Characteristics of Interstitial Fibrosis and Inflammatory Cell Infiltration in Right Ventricles of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Overbeek, Maria J.; Mouchaers, Koen T. B.; Niessen, Hans W.M.; Hadi, Awal M.; Kupreishvili, Koba; Boonstra, Anco; Voskuyl, Alexandre E.; Beliën, Jeroen A.M.; Smit, Egbert F.; Dijkmans, Ben C.; Vonk‐Noordegraaf, Anton; Grünberg, Katrien

doi:10.1155/2010/604615

Cited by 64 publications

(50 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SSc-PAH patients have more impaired RV function than that observed in IPAH patients despite comparable afterloads 28 ; notably, more inflammatory cells were found in RV tissue samples of the former. 29…”

Section: Inflammation and Autoimmunitymentioning

confidence: 99%

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Zanatta

Polito

Famoso

et al. 2019

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a serious complication of connective tissue disorders (CTDs), and CTD-PAH is the second cause of PAH after the idiopathic form. PAH is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance, which can lead to right heart failure and death. About 90% of CTD-PAH cases are associated with systemic sclerosis (SSc, 74%), mixed connective tissue disease (MCTD, 8%) or systemic lupus erythematosus (SLE, 8%). CTD-PAH has also been reported, albeit rarely, in Sjögren syndrome, inflammatory idiopathic myopathies and rheumatoid arthritis. As for idiopathic PAH, the impaired production of vasoactive mediators such as nitric oxide and prostacyclin, and the increased production of vasoconstrictors and proliferative mediators such as endothelin-1, affect the vascular tone and promote vascular remodeling. Moreover, there is growing evidence suggesting that inflammation and autoimmunity may contribute to the genesis and progression of CTD-PAH, especially in SLE and MCTD patients who require an early administration of corticosteroids and immunosuppressants in order to avoid irreversible pathologic changes in pulmonary vessels. Conversely, immunosuppressive agents are ineffective in SSc-PAH, which requires a timely and aggressive treatment with specific PAH therapies (combination therapy). In this review, we summarized the current data on the pathophysiology and treatment of CTD-PAH. Impact statement Our article focuses on the pathogenesis and treatment of CTD-PAH. In the latest ESC/ESR guidelines for PAH, the authors underline that although CTD-PAH should follow the same treatment protocol as idiopathic PAH, the therapeutic approach is more complex and difficult in the former. This review throws light on several peculiar aspects of CTD-PAH and the latest findings in the pathogenesis, namely, the role of inflammation in the maladaptive right ventricle remodeling in SSc-PAH where immunosuppressants are classically believed to be ineffective. Furthermore, we discuss the major critical points in the therapy of CTD-PAH which is one of the strengths of our article. To the best of our knowledge, there are no other reviews that exclusively focus on the pathogenesis and treatment of CTD-PAH patients, with an emphasis on the more critical issues. Thus, it is our contention that our work would be of interest to the readers.

show abstract

Section: Inflammation and Autoimmunitymentioning

confidence: 99%

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Zanatta

Polito

Famoso

et al. 2019

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

show abstract

“…Interestingly, only one single study has reported leukocyte infiltration in the right ventricles obtained from patients with idiopathic PAH (IPAH) and PAH associated with systemic sclerosis (SScPAH) (52). The authors reported a higher number of CD45 ϩ and CD68 ϩ cells in SScPAH compared with RV samples from IPAH patients.…”

Section: Mct-induced Myocarditismentioning

confidence: 99%

The monocrotaline model of pulmonary hypertension in perspective

Gomez-Arroyo

Farkas

Alhussaini

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

351

291

View full text Add to dashboard Cite

Severe forms of pulmonary arterial hypertension (PAH) are characterized by various degrees of remodeling of the pulmonary arterial vessels, which increases the pulmonary vascular resistance and right ventricular afterload, thus contributing to the development of right ventricle dysfunction and failure. Recent years have seen advances in the understanding of the pathobiology of PAH; however, many important questions remain unanswered. Elucidating the pathobiology of PAH continues to be critical to design new effective therapeutic strategies, and appropriate animal models of PAH are necessary to achieve the task. Although the monocrotaline rat model of PAH has contributed to a better understanding of vascular remodeling in pulmonary hypertension, we question the validity of this model as a preclinically relevant model of severe plexogenic PAH. Here we review pertinent publications that either have been forgotten or ignored, and we reexamine the monocrotaline model in the context of human forms of PAH.

show abstract

“…Macrophages are a prominent component of the inflammatory infiltrates in experimental and clinical PAH 9,35,[71][72][73][74] and are thought to play a very important role in modulating the disease. 9,74 Macrophage depletion or inactivation is shown to prevent experimentally induced hypoxic PH and portopulmonary hypertension.…”

Section: Discussionmentioning

confidence: 99%

Adverse effects of BMPR2 suppression in macrophages in animal models of pulmonary hypertension

et al. 2020

View full text Add to dashboard Cite

Inflammatory cells contribute to irreversible damage in pulmonary arterial hypertension (PAH). We hypothesized that in PAH, dysfunctional BMPR2 signaling in macrophages contributes to pulmonary vascular injury and phenotypic changes via proinflammatory cytokine production. Studies were conducted in: (1) Rosa26-rtTA2 3 X TetO7-Bmpr2delx4 FVB/N mice (mutant Bmpr2 is universally expressed, BMPR2delx4 mice) given a weekly intra-tracheal liposomal clodronate injections for four weeks; and (2) LysM-Cre X floxed BMPR2 X floxed eGFP monocyte lineage-specific BMPR2 knockout (KO) mouse model (Bmpr2 gene expression knockdown in monocytic lineage cells) (BMPR2KO) following three weeks of sugen/hypoxia treatment. In the BMPR2delx4 mice, increased right ventricular systolic pressure (RVSP; P < 0.05) was normalized by clodronate, and in monocyte lineage-specific BMPR2KO mice sugen hypoxia treatment increased ( P < 0.05) RVSP compared to control littermates, suggesting that suppressed BMPR2 in macrophages modulate RVSP in animal models of PH. In addition, in these mouse models, muscularized pulmonary vessels were increased ( P < 0.05) and surrounded by an increased number of macrophages. Elimination of macrophages in BMPR2delx4 mice reduced the number of muscularized pulmonary vessels and macrophages surrounding these vessels. Further, in monocyte lineage-specific BMPR2KO mice, there was significant increase in proinflammatory cytokines, including C-X-C Motif Chemokine Ligand 12 (CXCL12), complement component 5 a (C5a), Interleukin-16 (IL-16), and secretory ICAM. C5a positive inflammatory cells present in and around the pulmonary vessels in the PAH lung could potentially be involved in pulmonary vessel remodeling. In summary, our data indicate that, in BMPR2-related PAH, macrophages with dysfunctional BMPR2 influence pulmonary vascular remodeling and phenotypic outcomes via proinflammatory cytokine production.

show abstract

Characteristics of Interstitial Fibrosis and Inflammatory Cell Infiltration in Right Ventricles of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension

Cited by 64 publications

References 42 publications

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

Pulmonary arterial hypertension in connective tissue disorders: Pathophysiology and treatment

The monocrotaline model of pulmonary hypertension in perspective

Adverse effects of BMPR2 suppression in macrophages in animal models of pulmonary hypertension

Contact Info

Product

Resources

About