Common pathogenesis for sirenomelia, OEIS complex, limb-body wall defect, and other malformations of caudal structures.

Decades of clinical, pathological, and epidemiological study and the recent application of advanced microarray and gene sequencing technologies have led to an understanding of the causes and pathogenesis of most recognized patterns of malformation. Still, there remain a number of patterns of malformation whose pathogenesis has not been established. Six such patterns of malformation are sirenomelia, VACTERL association, OEIS complex, limb-body wall defect (LBWD), urorectal septum malformation (URSM) sequence, and MURCS association, all of which predominantly affect caudal structures. On the basis of the overlap of the component malformations, the co-occurrence in individual fetuses, and the findings on fetal examination, a common pathogenesis is proposed for these patterns of malformation. The presence of a single artery in the umbilical cord provides a visible clue to the pathogenesis of all cases of sirenomelia and 30%-50% of cases of VACTERL association, OEIS complex, URSM sequence, and LBWD. The single artery is formed by a coalescence of arteries that supply the yolk sac, arises from the descending aorta high in the abdominal cavity, and redirects blood flow from the developing caudal structures of the embryo to the placenta. This phenomenon during embryogenesis is termed vitelline vascular steal.

Endothelial Hypoxia-Inducible Factor-2α Is Required for the Maintenance of Airway Microvasculature.

BACKGROUND: Hypoxia-inducible factors (HIFs), especially HIF-1α and HIF-2α, are key mediators of the adaptive response to hypoxic stress and play essential roles in maintaining lung homeostasis. Human and animal genetics studies confirm that abnormal HIF correlates with pulmonary vascular pathology and chronic lung diseases, but it remains unclear whether endothelial cell HIF production is essential for microvascular health. The large airway has an ideal circulatory bed for evaluating histological changes and physiology in genetically modified rodents. METHODS: The tracheal microvasculature of mice, with conditionally deleted or overexpressed HIF-1α or HIF-2α, was evaluated for anatomy, perfusion, and permeability. Angiogenic signaling studies assessed vascular changes attributable to dysregulated HIF expression. An orthotopic tracheal transplantation model further evaluated the contribution of individual HIF isoforms in airway endothelial cells. RESULTS: The genetic deletion of Hif-2α but not Hif-1α caused tracheal endothelial cell apoptosis, diminished pericyte coverage, reduced vascular perfusion, defective barrier function, overlying epithelial abnormalities, and subepithelial fibrotic remodeling. HIF-2α promoted microvascular integrity in airways through endothelial angiopoietin-1/TIE2 signaling and Notch activity. In functional tracheal transplants, HIF-2α deficiency in airway donors accelerated graft microvascular loss, whereas HIF-2α or angiopoietin-1 overexpression prolonged transplant microvascular perfusion. Augmented endothelial HIF-2α in transplant donors promoted airway microvascular integrity and diminished alloimmune inflammation. CONCLUSIONS: Our findings reveal that the constitutive expression of endothelial HIF-2α is required for airway microvascular health.

Real-time confirmation of tracheal decompression.

AIMS: The primary objective was to highlight the role of intraoperative bronchoscopic guidance during the management of central airway obstruction. MATERIALS & METHODS: A 6-month-old child presented with recurrent chest infections due to innominate artery compression of distal trachea. Aortopexy was performed under real-time bronchoscopic guidance. RESULTS: Intraoperative bronchoscopic guidance helped in confirm a successful release of the central airway obstruction. DISCUSSION: When operations similar to aortopexy are performed for release of airway obstructions, intraoperative bronchoscopic guidance is a valuable tool for confirming a successful outcome. CONCLUSION: The successful surgical management of central airway obstruction due to an innominate artery compression of the distal trachea under real-time bronchoscopic guidance in a 6-month-old child is described.

Three-dimensional printing for surgical planning of a double aortic arch case.

BACKGROUND AND AIM: Over the past years, three-dimensional (3D) models of patient-specific anatomical conditions are being used to improve the comprehension and surgical management of a variety of diseases. It is an additional diagnostic tool that aids clinical decision-making. Furthermore, this technology is still not routinely used in the medical field since its availability is limited by cost and complex process. METHODS AND RESULTS: We describe a patient with a balanced-type double aortic arch encircling trachea and esophagus. Considering the clinical symptoms, surgical decompression of these structures and defined aortic arch reconstruction was indicated. The 3D printed model revealed narrowing of the left aortic arch at the junction of the descending thoracic aorta that did not clearly appear on the conventional images reconstruction. The left aortic arch was divided and the symptoms completely disappeared. No immediate or late complications occurred. CONCLUSION: 3D printed models can be helpful in surgical planning of congenital heart malformations. It should be strongly considered as an additional tool in complex cases.

