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Control lungs may have significant disorders in pulmonary arteries that need to be considered when studied in the context of pulmonary vascular or interstitial disease samples.
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Pulmonary arterial hypertension (PAH) lungs show increased pulmonary remodeling compared with control lungs. These parameters correlate with pulmonary hemodynamics.
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The 2 histopathologic patterns, idiopathic PAH (IPAH)–type (seen in IPAH, familial PAH, or PAH associated with congenital heart disease) and PAH associated
Pathology of Pulmonary Hypertension
Section snippets
Key points
Normal pulmonary circulation
We have described previously the histology of the normal pulmonary circulation.5, 6 However, it is worth revisiting some important characteristics of the pulmonary circulation because they have important implications in the interpretation of the pulmonary vascular remodeling in PH. Based on a casting study of the left lung of a 43-year-old male donor, it was estimated that the pulmonary artery (PA) branches approximately 15 times from the main PA (largest order) to the precapillary level
Intimal lesions
The reduction of PA luminal area is probably the critical factor in the increase in pulmonary vascular resistance (PVR) in PAH (Fig. 8A).3 We have previously outlined the range of pathologic alterations involving the intima in lungs of patients with PH.9 Although these lesions impinge significantly on the normal pulmonary blood flow and account for the increase in PVR, their distribution, cellular nature, and natural history are largely unknown (see Fig. 7C). The cellular composition ranges
Medial remodeling
Contrary to previously descriptions,1 pulmonary vascular medial remodeling, although statistically more marked in severe PAH, had a quartile distribution largely within the range seen in normal lungs (see Fig. 8C, D).3 This finding raises the possibility that the current treatments for PAH,20 which extend survival and improve overall morbidity of the disease, may do it by promoting regression of medial remodeling. Given that all patients had advance disease, the lack of pronounced medial
Adventitial remodeling
Early studies showed that adventitia thickening was also part of the remodeling spectrum seen in patients with IPAH.1 It is difficult to define the exact boundaries of the adventitia because it blends with the peribronchiolar connective tissue; the only clear demarcating landmark is the abrupt interface with the teetered alveolar septa. Using an arbitrary criterion based on the projection of this boundary to the transition region between the vessel and the accompanying airway, we did not find
Veins in PAH
The understanding of pulmonary vein remodeling in arterial and venous forms of PAH has lagged behind the focus on pulmonary arterial changes. This limitation is compounded by the lack of specific venous markers, therefore requiring architectural landmarks (ie, location in interlobular septa) for the proper identification of pulmonary veins. Despite these limitations, we investigated the degree of pulmonary vein remodeling when veins were identified in interlobular septa. We did not find any
Inflammation in PAH
The inflammatory angle in PH has become a promising area of investigation in PAH. Earlier studies have delineated the presence of inflammatory cells around the vascular lesions in PAH.12, 22 These studies identified a mixed population of inflammatory cells, including macrophages, T cells, B cells, and mast cells. The potential importance of lung (interstitial and perivascular) inflammation was recently underscored by our finding that perivascular inflammation is more pronounced in PAH lungs and
Methodological approaches to sampling
More than 100 years after formal recognition of PAH, a stringent stereological analysis of the key lesions in PAH remains lacking. All published pathologic studies in this area have biases: even involuntary biases or the superficially compelling nature of the results does not mitigate the limitations that these errors impose on understanding of the disease. These errors have occurred in multiple stages of the analytical process, most importantly related to sampling. Lung sampling is often not
Relevance of animal models
A detailed review of animal models in PAH research is beyond the scope of this article. However, the recognition of their strengths and weaknesses depends on the extent that these models are used to answer key questions related to human disease. The phenotype of an ideal animal model would involve integrated intimal and medial remodeling in the setting of almost systemic levels of PA pressures. Moreover, this phenotype would be triggered by causally relevant processes, referenced to human
Summary
The ultimate article in detailing the pathology of PH remains to be written. Despite the contributions brought about by initiatives like the PHBI, knowledge of the relationship between pulmonary vascular disorders and human disease remains restricted by a lack of stereological validation. Although insights have been gained into how the integrated intimal and medial remodeling relates to pulmonary hemodynamics in the modern age of PAH-specific therapy, it is not known whether more than 1 lesion
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2021, Free Radical Biology and MedicineA <sup>1</sup>H NMR spectroscopic metabolomic study of the protective effects of irbesartan in a rat model of chronic mountain sickness
2021, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :CMS causes erythrocytosis and increased blood resistance, followed by pulmonary artery endothelial cell injury and pulmonary artery smooth muscle cell proliferation, and eventually leads to pulmonary vascular pathological thickening and lesions. Chronic hypoxia at high altitude stimulates the synthesis of ACE in pulmonary vascular endothelial cells, accelerates the conversion of angiotensin I (Ang I) to angiotensin II (Ang II), and constricts pulmonary vessels by degrading vasomotor substances, which leads to increased pulmonary vascular resistance, pulmonary arteriole smooth muscle cell proliferation, pulmonary vascular remodeling and pulmonary hypertension [16–18]. Studies have shown that Ang II up-regulates VEGF expression and oxidative stress mechanisms in the kidney [19].
Supported by the Cardiovascular Medical and Research Educational Fund (to R.M. Tuder), Parker B. Francis, NIH K08HL105536, and Pfizer ASPIRE grants (to B.B. Graham).
The authors have nothing to disclose.