During a right upper and middle lobe resection surgery seven years ago, the patient's right pulmonary artery main trunk was inadvertently ligated. However, the right lower lobe of the patient did not completely undergo necrosis but was maintained by blood supply from other arteries branching out. First and foremost, we need to understand why the right lower lobe of the lung did not immediately undergo necrosis after the ligation of the right pulmonary artery. We believe this may be related to the dual blood supply of the lung. Charan and colleagues' study demonstrated in an experimental study involving 13 sheep that unilateral pulmonary artery ligation resulted in an increase in bronchial blood flow approximately four days after the ligation. The bronchial artery diameter was about three times that of the control value within one week and reached its maximum diameter in approximately four weeks. In dogs, after 12 weeks of unilateral pulmonary artery ligation, the bronchial artery vessels exhibited similar dilation and curvature. The dilated bronchial arteries were capable of supplying up to two-thirds of the normal pulmonary artery blood flow. Furthermore, they observed that significant vascular growth in the bronchial circulatory system was consistently accompanied by the curvature of the bronchial arteries. An explanation for this could be that during the process of vascular growth, the bronchial arteries not only increase in diameter but also in length, resulting in vascular curvature(4). Weibel et al. observed bronchial artery enlargement under macroscopic and microscopic examination. They believed that the compensatory enlargement of the bronchial arteries was induced by the increased bronchial artery blood flow(5). When the pulmonary artery experiences partial or complete occlusion, there is a significant drop in pressure at its distal end, which can create a siphoning effect, allowing the "stealing" of blood from adjacent vessels through arterial collateral branches. The blood from nearby vessels is "stolen," leading to the development of arterial or arteriolar anastomoses. These anastomoses widen for several reasons, with the most apparent being local ischemia due to the accumulation of metabolic end-products (such as CO2)(6). This is referred to as bronchial artery blood stealing. Heil et al. on the other hand, elucidated the process of bronchial artery remodeling. They believed that the success of bronchial artery remodeling depended on the following conditions: (1) the existence of arteriolar networks connecting the pre-anastomosis and post-anastomosis microcirculation;(2) Activation of arteriolar endothelium through increased fluid shear stress; (3) infiltration (but not incorporation) of bone marrow-derived cells; and (4) proliferation of endothelial cells and smooth muscle cells. They believed that arterial occlusion increases collateral artery pressure gradient, thereby elevating fluid shear stress, resulting in endothelial cell activation and cell swelling, upregulation of adhesion molecules, mitogenic factors, prothrombotic factors, and fibrinolytic factors, ultimately leading to monocyte invasion through matrix digestion. Smooth muscle cell migration and proliferation cause bronchial arteries to expand under the influence of increased circumferential wall stress. The increase in vessel diameter and thickening of the vessel wall restore fluid shear stress and circumferential wall stress to normal levels, resulting in the cessation of vascular growth(7). Mitzner found that compensatory growth in the bronchial circulation within 1–3 days after blocking pulmonary artery blood flow in all mammals can increase to 30% of the original lung blood flow. However, the bronchial circulation is perfused with already oxygen-saturated systemic arterial blood and only has minimal additional oxygen uptake. Therefore, it does not play a significant role in gas exchange under physiological conditions(4). Hence, we believe that in the early stages of pulmonary artery ligation, it's not just the bronchial arteries supplying blood to the remaining lung tissue. The lack of early necrosis in the right lower lobe is also thought to be associated with the left atrium. Fieldes et al. suggest that in the early stages of pulmonary artery main trunk ligation, a possible source of pulmonary blood supply could be retrograde perfusion from the left atrium. Retrograde perfusion must be sufficient to meet the metabolic demands of lung tissue during acute pulmonary ischemia(8). We believe that in the early stages of right pulmonary artery ligation in this patient, compensatory growth and thickening of the bronchial arteries provide increased blood flow to the lung tissue. Additionally, due to reduced pulmonary venous pressure, the left atrium begins retrograde perfusion into the right lower lobe of the lung. Both these vessels together ensure blood supply to the right lower lobe.