Indocyanine Green Fluorescence Imaging of the Tracheal Blood Flow During Esophagectomy.

BACKGROUND: Tracheobronchial ischemia and necrosis are uncommon causes of pulmonary complications that can be lethal on development. Surgical manipulation considering tracheal blood flow is important in radical esophagectomy with extensive lymph node dissection. This study introduces a novel method for assessing tracheal blood perfusion using indocyanine green (ICG) fluorescence imaging. MATERIALS AND METHODS: Twenty patients who underwent esophagectomy with lymph node dissection for esophageal cancer were prospectively enrolled in this study. Tracheal blood flow after esophagectomy was quantitatively assessed using ICG fluorescence imaging. Region-of-interest software was used, and a time-intensity curve was created for the quantitative assessment of tracheal blood flow. RESULTS: We assessed ICG fluorescence imaging of the trachea during esophagectomy for esophageal cancer in all 20 cases. In the quantitative assessment of this pilot study, postoperative tracheal ischemic change and sputum discharge disorder tended to be associated with decreased tracheal blood flow (P = 0.084, P = 0.044). Resection of the right bronchial artery (BA) tended to be associated with decreased tracheal blood flow (P = 0.109), but the preoperative treatment, including chemotherapy and chemoradiotherapy, did not influence tracheal blood flow (P = 0.861, P = 0.435). The subgroup analysis of the preoperative chemoradiation group showed that the tracheal blood flow was significantly reduced with right BA resection compared with right BA preservation (P = 0.049). CONCLUSIONS: We assessed ICG fluorescence imaging of the trachea during esophagectomy for esophageal cancer. Further studies are needed to explore the significance of the assessment of tracheal blood flow during esophagectomy using ICG fluorescence imaging.

Prevalence of major vessels anterior to the trachea at sites of potential front-of-neck emergency airway access in adults.

BACKGROUND: Several case reports have described anatomical variations that can cause difficulty with front-of-neck airway access, such as major vessels anterior to the trachea. The prevalence of these anomalies is unknown. METHODS: We screened 500 consecutive thoracic computed tomography (CT) scans in adult patients performed independently in any public hospital in Western Australia. The prevalence of major vessels anterior to the trachea in the anterior triangle of the neck was determined. RESULTS: In the suprasternal notch, 264 CT scans (53%) demonstrated part of a major vessel anterior to the trachea, most commonly the brachiocephalic artery. At 10, 20, and 30 mm above the suprasternal notch, respectively, 126 (25%), 48 (9%), and 5 (1%) CT scans showed a major vessel anterior to the trachea. None showed a major vessel anterior to the cricothyroid membrane. In the suprasternal notch, a major vessel was anterior to the trachea in 10 of 120 CT scans (8%) that had a manubrio-cricoid distance <25 mm, and 108 of 116 CT scans (93%) that had a manubrio-cricoid distance >50 mm. In a logistic-regression model, increased length of trachea above the manubrium was a strong predictor of major vessels anterior to the trachea in the suprasternal notch, whilst sex, age, thoracic kyphosis, tracheal diameter, and the origin of the brachiocephalic artery were not strong predictors. CONCLUSIONS: It is common for patients to have some portion of a major vessel anterior to the trachea at sites where an emergency tracheostomy might be performed.

[Long-term oucomes of tracheal transplantation: success and unsolved problems]. / Otdalennyi rezul'tat transplantatsii trakhei: uspekh i nereshennye problemy.

AIM: To analyze long-term outcomes of tracheal transplantation. MATERIAL AND METHODS: There were 1128 patients with cicatricial tracheal stenosis who have been operated at the Petrovsky Russian Research Center for Surgery and the Sechenov First Moscow State Medical University for the period 1963-2015. RESULTS: Operations have become safer. Postoperative morbidity and mortality reduced from 41.4% (1963-1980) to 5.6% (2001-2015) and from 21.9% (1963-1980) to 0.5% (2001-2015), respectively. Tracheal transplantation was performed in 2 cases and fundamentally different tracheal structures were applied. Donor thyreotracheal complex with restored blood supply through thyroid vessels was used in the first case (2006). Perennial experimental trials preceded clinical application of this technique. In the second case (2010) we applied scientific results of foreign colleagues (cellular technologies and methods of regenerative medicine to create artificial trachea). Patients are still alive after 12 and 8 years, respectively. Restoration of blood supply of donor trachea is possible through thyroid collaterals. This technique is successful in long-term period. Tissue-engineered trachea cannot be considered true trachea due to no all tracheal components. However, such trachea provides air-conducting, evacuation and protective functions. Tracheomalacia requires further researches as one of the main problems of tracheal transplantation.

