B-lines). A review of the existing literature suggests that several readily available and cost-effective biomarkers show promise for early identification. These include markers of inflammation (e.g., AAD%, CRP and IL-6) (6, 7), and platelet activation (MPV/platelet count ratio) (59). Although preliminary evidence from single-center, small-scale studies suggests that some biomarkers (e.g., Ang II, MCP-1, MMP-9, HMGB1/RAGE, TF, PAI-1, TXB2 and PGI2/TXB2 ratio) may have value in identifying patients and stratifying risk, their translation to routine clinical screening remains limited by the challenges of standardization, cost, and the need for validation in larger, prospective cohorts (28–30, 38, 40, 60). Beyond these, biomarkers like AT1-R and VE-cadherin (including pY685-VE-cadherin), while mechanistically linked to AAD-induced lung injury in preclinical models, represent a more nascent area of research (30, 33) (Supplementary Table S2). From a different methodological perspective, recent advances in serum metabolomics, derived from studies of ALI, provide novel insights into investigating the pathogenesis and potential predictors for AAD-induced lung injury (82).