Depletion of Alveolar Macrophages Attenuates Hypoxic Pulmonary Hypertension but not Hypoxia-Induced Increase in Serum Concentration of MCP-1

Žaloudíková, Marie; Vytášek, Richard; Vajnerová, Olga; Hnilickova, Olga; Vízek, M; Hampl, Václav; Herget, J

doi:10.33549/physiolres.933187

Cited by 34 publications

(18 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast to the progressive expansion of interstitial macrophages, we found that alveolar macrophages were decreased in both rodent and human instances of PH. To our knowledge, alveolar macrophages have not previously been quantified in depth in human PH, but other groups have conversely reported their increase [72] and activation [73] in chronically hypoxic mice. These discrepancies may be explained by a recent report delineating a spatio-temporal program of at times divergent alveolar and interstitial macrophage activation in hypoxic lungs of mice [21].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes

Florentin

Coppin

Vasamsetti

et al. 2018

The Journal of Immunology

120

110

View full text Add to dashboard Cite

Pulmonary inflammation, which is characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of blood-borne monocytes in PH are poorly understood. Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. In parallel, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment, such as and, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of or in chronically hypoxic male mice and by pharmacologic inhibition of Cxcl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes, as well as interstitial macrophages, leading to a substantial decrease in arteriolar remodeling but with a less robust hemodynamic effect. This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage-dependent inflammation yet is dissociated, at least in part, from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes

Florentin

Coppin

Vasamsetti

et al. 2018

The Journal of Immunology

120

110

View full text Add to dashboard Cite

show abstract

“…Interventions targeting macrophages have confirmed their role in PAH and pulmonary vascular remodeling. An intratracheal depletion of alveolar macrophages with liposome-encapsulated clodronate attenuated the increase in pulmonary arterial pressure in response to chronic hypoxia in rats [ 82 ]. Furthermore, the depletion of macrophages normalized the increase in RVSP seen in BMPR2 knockout mice exposed to chronic hypoxia [ 83 ].…”

Section: Inflammatory Mediators and Their Effects On Vascular Remomentioning

confidence: 99%

Perivascular Inflammation in Pulmonary Arterial Hypertension

Chi

Kuebler

et al. 2020

Cells

131

109

View full text Add to dashboard Cite

Perivascular inflammation is a prominent pathologic feature in most animal models of pulmonary hypertension (PH) as well as in pulmonary arterial hypertension (PAH) patients. Accumulating evidence suggests a functional role of perivascular inflammation in the initiation and/or progression of PAH and pulmonary vascular remodeling. High levels of cytokines, chemokines, and inflammatory mediators can be detected in PAH patients and correlate with clinical outcome. Similarly, multiple immune cells, including neutrophils, macrophages, dendritic cells, mast cells, T lymphocytes, and B lymphocytes characteristically accumulate around pulmonary vessels in PAH. Concomitantly, vascular and parenchymal cells including endothelial cells, smooth muscle cells, and fibroblasts change their phenotype, resulting in altered sensitivity to inflammatory triggers and their enhanced capacity to stage inflammatory responses themselves, as well as the active secretion of cytokines and chemokines. The growing recognition of the interaction between inflammatory cells, vascular cells, and inflammatory mediators may provide important clues for the development of novel, safe, and effective immunotargeted therapies in PAH.

show abstract

“…Moreover, the depletion of recruited monocytes with gadolinium chloride in neonatal hyperoxia-exposed rats demonstrated reduced RVH and decreased SMC proliferation [ 34 ]. Recently, Zaloudikova et al demonstrated that depletion of alveolar macrophages attenuates hypoxic PH, emphasizing the role of pulmonary macrophages in PH pathogenesis [ 35 ]. Like pulmonary resident macrophages, myeloid-derived suppressor cells (MDSCs) are a different type of myeloid cell with immuno-modulatory activity.…”

Section: Macrophage-mediated Immunity In Pahmentioning

confidence: 99%

Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

Willis

Fernandez-Gonzalez

Reis

et al. 2018

IJMS

View full text Add to dashboard Cite

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by remodeling of the pulmonary arteries, increased pulmonary infiltrates, loss of vascular cross-sectional area, and elevated pulmonary vascular resistance. Despite recent advances in the management of PAH, there is a pressing need for the development of new tools to effectively treat and reduce the risk of further complications. Dysregulated immunity underlies the development of PAH, and macrophages orchestrate both the initiation and resolution of pulmonary inflammation, thus, manipulation of lung macrophage function represents an attractive target for emerging immunomodulatory therapies, including cell-based approaches. Indeed, mesenchymal stem cell (MSC)-based therapies have shown promise, effectively modulating the macrophage fulcrum to favor an anti-inflammatory, pro-resolving phenotype, which is associated with both histological and functional benefits in preclinical models of pulmonary hypertension (PH). The complex interplay between immune system homeostasis and MSCs remains incompletely understood. Here, we highlight the importance of macrophage function in models of PH and summarize the development of MSC-based therapies, focusing on the significance of MSC exosomes (MEx) and the immunomodulatory and homeostatic mechanisms by which such therapies may afford their beneficial effects.

show abstract

Depletion of Alveolar Macrophages Attenuates Hypoxic Pulmonary Hypertension but not Hypoxia-Induced Increase in Serum Concentration of MCP-1

Cited by 34 publications

References 17 publications

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes

Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes

Perivascular Inflammation in Pulmonary Arterial Hypertension

Macrophage Immunomodulation: The Gatekeeper for Mesenchymal Stem Cell Derived-Exosomes in Pulmonary Arterial Hypertension?

Contact Info

Product

Resources

About