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Rationale: Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal developmental disorder of lung morphogenesis caused by insufficiency of FOXF1 (forkhead box F1) transcription factor function. The cellular and transcriptional mechanisms by which FOXF1 deficiency disrupts human lung formation are unknown. Objectives: To identify cell types, gene networks, and cell-cell interactions underlying the pathogenesis of ACDMPV. Methods: We used single-nucleus RNA and assay for transposase-accessible chromatin sequencing, immunofluorescence confocal microscopy, and RNA in situ hybridization to identify cell types and molecular networks influenced by FOXF1 in ACDMPV lungs. Measurements and Main Results: Pathogenic single-nucleotide variants and copy-number variant deletions involving the FOXF1 gene locus in all subjects with ACDMPV ( n  = 6) were accompanied by marked changes in lung structure, including deficient alveolar development and a paucity of pulmonary microvasculature. Single-nucleus RNA and assay for transposase-accessible chromatin sequencing identified alterations in cell number and gene expression in endothelial cells (ECs), pericytes, fibroblasts, and epithelial cells in ACDMPV lungs. Distinct cell-autonomous roles for FOXF1 in capillary ECs and pericytes were identified. Pathogenic variants involving the FOXF1 gene locus disrupt gene expression in EC progenitors, inhibiting the differentiation or survival of capillary 2 ECs and cell-cell interactions necessary for both pulmonary vasculogenesis and alveolar type 1 cell differentiation. Loss of the pulmonary microvasculature was associated with increased VEGFA (vascular endothelial growth factor A) signaling and marked expansion of systemic bronchial ECs expressing COL15A1 (collagen type XV α 1 chain). Conclusions: Distinct FOXF1 gene regulatory networks were identified in subsets of pulmonary endothelial and fibroblast progenitors, providing both cellular and molecular targets for the development of therapies for ACDMPV and other diffuse lung diseases of infancy.

Rationale: Lymphangioleiomyomatosis (LAM) is a metastatic neoplasm of reproductive-age women associated with mutations in tuberous sclerosis complex genes. LAM causes cystic remodeling of the lung and progressive respiratory failure. The sources and cellular characteristics of LAM cells underlying disease pathogenesis remain elusive. Objectives: Identification and characterization of LAM cells in human lung and uterus using a single-cell approach. Methods: Single-cell and single-nuclei RNA sequencing on LAM ( n  = 4) and control ( n  = 7) lungs, immunofluorescence confocal microscopy, ELISA, and aptamer proteomics were used to identify and validate LAM CORE cells and secreted biomarkers, predict cellular origins, and define molecular and cellular networks in LAM. Measurements and Main Results: A unique cell type termed LAM CORE was identified, which was distinct from, but closely related to, lung mesenchymal cells. LAM CORE cells expressing signature genes included known LAM markers such as PMEL , FIGF , CTSK , and MLANA and novel biomarkers validated by aptamer screening, ELISA, and immunofluorescence microscopy. LAM cells in lung and uterus are morphologically indistinguishable and share similar gene expression profiles and biallelic TSC2 mutations, supporting a potential uterine origin for the LAM CORE cell. Effects of LAM on resident pulmonary cell types indicated recruitment and activation of lymphatic endothelial cells. Conclusions: A unique population of LAM CORE cells was identified in lung and uterus of patients with LAM, sharing close transcriptomic identity. LAM cell selective markers, secreted biomarkers, and the predicted cellular molecular features provide new insights into the signaling and transcriptional programs that may serve as diagnostic markers and therapeutic targets to influence the pathogenesis of LAM.

Background: Recommendations regarding key aspects related to the diagnosis and pharmacological treatment of lymphangioleiomyomatosis (LAM) were recently published. We now provide additional recommendations regarding four specific questions related to the diagnosis of LAM and management of pneumothoraces in patients with LAM., Methods: Systematic reviews were performed and then discussed by a multidisciplinary panel. For each intervention, the panel considered its confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences, patient values and preferences, cost, and feasibility. Evidence-based recommendations were then formulated, written, and graded using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach., Results: For women who have cystic changes on high-resolution computed tomography of the chest characteristic of LAM, but who have no additional confirmatory features of LAM (i.e., clinical, radiologic, or serologic), the guideline panel made conditional recommendations against making a clinical diagnosis of LAM on the basis of the high-resolution computed tomography findings alone and for considering transbronchial lung biopsy as a diagnostic tool. The guideline panel also made conditional recommendations for offering pleurodesis after an initial pneumothorax rather than postponing the procedure until the first recurrence and against pleurodesis being used as a reason to exclude patients from lung transplantation., Conclusions: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Background: Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM., Methods: Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach., Results: After considering the panel's confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy., Conclusions: Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

The diffuse cystic lung diseases have a broad differential diagnosis. A wide variety of pathophysiological processes spanning the spectrum from airway obstruction to lung remodeling can lead to multifocal cyst development in the lung. Although lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis are perhaps more frequently seen in the clinic, disorders such as Birt-Hogg-Dubé syndrome, lymphocytic interstitial pneumonia, follicular bronchiolitis, and light-chain deposition disease are increasingly being recognized. Obtaining an accurate diagnosis can be challenging, and management approaches are highly disease dependent. Unique imaging features, genetic tests, serum studies, and clinical features provide invaluable clues that help clinicians distinguish among the various etiologies, but biopsy is often required for definitive diagnosis. In part II of this review, we present an overview of the diffuse cystic lung diseases caused by lymphoproliferative disorders, genetic mutations, or aberrant lung development and provide an approach to aid in their diagnosis and management.

The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air-filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction, or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those caused by low-grade or high-grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two-part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking-related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.