This review summarizes an expanding body of knowledge indicating that failure to resolve inflammation and altered immune processes underlie the development of pulmonary arterial hypertension. The chemokines and cytokines implicated in pulmonary arterial hypertension that could form a biomarker platform are discussed. Pre-clinical studies that provide the basis for dysregulated immunity in animal models of the disease are reviewed. In addition, we present therapies that target inflammatory/immune mechanisms that are currently enrolling patients, and discuss others in development. We show how genetic and metabolic abnormalities are inextricably linked to dysregulated immunity and adverse remodeling in the pulmonary arteries.

Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension.

http://dbbs.wustl.edu/curstudents/Documents/Markey/Pathobiology_Tuder%20JACC%202013.pdf

Relevant issues in the pathology and pathobiology of pulmonary hypertension

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary hypertension (PH) characterised by preferential remodelling of the pulmonary venules. In the current PH classification, PVOD and pulmonary capillary haemangiomatosis (PCH) are considered to be a common entity and represent varied expressions of the same disease. The recent discovery of biallelic mutations in the EIF2AK4 gene as the cause of heritable PVOD/PCH represents a major milestone in our understanding of the molecular pathogenesis of PVOD. Although PVOD and pulmonary arterial hypertension (PAH) share a similar clinical presentation, with features of severe precapillary PH, it is important to differentiate these two conditions as PVOD carries a worse prognosis and life-threatening pulmonary oedema may occur following the initiation of PAH therapy. An accurate diagnosis of PVOD based on noninvasive investigations is possible utilising oxygen parameters, low diffusing capacity for carbon monoxide and characteristic signs on high-resolution computed tomography of the chest. No evidence-based medical therapy exists for PVOD at present and lung transplantation remains the preferred definitive therapy for eligible patients.

https://erj.ersjournals.com/content/erj/47/5/1518.full.pdf

Pulmonary veno-occlusive disease

Dysfunctional bone morphogenetic protein receptor-2 (BMPR2) signaling is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). We used a transcriptional high-throughput luciferase reporter assay to screen 3,756 FDA-approved drugs and bioactive compounds for induction of BMPR2 signaling. The best response was achieved with FK506 (tacrolimus), via a dual mechanism of action as a calcineurin inhibitor that also binds FK-binding protein-12 (FKBP12), a repressor of BMP signaling. FK506 released FKBP12 from type I receptors activin receptor-like kinase 1 (ALK1), ALK2, and ALK3 and activated downstream SMAD1/5 and MAPK signaling and ID1 gene regulation in a manner superior to the calcineurin inhibitor cyclosporine and the FKBP12 ligand rapamycin. In pulmonary artery endothelial cells (ECs) from patients with idiopathic PAH, low-dose FK506 reversed dysfunctional BMPR2 signaling. In mice with conditional Bmpr2 deletion in ECs, low-dose FK506 prevented exaggerated chronic hypoxic PAH associated with induction of EC targets of BMP signaling, such as apelin. Low-dose FK506 also reversed severe PAH in rats with medial hypertrophy following monocrotaline and in rats with neointima formation following VEGF receptor blockade and chronic hypoxia. Our studies indicate that low-dose FK506 could be useful in the treatment of PAH.

/pdf/fk506-activates-bmpr2-rescues-endothelial-dysfunction-and-4k5zf4gsae.pdf

FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension

Rationale: Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and vascular remodeling. Recent studies have revealed that immune and inflammatory responses play a crucial role in pathogenesis of idiopathic PAH.Objectives: To systematically evaluate the number and cross-sectional distribution of inflammatory cells in different sizes of pulmonary arteries from explanted lungs of patients with idiopathic PAH versus healthy donor lungs and to demonstrate functional relevance by blocking stromal-derived factor-1 by the Spiegelmer NOX-A12 in monocrotaline-induced pulmonary hypertension in rats.Methods: Immunohistochemistry was performed on lung tissue sections from patients with idiopathic PAH and healthy donors. All positively stained cells in whole-lung tissue sections, surrounding the vessels, and in the different compartments of the vessels were counted. To study the effects of blocking SDF-1, rats with monocrotaline-induced pulmonary hypertension were treated with NOX-A12 from Day 21...

Immune and inflammatory cell involvement in the pathology of idiopathic pulmonary arterial hypertension.