Secondly, arterial angiography and enhanced chest CT in the patient revealed that the subclavian artery, intrathoracic arteries, intercostal arteries, and inferior diaphragmatic artery, among other vessels, supply blood to the right lower lobe of the lung. The parietal pleura is supplied by vessels like the intercostal arteries, intrathoracic arteries, and subclavian arteries, whereas the arterial supply to the visceral pleura comes from the bronchial arteries(9). In normal individuals, these non-bronchial systemic arteries do not send branches to nourish the lung lobes. So, in the case of right pulmonary artery ligation, how does lung tissue receive a blood supply from these non-bronchial systemic arteries for the development of new vessels? Yu et al. found that diseases involving the pleura are more likely to lead to non-bronchial systemic artery development through the pleura(10). The 6 cases studied by Maini et al. demonstrated the generation of non-bronchial systemic arteries in chronic inflammatory diseases such as tuberculosis and pulmonary aspergillosis. Among them, the intrathoracic arteries were observed in 4 cases, intercostal arteries in 2 cases, extrathoracic arteries in 2 cases, and one case each of subclavian, thyroid cervical, and inferior diaphragmatic arteries. Furthermore, the proliferation of non-bronchial systemic circulation arteries depends on the location of the lesion. When the lesion is situated in the pulmonary parenchyma, especially near the pleura, it may be more likely to trigger the proliferation of non-bronchial systemic arteries in the vicinity of the lesion. These non-bronchial systemic circulation arteries can lead to hemoptysis(11). Yu et al. analyzed and detected 42 non-bronchial systemic arteries in 39 patients, including 19 internal mammary artery branches, 8 subclavian artery branches, 5 intercostal artery branches, 1 thyroid cervical trunk branch, and 1 abdominal trunk branch. There were 35 dilated and tortuous non-bronchial systemic arteries entering the lung parenchyma. Apart from one isolated case, all instances were associated with pleural thickening, and the vascular structures at the site of pleural thickening penetrated the extrapleural fat(10). Yoon et al. clarified that the cause of hemoptysis in patients was non-bronchial systemic circulation arteries by comparing enhanced CT scans in patients with and without hemoptysis, which revealed pleural thickening and enlargement of extrapleural fat vascular structures near lung parenchymal lesions(12). Wagner found that new blood vessels formed within the thickened pleura of the upper left lung four days after left pulmonary artery ligation. This indicates that the new blood vessels originate from intercostal arteries at the site of chest wall wound healing and invade the visceral pleura of the ischemic upper left lung(13). Mesurolle et al. found that in patients with chronic pleuritis, the extrapleural fat layer thickens significantly in enhanced CT scans. In enhanced CT scans, curved tubular enhancing structures are easily visible, and non-bronchial systemic blood vessels may enlarge. They suggest that CT examination revealing pleural thickness exceeding 3 mm and the presence of systemic blood vessels within the extrapleural fat layer should be considered as CT criteria for the presence of non-bronchial systemic circulation arterial supply(14). Tamura et al. found that in cases of pleural thickening, non-bronchial systemic circulation blood vessels originating from various arteries, such as intercostal arteries, subclavian artery, axillary artery branches, and inferior diaphragmatic artery, would develop and enlarge due to the inflammatory process(15). Therefore, it can be inferred that the formation of non-bronchial systemic circulation arteries in the lung is related to pleural thickening. Akahane et al. discovered, through computer-based three-dimensional reconstruction, that several branches of the intercostal arteries enter the subpleural area through adhesive regions of the pleura; they move towards the membranous peripheral bronchi located in the resected lung lobe. These dense fibrous bands connect the lung lobe to the chest wall. The high vascular lesions themselves have been shown to consist of dilated vessels with a diameter of 200 mm. These vessels are situated directly beneath the bronchial mucosa's basement membrane, protruding into their lumens in a polypoid lesion-like form(16). Maini et al. also found that in chronic inflammatory lung diseases, non-bronchial systemic arteries can reach the lung parenchyma through adhesions formed in the pleura during the inflammatory process and anastomose with the pulmonary arterial circulation(11). The above findings indicate that blood vessels supplying the parietal layer of the pleura can penetrate the visceral layer of the pleura and supply lung tissue due to pleural thickening and adhesions. However, Fadel et al. conducted pulmonary artery ligation through sternotomy, preventing the development of pleural lung adhesions. Still, the intercostal arteries facilitated vascular growth(8). This suggests that pleural adhesions are not the determining