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Pulmonary Circulation in Obesity, Diabetes, and Metabolic Syndrome

Phue Khaing, Pooja Pandit, Bharat Awsare, Ross Summer

10.1002/cphy.c190018

Source: Volume 10, Issue 1, January 2020

Published online: December 2019

Full Article on Wiley Online Library



Abstract

Obesity, diabetes mellitus, and the metabolic syndrome are important risk factors for the development of cardiovascular disease, with significant impact on human morbidity and mortality. Several decades of research have accumulated considerable knowledge about the mechanisms by which metabolic conditions precipitate systemic cardiovascular diseases. In short, these mechanisms are thought to involve changes in the external environment of vascular cells, which are mediated by the pro‐inflammatory effects of adipokines, free fatty acids, and hyperglycemia. Thus, it has been hypothesized that the pulmonary circulation, witnessing similar insults as the systemic circulation, may be equally vulnerable to the development of vascular disease. Accordingly, recent attention has focused on exploring the mechanistic and epidemiological relationships among obesity, type 2 diabetes mellitus, metabolic syndrome, and pulmonary vascular diseases. In this article, we discuss in detail the preclinical evidence showing a modest but perceivable impact of metabolic disorders on the pulmonary circulation. In addition, we review the existing epidemiological studies examining the relationship among cardiovascular risk factors and pulmonary vascular diseases, using the acute respiratory distress syndrome and pulmonary arterial hypertension as examples. We conclude by discussing areas of limitations in the field and by suggesting future directions for investigation, including the notion that the pulmonary circulation may, in fact, be a resilient entity in the setting of some metabolic perturbations. © 2020 American Physiological Society. Compr Physiol 10:297‐316, 2020.

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Figure 1. Figure 1. Mechanisms by which obesity causes systemic cardiovascular disease. In the obese state, adipose tissue adopts a dysfunctional phenotype. In this state, increased levels of pro‐inflammatory adipokines (such as leptin) and free fatty acids (FFAs) are released into the circulation. These mediators induce inflammatory and oxidative pathways, which significantly alter important intracellular and extracellular processes. Ultimately, these processes result in tissue damage and contribute to the development of disease.
Figure 2. Figure 2. Mechanisms by which diabetes mellitus causes systemic cardiovascular disease. Insulin resistance, which often occurs concurrently with obesity in the case of type 2 diabetes mellitus, leads to elevated blood glucose levels (i.e., hyperglycemia). Although most cell types reduce glucose uptake when chronically exposed to hyperglycemia, some cells, including endothelial cells, display increased glucose uptake. As a result, high levels of intracellular glucose injure cells in various ways. One such mechanism involves increased flux through the polyol pathway, leading to increased sorbitol production, which depletes intracellular NADPH levels and decreases reduced glutathione (GSH) levels. A second mechanism involves increased formation of advanced glycation end products (AGEs), which alters the function of intracellular and extracellular proteins. Additionally, elevated intracellular glucose levels can induce increased protein kinase C (PKC) activity, which leads to activation of pro‐inflammatory genes, thrombotic cascades, and release of growth factors.
Figure 3. Figure 3. Mechanisms of epithelial and endothelial injury in acute respiratory distress syndrome (ARDS). Aberrant inflammation along the alveolar‐capillary space results in loss of epithelial and endothelial barrier function. As a result, immune cells, particularly neutrophils, enter the distal alveolar spaces of the lung. These activated immune cells, then, release inflammatory and oxidative mediators, which cause tissue damage and leads to an accumulation of a protein‐rich, hypercellular fluid within the alveolar space. Both direct (airway) and indirect (vascular) insults can trigger the initiation of biological events that lead to ARDS.
Figure 4. Figure 4. Comparison of histological features of pulmonary blood vessels in normal and PAH lung. The progressive and irreversible vascular remodeling in PAH is associated with increased perivascular presence of inflammatory cells and mediators, which leads to endothelial dysfunction, in which injured endothelial cells adopt a hyperproliferative and antiapoptotic phenotype. In this state, there is increased production of vasoconstrictors (such as endothelin‐1) and decreased availability of vasodilators (such as nitric oxide), the effects of which include an overall increase in vascular tone and promotion of cellular proliferation within the layers of the blood vessel. Thus, PAH is also characterized by adventitial and medial thickening due to fibroblast and smooth muscle cell (SMC) proliferation and increased collagen deposition.