Rationale: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. Objectives:Toassessthespectrumofpulmonaryvascularremodeling in the modern era of PAH medication. Methods: Assessmentofpulmonaryvascularremodelingandinflammation in 62 PAH and 28 control explanted lungs systematically sampled. Measurements and Main Results: Intima and intima plus media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the control lungs and correlated with pulmonary hemodynamicmeasurements.DespiteahighvariabilityofmorphologicalmeasurementswithinagivenPAHlungandamongallPAHlungs, distinct pathological subphenotypes were detected in cohorts of PAH lungs. These included a subset of lungs lacking intima or, most prominently, media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling.Markedperivascularinflammationwaspresentinahigh number of PAH lungs and correlated with intima plus media remodeling. The number of profiles of plexiform lesions was significantly lower in lungs of male patients and those never treated with prostacyclin or its analogs. Conclusions:Our resultsindicate thatmultiplefeaturesofpulmonary vascular remodeling are present in patients treated with modern PAH therapies. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure. Moreover, our study provides a framework to interpret and design translational studies in PAH.

/pdf/modern-age-pathology-of-pulmonary-arterial-hypertension-5e3jtr8jfx.pdf

Modern age pathology of pulmonary arterial hypertension.

Introduction: The impact of modern treatments of pulmonary arterial hypertension (PAH) on pulmonary vascular pathology remains unknown. The last series reporting the pathology of severe pulmonary hypertension date back two decades, well before usage of current therapies for the disease. Methods: Assessment of pulmonary vascular remodelling and inflammation in 62 PAH and 28 control explanted lungs systematically sampled, with matched clinical data. The tissue was obtained by the Pulmonary Hypertension Breakthrough Initiative. Results: Total wall, intima, and media fractional thicknesses of pulmonary arteries were increased in the PAH group versus the controls, and correlated with pulmonary hemodynamics. Despite a high variability of morphological measurements within a given PAH lung and among all PAH lungs, pathological subphenotypes were detected in cohorts of PAH lungs. This included a subset of lungs lacking intima or media remodeling, which had similar numbers of profiles of plexiform lesions as those in lungs with more pronounced remodeling. Perivascular inflammation was present in a high number of PAH lungs and correlated with mean pulmonary arterial pressure (mPAP) as well as intima and total wall thickness. The number of profiles of plexiform lesions was significantly lower in lungs of patients who were never treated with prostacyclin or its analogues. Conclusions: Our results indicate that multiple features of pulmonary vascular remodeling are present in patients treated with modern PAH regimens. Perivascular inflammation may have an important role in the processes of vascular remodeling, all of which may ultimately lead to increased pulmonary artery pressure.

https://erj.ersjournals.com/content/erj/40/Suppl_56/P3922.full.pdf

Modern age pathology of pulmonary arterial hypertension

Despite the importance of pulmonary veins in normal lung physiology and the pathobiology of pulmonary hypertension with left heart disease (PH-LHD), pulmonary veins remain largely understudied. Difficult to identify histologically, lung venous endothelium or smooth muscle cells display no unique characteristic functional and structural markers that distinguish them from pulmonary arteries. To address these challenges, we undertook a search for unique molecular markers in pulmonary veins. In addition, we addressed the expression pattern of a candidate molecular marker and analyzed the structural pattern of vascular remodeling of pulmonary veins in a rodent model of PH-LHD and in lung tissue of patients with PH-LHD obtained at time of placement on a left ventricular assist device. We detected urokinase plasminogen activator receptor (uPAR) expression preferentially in normal pulmonary veins of mice, rats, and human lungs. Expression of uPAR remained elevated in pulmonary veins of rats with PH-LHD; however, we also detected induction of uPAR expression in remodeled pulmonary arteries. These findings were validated in lungs of patients with PH-LHD. In selected patients with sequential lung biopsy at the time of removal of the left ventricular assist device, we present early data suggesting improvement in pulmonary hemodynamics and venous remodeling, indicating potential regression of venous remodeling in response to assist device treatment. Our data indicate that remodeling of pulmonary veins is an integral part of PH-LHD and that pulmonary veins share some key features present in remodeled yet not normotensive pulmonary arteries.

https://www.physiology.org/doi/pdf/10.1152/ajplung.00186.2013

James M. Hunt

Papers

Modern age pathology of pulmonary arterial hypertension.

Modern age pathology of pulmonary arterial hypertension

Pulmonary veins in the normal lung and pulmonary hypertension due to left heart disease.

Hyperoxia and apoptosis. Too much of a good thing