factor for the development of non-bronchial systemic arteries. Mitzner et al.'s research in mice indicates that intercostal arteries serve as a source for new blood vessel formation in the lung following left pulmonary artery ligation. They found that the intercostal arteries near the ischemic lung form dense vascular networks, bridging the pleural space and invading the lung parenchyma(17). Pathological studies of resected specimens by Akahane showed that arteries from the extrapleural space penetrate the pleura and extend into the lung parenchyma. These arteries connect with the arteriovenous plexus located just beneath the thin wall of the small bronchi(18). However, how non-bronchial systemic arteries like intercostal arteries penetrate the visceral pleura and provide blood supply to the ischemic lung remains a question. Bergers et al. proposed that vascular genesis originates from pre-existing capillaries or post-capillary venules. In the process of neovascularization, the basement membrane and extracellular matrix are initially locally degraded to allow endothelial cells beneath to migrate into the perivascular space in response to angiogenic stimuli. Subsequently, endothelial cells proliferate and loosely follow one another into the perivascular space, forming a migration pillar. The perivascular cells then detach, and the vessel expands; endothelial cells migrate in the direction of the angiogenic stimulus. They then proliferate along the direction of vessel formation, possibly guided by surrounding cells. Endothelial cells adhere to each other, forming a lumen, accompanied by the development of the basement membrane and attachment of surrounding cells. Finally, vascular buds fuse with others, establishing a new circulatory system(19). Herve et al. propose that when pulmonary arteries are occluded, the lung likely requires both angiogenesis to connect the systemic circulation with the ischemic pulmonary microcirculation and arteriogenesis to increase pulmonary collateral flow from systemic sources. Angiogenesis involves the differentiation of endothelial progenitor cells derived from circulating bone marrow into mature endothelial cells, contributing to the formation of new vessels in response to ischemia. On the other hand, vascular genesis involves the remodeling of established capillary networks to create new capillaries, while arteriogenesis includes the development of collateral arteries from pre-existing small artery connections. They suggest that arteriogenesis is initiated by physical forces (such as fluid shear stress) and vascular remodeling related to monocyte-macrophage activity. Macrophages are likely to play a central role in tissue remodeling and the recruitment of ischemic pulmonary vascular circulation(20). Various cytokines are required to promote pleural permeability and stimulate vascular genesis in non-bronchial systemic arteries. VEGF mRNA and protein increase in the early stages after left pulmonary artery occlusion, indicating its role in early vascular genesis in response to pulmonary ischemia. Interleukin genes (IL-6, IL-1), three CXC chemokines (Macrophage Inflammatory Protein-2, Keratinocyte-Derived Chemokine, and Lipopolysaccharide-Induced CXC Chemokine) all increase within 24 hours after left pulmonary artery ligation. These cytokines are likely involved in the generation of non-bronchial systemic arteries in ischemic lung tissues(20). Peppa et al. discovered that VEGF has a direct impact on the pleura and, by stimulating VEGFR2, can increase the pleural permeability in both healthy sheep's visceral and parietal pleura, facilitating the penetration of new blood vessels. They believe that the mechanism by which VEGFR-2 increases pleural permeability may involve VEGFR-2 activating its downstream signaling cascade, including PI3K, leading to the upregulation of EphA2, thus increasing paracellular permeability/Akt and ERK1/2 in nearby cells(21). Wagner's research indicates that the visceral pleura is enhanced through the renewal and/or remodeling of new blood vessels connecting to pre-existing capillaries. Proliferating cell nuclear antigen (PCNA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) positive cell levels significantly increase, and mesenchymal cells also demonstrate increased proliferation and apoptosis. Sánchez et al. discovered that treating mice with neutralizing antibodies against CXCR2 resulted in reduced formation of new blood vessels following left pulmonary artery ligation. They suggested that the chemokine factor CXCR2 contributes to the induced systemic blood vessel formation after pulmonary artery obstruction(22). Nijmeh et al. furthered that ROS (reactive oxygen species) influences endothelial cell migration, proliferation, and vascular formation. Their view is that ROS triggers a series of pro-angiogenic events by altering the transcription factor NF-κB's redox state, leading to NF-κB pathway activation. Once translocated into the cell nucleus, NF-κB can promote genes responsible for cell proliferation and angiogenesis, such as CXC chemokines. Through this pathway, NF-κB plays a role in ischemia-induced vascular formation(22).