Kindlin-2 interacts with endothelial adherens junctions to support vascular barrier integrity.

KEY POINTS: A reduction in Kindlin-2 levels in endothelial cells compromises vascular barrier function. Kindlin-2 is a previously unrecognized component of endothelial adherens junctions. By interacting directly and simultaneously with ß- or γ-catenin and cortical actin filaments, Kindlin-2 stabilizes adherens junctions. The Kindlin-2 binding sites for ß- and γ-catenin reside within its F1 and F3 subdomains. Although Kindlin-2 does not associate directly with tight junctions, its downregulation also destabilizes these junctions. Thus, impairment of both adherens and tight junctions may contribute to enhanced leakiness of vasculature in Kindlin-2+/- mice. ABSTRACT: Endothelial cells (EC) establish a physical barrier between the blood and surrounding tissue. Impairment of this barrier can occur during inflammation, ischaemia or sepsis and cause severe organ dysfunction. Kindlin-2, which is primarily recognized as a focal adhesion protein in EC, was not anticipated to have a role in vascular barrier. We tested the role of Kindlin-2 in regulating vascular integrity using several different approaches to decrease Kindlin-2 levels in EC. Reduced levels of Kindlin-2 in Kindlin-2+/- mice aortic endothelial cells (MAECs) from these mice, and human umbilical ECs (HUVEC) treated with Kindlin-2 siRNA showed enhanced basal and platelet-activating factor (PAF) or lipopolysaccharide-stimulated vascular leakage compared to wild-type (WT) counterparts. PAF preferentially disrupted the Kindlin-2+/- MAECs barrier to BSA and dextran and reduced transendothelial resistance compared to WT cells. Kindlin-2 co-localized and co-immunoprecipitated with vascular endothelial cadherin-based complexes, including ß- and γ-catenin and actin, components of adherens junctions (AJ). Direct interaction of Kindlin-2 with ß- and γ-catenin and actin was demonstrated in co-immunoprecipitation and surface plasmon resonance experiments. In thrombin-stimulated HUVECs, Kindlin-2 and cortical actin dissociated from stable AJs and redistributed to radial actin stress fibres of remodelling focal AJs. The ß- and γ-catenin binding site resides within the F1 and F3 subdomains of Kindlin-2 but not the integrin binding site in F3. These results establish a previously unrecognized and vital role of Kindlin-2 with respect to maintaining the vascular barrier by linking Vascuar endothelial cadherin-based complexes to cortical actin and thereby stabilizing AJ.

Comparison of Salvage Total Pharyngolaryngectomy and Cervical Esophagectomy Between Hypopharyngeal Cancer and Cervical Esophageal Cancer.

BACKGROUND: Total pharyngolaryngectomy and cervical esophagectomy (TPLCE) after chemoradiotherapy remains a challenge because of the high rate of complications and few available data on outcomes and safety. The purpose of this study was to evaluate the clinical significance of salvage TPLCE and to compare treatment outcomes between hypopharyngeal cancer and cervical esophageal cancer. METHODS: Data from 37 consecutive patients who were diagnosed with potentially resectable hypopharyngeal and cervical esophageal cancer after chemoradiotherapy were retrospectively analyzed. The survival and surgical outcomes were investigated between the hypopharyngeal cancer and cervical esophageal cancer groups. RESULTS: Twenty-six patients were included in hypopharyngeal cancer group and 11 patients were included in cervical esophageal cancer group. The baseline characteristics were balanced between the two groups. Compared to the hypopharyngeal cancer group, the cervical esophageal cancer group had significantly more frequent tracheal-related complications (p < 0.05) and stronger association of distal margin of the cervical esophagus and radiation field with tracheal ischemia after salvage surgery. CONCLUSIONS: Salvage TPLCE can offer the exclusive chance of prolonged survival. Association of tracheal ischemia with salvage TPLCE was seen more frequently for cervical esophageal cancer. Therefore, the indication for salvage TPLCE must be carefully considered to maintain the balance between curability and safety.

