The Reversal of Pulmonary Vascular Remodeling Through Inhibition of p38MAPK-alpha: A Potential Novel Anti-Inflammatory Strategy in Pulmonary Hypertension
Editor's Note: This Expert Analysis is based on the following article: Church AC, Martin DH, Wadsworth R., et al. The Reversal of Pulmonary Vascular Remodeling Through Inhibition of p38 MAPK-alpha: A Potential Novel Anti-inflammatory Strategy in Pulmonary Hypertension. Am J Physiol Lung Cell Mol Physiol. 2015 Aug 15;309(4):L333-47.
Pulmonary arterial hypertension is a life-limiting condition which arises from progressive narrowing of the pulmonary vasculature leading to increased pulmonary vascular resistance and eventual right ventricular failure1. It is increasingly recognized that inflammation plays an important role in the development and progression of pulmonary hypertension (PH)2. A number of diseases with inflammatory phenotypes have been associated with the development of PH and pulmonary vascular remodeling and indeed anti-inflammatory therapies can in some cases prevent or even reverse disease3,4. The p38MAPK pathway is a critical pathway in many pro-inflammatory cells but its role in PH is not clear. Increased activity of the p38MAPK pathway is observed in the pulmonary artery fibroblast in both acute and chronic hypoxic conditions and leads to increased cellular proliferation and differentiation into myofibroblasts which are some of the initial features of the remodeling process 5,6.
In this paper the role of p38MAPK in the pathobiology of pulmonary arterial hypertension was explored. This study shows that the p38MAPK pathway is upregulated in the pulmonary vasculature of experimental models of PH with the alpha isoform being the predominant isofrm expressed and regulated. Furthermore inhibition of this isoform using a selective inhibitor which is clinically available was shown to prevent and reverse disease in these experimental models. Not only did the haemodynamics improve but clear evidence of regression of right ventricular hypertrophy and vascular remodeling was observed. This may have important implications for the treatment of patients with PAH in the future.
In order to understand the mechanisms underlying this reversal of PAH and RVH with p38-alpha inhibitors, the effect on pro-inflammatory cytokines was investigated with particular focus on Interleukin-6. Previous studies have shown a strong molecular and clinical link between IL-6 and pulmonary hypertension, and indeed this paper shows that pulmonary artery fibroblasts under chronic hypoxia and from monocrotaline induced pulmonary hypertension release increased levels of IL-67,8. Blocking the p38MAPK pathway reduces the IL-6 levels secreted and this is mirrored in lower serum levels and tissue levels of IL-6 in experimental animal models treated with p38MAPK inhibitors.
Obviously results in animal models of disease can give indications as to underlying pathways responsible in disease processes but this is not always then proven to be true in human disease. The relevance of this pathway in human pulmonary arterial hypertension was investigated in this study. Immunohistochemistry of tissue from patients who had undergone lung transplantation for end-stage PAH demonstrated increased levels of phosphorylated p38MAPK and hence p38MAPK activity compared to normal control lung. Furthermore the expression of the p38MAPK-alpha isoform was increased in the pulmonary vasculature and especially seen in that of the pathognomonic feature of pulmonary hypertension the plexiform lesion.
Previously the use of p38MAPK inhibitors in inflammatory diseases has been marked by intolerable side effects such as gastrointestinal upset and liver toxicity. However a new generation of inhibitors have been developed and have been well tolerated in phase 2/3 trials in other diseases such as chronic obstructive pulmonary disease9. This opens the opportunity that these newer generation molecules could have real clinical applicability and trials using direct p38MAPK inhibitors or targeting more upstream molecules are planned.
This study underpins current feelings that inflammation is an important biological process in the development and progression of pulmonary hypertension. It suggests a direct link between increased levels of IL-6 and pulmonary hypertension mediated through the pro-inflammatory p38MAPK pathway. It also confirms that the pulmonary artery fibroblast is an important contributing cell to the remodeling process. Inhibition of this p38 pathway may, in turn, allow direct targeting of one or more inflammatory pathways driving the biology of pulmonary hypertension and provide a novel treatment strategy in this disease.
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