The third point is that, during the chronic ischemic process following pulmonary artery ligation, the bronchial arteries undergo continuous remodeling, giving rise to new bronchial arteries. Weibel et al. described how regions devoid of granulation tissue can prompt the development of new bronchial arteries in those areas. The original bronchial arteries are comprised of a solid cell cord that quickly gets enveloped by spindle-shaped cells. The cell cord, by creating a tube, undergoes secondary differentiation into an endothelial tube, thus producing new bronchial arteries(5). Cytokines play a role in the generation of bronchial arteries. Charan et al. suggest that endothelin-1 might have a role in the bronchial vascular formation that occurs following pulmonary artery blockage(4). Perino et al. propose that vascular generation in the lungs is triggered by an inflammatory response, particularly the upregulation of CXC chemokines. The cytokine CXCL2 and its high-affinity receptor CXCR2 are involved in the entire process of bronchial vascular generation following pulmonary hypoxia(23).
Fourth, we aimed to determine the cause of persistent hemoptysis in this patient. Some suggest that when the pulmonary circulation is compromised, bronchial supply gradually increases, leading to hyperemia in anastomotic vessels, the proliferation of anastomotic vessels, thinning of their walls, and a tendency to rupture into alveoli and bronchi, thereby causing hemoptysis(24). We believe this is the primary reason for early hemoptysis after pulmonary artery ligation. Once the patient passes the early high-risk phase for hemoptysis, non-bronchial systemic arteries begin to form. When the lesion comes into contact with the pleura, various non-bronchial systemic circulatory arteries near the lesion can develop within the lung parenchyma through adhesive pleura, leading to hemoptysis(11). The patient also has concurrent pulmonary aspergillosis, which is considered a significant factor leading to the patient's hemoptysis. Patients with pulmonary aspergilloma often lack specific clinical manifestations and may exhibit no evident systemic symptoms. Most cases present with chronic cough, general discomfort, weight loss, and hemoptysis(25). Hemoptysis is considered the most common symptom of this condition, reported in around 50–90% of cases. Severe hemoptysis often poses life-threatening risks, and approximately 2–10% of pulmonary aspergilloma patients die due to massive hemoptysis. Emergency surgical intervention is required in the event of significant hemoptysis(26). Some perspectives suggest that aspergillomas may cause bleeding due to the purulent inflammation of granulomatous tissue. Moreover, the active enzymes and toxins produced by the fungus can lead to the erosion of blood vessels, resulting in tissue vascular necrosis and subsequent bleeding(27). Hu et al. summarized the primary causes of hemoptysis due to aspergillomas, including: (1) Inflammatory reactions around the cavity wall and the surrounding lung tissue caused by aspergillomas, leading to secondary vascular abnormalities and the formation of an extensive vascular network. Mechanical movement or friction of the aspergillomas within the cavity with the rich vascular network or vascular tumor on the cavity wall can cause vascular rupture and bleeding. (2) The endotoxins and proteolytic enzymes produced by the aspergillus cause tissue vascular necrosis and dissolution, leading to bleeding; (3) Stimulated by inflammatory damage, changes within the cavity lead to bleeding; (4) Concurrent bronchiectasis on the basis of tuberculosis can cause bleeding(28). For treating hemoptysis, standard approaches involve conservative treatment, bronchoscopy for examination and treatment, arterial embolization through angiography, and surgical intervention(29). For treating hemoptysis, standard approaches involve conservative treatment, bronchoscopy for examination and treatment, arterial embolization through angiography, and surgical intervention(29). The goal of bronchoscopy is to identify the site of hemoptysis and specifically isolate the affected area by occluding the related bronchus. However, in cases of severe bleeding, it can be challenging to identify the exact source of bleeding through bronchoscopy. Prolonged bronchial occlusion during the procedure might lead to infections after occlusion(29). Transcatheter arterial embolization (TAE) is the preferred method for treating severe or recurrent massive hemoptysis(29). Due to the existence of non-bronchial systemic arteries, embolization procedures might lead to increased blood flow from other arteries, resulting in continued hemoptysis(30). The surgical approach includes reopening the ligated artery to restore blood flow. However, this method is only effective in the early stages of artery ligation(30). Surgical removal of lung tissue is applicable when bronchial artery embolization fails or in specific cases like traumatic or iatrogenic lung vascular injuries. Complete removal of the bleeding source signifies that surgical excision is a definitive curative surgery with good long-term outcomes(29). Chen et al. suggest that once aspergilloma forms, antifungal medications are ineffective. In some patients, fatal massive hemoptysis can suddenly occur without warning. Surgical treatment offers a chance for a definitive cure(31).