A new anatomical classification of the bronchial arteries based on the spatial relationships to the esophagus and the tracheobronchus.

PURPOSE: To reveal the patterns of the mediastinal course of the bronchial arteries (BAs). METHODS: The BAs were dissected to determine the positional relationships of their mediastinal courses with the tracheobronchus and the esophagus in 72 adult cadavers. RESULTS: The mediastinal courses of the 227 BAs found in this study were classified into 4 types. There were 61 and 163 BAs passing the right side (Type I) and the left side (Type II reaching dorsal surface (n = 98), or Type III reaching ventral surface (n = 65) of the tracheobronchus) of the esophagus, respectively. Three BAs originated from the subclavian artery (Type IV). All Type I BAs were right BAs, whereas 91.8% of the Type II BAs were left BAs. However, 43.1 and 56.9% of the Type III BAs were the right and left BAs, respectively. CONCLUSION: The classification of the mediastinal course of the BAs determined by the spatial relationships to the tracheobronchus and the esophagus may be clinically useful, because each category of this classification can be determined during esophagectomy and indicates whether the BA is a right or left BA.

Endotracheal Cuff Pressure Changes During Helicopter Transport: A Systematic Review.

OBJECTIVE: Cuff pressures are important in ventilated patients undergoing helicopter transport. An altitude-related increase in endotracheal tube (ETT) intracuff pressure has been shown in simulated hypobaric environments, model tracheas, and animal studies and may not accurately reflect in vivo pressures. The aim of this study was to determine if ETT intracuff pressure increases above the critical perfusion pressure of the trachea in ventilated patients during helicopter transport. METHODS: Ovid Medline, CINAHL, Embase, Scopus, and the Cochrane Library were searched from their commencement to January 29, 2016. Google Scholar was searched, and reference lists of relevant articles were examined to identify additional studies. Articles were included if they reported on ETT intracuff pressure in ventilated patients during helicopter emergency medical service transport. RESULTS: A total of 330 articles were identified; only 2 prospective observational studies met the inclusion criteria. The studies reported a mean cuff pressure increase of 23 cm H2O and 33.9 cm H2O. Both studies reported ETT intracuff pressure to frequently exceed the critical perfusion pressure of the tracheal mucosa during helicopter transport. CONCLUSION: Further research with longitudinal follow-up is required to confirm these findings to determine if the effects of transient increased ETT intracuff pressure are clinically significant.

[The iatrogenic complications of tracheostomy]. / Iatrogennye oslozhneniia trakheostomii.

The objective of the present study was to analyze the complications of tracheostomy associated with bleeding from the brachiocephalic trunk. A total of 13 protocols of the autopsy study of the patients who had died in the intensive care unit were available for the analysis. These patients had experienced heavy external bleeding from the tracheostomy defect shortly before death. The study has demonstrated that all the victims had the tracheostomy hole localized below the level of the standard dissection of the tracheal rings. Nine patients presented with a damage to the brachiocephalic trunk while four others had a pressure injury to the blood vessels. The study included the elucidation of the possible relationship between the anthropometric characteristics of the patients and the variability of the passage of the brachiocephalic trunk in front of the trachea. The length of the neck was found to usually correlate with the length of the body and the brachiocephalic trunk to run in front of the trachea at the level of its 8th-11th rings. The results of the present study may be instrumental in reducing the risk of complications after tracheostomy.

Autofluorescence multiphoton microscopy for visualization of tissue morphology and cellular dynamics in murine and human airways.

The basic understanding of inflammatory airway diseases greatly benefits from imaging the cellular dynamics of immune cells. Current imaging approaches focus on labeling specific cells to follow their dynamics but fail to visualize the surrounding tissue. To overcome this problem, we evaluated autofluorescence multiphoton microscopy for following the motion and interaction of cells in the airways in the context of tissue morphology. Freshly isolated murine tracheae from healthy mice and mice with experimental allergic airway inflammation were examined by autofluorescence multiphoton microscopy. In addition, fluorescently labeled ovalbumin and fluorophore-labeled antibodies were applied to visualize antigen uptake and to identify specific cell populations, respectively. The trachea in living mice was imaged to verify that the ex vivo preparation reflects the in vivo situation. Autofluorescence multiphoton microscopy was also tested to examine human tissue from patients in short-term tissue culture. Using autofluorescence, the epithelium, underlying cells, and fibers of the connective tissue, as well as blood vessels, were identified in isolated tracheae. Similar structures were visualized in living mice and in the human airway tissue. In explanted murine airways, mobile cells were localized within the tissue and we could follow their migration, interactions between individual cells, and their phagocytic activity. During allergic airway inflammation, increased number of eosinophil and neutrophil granulocytes were detected that moved within the connective tissue and immediately below the epithelium without damaging the epithelial cells or connective tissues. Contacts between granulocytes were transient lasting 3 min on average. Unexpectedly, prolonged interactions between granulocytes and antigen-uptaking cells were observed lasting for an average of 13 min. Our results indicate that autofluorescence-based imaging can detect previously unknown immune cell interactions in the airways. The method also holds the potential to be used during diagnostic procedures in humans if integrated into a bronchoscope.

Pediatric Endotracheal Tube Cuff Pressures During Aeromedical Transport.

OBJECTIVES: Cuffed endotracheal tubes (ETTs) are frequently used in children, allowing fewer air leaks and helping prevent ventilator-associated pneumonia. Tracheal mucosal perfusion is compromised at an ETT cuff pressure (ETTCP) of 30 cm H2O with blood flow completely absent above 50 cm H2O. Our objective was to compare multiple pediatric-sized ETTCPs at ground level and various altitudes during aeromedical transport. METHODS: Simulating the transport environment, 4 pediatric-sized mannequin heads were intubated with appropriately sized cuffed ETTs (3.0, 4.0, 5.0, 6.0) and transported by helicopter or nonpressurized fixed-wing aircraft 20 times each. The ETTCP was set to 10 cm H2O before transport, and the pressure was measured with a standard manometer at 1000-ft intervals until reaching peak altitude or CP greater than 60 cm H2O. Ground elevation ranged from 400-650 ft mean sea level (MSL) and peak altitude from 3500 to 5000 ft MSL. RESULTS: Increased altitude caused a significant increase in ETTCP of all ETT sizes (P < 0.001). However, there is no statistical difference in pressures between ETT sizes (P = 0.28). On average, ETTCP in 3.0, 4.0, and 6.0 ETTs surpassed 30 cm H2O at approximately 1500 ft MSL and 50 cm H2O at approximately 2800 ft MSL. In the 5.0 ETT, the CP reached 30 cm H2O at 2000 ft MSL and 50 cm H2O at 3700 ft MSL. CONCLUSIONS: The ETTCP in pediatric-sized ETTs regularly exceed recommended pressure limits at relatively low altitudes. There is no additional pressure increase related to ETT size. This has the potential to decrease mucosal blood flow, possibly increasing risk of subsequent tracheal stenosis, rupture, and other complications.

Laryngeal Cuff Force Application Modeling During Air Medical Evacuation Simulation.

Endotracheal tubes are intended to protect the airway and assist with mechanical ventilation in sedated patients. The blood vessels of the tracheal mucosa can be compressed by high tracheal tube cuff pressures (> 30 cm H2O), leading to reduced mucosal blood flow with resulting ischemia and morbidity. Previous research showed a direct correlation between aircraft pressure altitude and the pressure reading from the tracheal cuff, with resulting pressures > 80 cm H2O at 10,000 ft. Standard practice is to periodically remove air from the cuff during ascent based on assumed increased pressure on the adjacent tracheal mucosa. Using a vacuum chamber and a direct reading micropressure sensor in a 22-mm-diameter semirigid tube, we assessed the direct force applied by the tracheal cuff against the laryngeal tube analog. Standard tracheal cuffs showed direct force/pressure relationships when properly inflated to 20 cm H2O but much less than reported in the literature. Current literature reports values of 55 to 150 cm H2O at 5,000 ft, whereas we report 23 to 25 cm H2O. Our data indicate that a properly inflated cuff does not exceed the critical pressure of 30 cm H2O until the altitude exceeds 8,000 ft. Thus, the standard practice of deflating the laryngeal cuff on ascent should be reconsidered because it may be counterproductive to patient safety.

Perfusion-Decellularization of Porcine Lung and Trachea for Respiratory Bioengineering.

Decellularization of native organs may provide an acellular tissue platform for organ regeneration. However, decellularization involves a trade-off between removal of immunogenic cellular elements and preservation of biomechanical integrity. We sought to develop a bioartificial scaffold for respiratory tissue engineering by decellularization of porcine lungs and trachea while preserving organ architecture and vasculature. Lung-trachea preparations from 25 German Landrace pigs were perfused in a modified Langendorff circuit and decellularized by an SDC (sodium deoxycholate)-based perfusion protocol. Decellularization was evaluated by histology and fluorescence microscopy, and residual DNA quantified spectrophotometrically and compared with controls. Airway compliance was evaluated by endotracheal intubation and mechanical ventilation to simulate physiological breathing-induced stretch. Structural integrity was evaluated by bronchoscopy and biomechanical stress/strain analysis by measuring passive tensile strength, all compared with controls. Decellularized lungs and trachea lacked intracellular components but retained specific collagen fibers and elastin. Quantitative DNA analysis demonstrated a significant reduction of DNA compared with controls (32.8 ± 12.4 µg DNA/mg tissue vs. 179.7 ± 35.8 µg DNA/mg tissue, P < 0.05). Lungs and trachea decellularized by our perfusion protocol demonstrated increased airway compliance but preserved biomechanical integrity as compared with native tissue. Whole porcine lungs-tracheae can be successfully decellularized to create an acellular scaffold that preserves extracellular matrix and retains structral integrity and three-dimensional architecture to provide a bioartifical platform for respiratory tissue engineering.

Tracheal varices caused by mediastinal compression of a large intrathoracic goiter: report of a case.

INTRODUCTION: Tracheal varices are a rare condition but they can be an important source of massive or recurrent haemoptysis. Usually they are related to increased pressure in the pulmonary veins. Mediastinal goiter is often associated to compressive effects on the surrounding structures, including mediastinal vessels with potential superior vena cava syndrome. CASE REPORT: We describe a case, not previously reported in literature, of mediastinal goiter with hemoptysis as first clinical manifestation. Bleeding was attributed to a superior vena cava syndrome associated to a tracheal fragile mucosa with an easily bleeding intramural nodule which was diagnosed as tracheal varices after total thyroidectomy. The nodule in fact disappeared together with the venous hypertensive signs after venous decompression of the mediastinum. CONCLUSIONS: Compressive symptoms including tracheal varices, related to mediastinal goiter, can be treated surgically by total thyroidectomy via cervicotomy and when required with associated median sternotomy.

[TRANSPLANTATION OF TRACHEAL-LUNG COMPLEX IN EXPERIMENT].

The article described the developed and patented method of removal of trancheal-lung complex from dead body and its transplantation to the recipient-corps.

Transgenic overexpression of interleukin-1ß induces persistent lymphangiogenesis but not angiogenesis in mouse airways.

These studies used bi-transgenic Clara cell secretory protein (CCSP)/IL-1ß mice that conditionally overexpress IL-1ß in Clara cells to determine whether IL-1ß can promote angiogenesis and lymphangiogenesis in airways. Doxycycline treatment induced rapid, abundant, and reversible IL-1ß production, influx of neutrophils and macrophages, and conspicuous and persistent lymphangiogenesis, but surprisingly no angiogenesis. Gene profiling showed many up-regulated genes, including chemokines (Cxcl1, Ccl7), cytokines (tumor necrosis factor α, IL-1ß, and lymphotoxin-ß), and leukocyte genes (S100A9, Aif1/Iba1). Newly formed lymphatics persisted after IL-1ß overexpression was stopped. Further studies examined how IL1R1 receptor activation by IL-1ß induced lymphangiogenesis. Inactivation of vascular endothelial growth factor (VEGF)-C and VEGF-D by adeno-associated viral vector-mediated soluble VEGFR-3 (VEGF-C/D Trap) completely blocked lymphangiogenesis, showing its dependence on VEGFR-3 ligands. Consistent with this mechanism, VEGF-C immunoreactivity was present in some Aif1/Iba1-immunoreactive macrophages. Because neutrophils contribute to IL-1ß-induced lung remodeling in newborn mice, we examined their potential role in lymphangiogenesis. Triple-transgenic CCSP/IL-1ß/CXCR2(-/-) mice had the usual IL-1ß-mediated lymphangiogenesis but no neutrophil recruitment, suggesting that neutrophils are not essential. IL1R1 immunoreactivity was found on some epithelial basal cells and neuroendocrine cells, suggesting that these cells are targets of IL-1ß, but was not detected on lymphatics, blood vessels, or leukocytes. We conclude that lymphangiogenesis triggered by IL-1ß overexpression in mouse airways is driven by VEGF-C/D from macrophages, but not neutrophils, recruited by chemokines from epithelial cells that express IL1R1.