Figure 1. Mechanisms by which obesity causes systemic cardiovascular disease. In the obese state, adipose tissue adopts a dysfunctional phenotype. In this state, increased levels of pro‐inflammatory adipokines (such as leptin) and free fatty acids (FFAs) are released into the circulation. These mediators induce inflammatory and oxidative pathways, which significantly alter important intracellular and extracellular processes. Ultimately, these processes result in tissue damage and contribute to the development of disease.


Figure 2. Mechanisms by which diabetes mellitus causes systemic cardiovascular disease. Insulin resistance, which often occurs concurrently with obesity in the case of type 2 diabetes mellitus, leads to elevated blood glucose levels (i.e., hyperglycemia). Although most cell types reduce glucose uptake when chronically exposed to hyperglycemia, some cells, including endothelial cells, display increased glucose uptake. As a result, high levels of intracellular glucose injure cells in various ways. One such mechanism involves increased flux through the polyol pathway, leading to increased sorbitol production, which depletes intracellular NADPH levels and decreases reduced glutathione (GSH) levels. A second mechanism involves increased formation of advanced glycation end products (AGEs), which alters the function of intracellular and extracellular proteins. Additionally, elevated intracellular glucose levels can induce increased protein kinase C (PKC) activity, which leads to activation of pro‐inflammatory genes, thrombotic cascades, and release of growth factors.


Figure 3. Mechanisms of epithelial and endothelial injury in acute respiratory distress syndrome (ARDS). Aberrant inflammation along the alveolar‐capillary space results in loss of epithelial and endothelial barrier function. As a result, immune cells, particularly neutrophils, enter the distal alveolar spaces of the lung. These activated immune cells, then, release inflammatory and oxidative mediators, which cause tissue damage and leads to an accumulation of a protein‐rich, hypercellular fluid within the alveolar space. Both direct (airway) and indirect (vascular) insults can trigger the initiation of biological events that lead to ARDS.


Figure 4. Comparison of histological features of pulmonary blood vessels in normal and PAH lung. The progressive and irreversible vascular remodeling in PAH is associated with increased perivascular presence of inflammatory cells and mediators, which leads to endothelial dysfunction, in which injured endothelial cells adopt a hyperproliferative and antiapoptotic phenotype. In this state, there is increased production of vasoconstrictors (such as endothelin‐1) and decreased availability of vasodilators (such as nitric oxide), the effects of which include an overall increase in vascular tone and promotion of cellular proliferation within the layers of the blood vessel. Thus, PAH is also characterized by adventitial and medial thickening due to fibroblast and smooth muscle cell (SMC) proliferation and increased collagen deposition.
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Teaching Material

Phue Khaing, Pooja Pandit, Bharat Awsare, Ross Summer. Pulmonary Circulation in Obesity, Diabetes, and Metabolic Syndrome. Compr Physiol 10: 2020, 297-316.

Didactic Synopsis

Major teaching points:

  1. Obesity and type 2 diabetes mellitus (T2DM) are major risk factors for the development and progression of systemic cardiovascular diseases.
  2. The pulmonary circulation receives comparable exposures as the systemic circulation, yet the pulmonary circulation is mostly immune from developing atherosclerotic diseases.
  3. The effects of obesity and T2DM on the pulmonary circulation vary depending on the type of experimental models employed.
  4. An accepted gold-standard preclinical model for obesity or T2DM does not exist.
  5. Human studies suggest that obesity increases susceptibility for ARDS but reduces its overall mortality.
  6. WHO groups 2 and 3 are the most common causes of pulmonary hypertension in individuals with obesity and T2DM.
  7. Obesity, T2DM, and the metabolic syndrome have a modest but observable impact on the pulmonary circulation, but overall findings suggest that the pulmonary vasculature may be a resilient entity to metabolic exposures.

Didactic Legends

The following legends to the figures that appear throughout the article are written to be useful for teaching.

Figure 1. Teaching points: Adipose tissue adopts a dysfunctional phenotype in the obese state, releasing higher concentrations of pro-inflammatory adipokines and free fatty acids into the circulation, which then impart deleterious effects on systemic blood vessels by inducing inflammation and oxidative stress.

Figure 2. Teaching points: Insulin resistance in type 2 diabetes mellitus is associated with elevated blood glucose levels (i.e. hyperglycemia). As a result, high levels of intracellular glucose lead to cellular injury of endothelial cells via several mechanisms, including increased production of sorbitol, formation of advanced glycation end products (AGEs), and activation of protein kinase C (PKC).

Figure 3. Teaching points: The Acute Respiratory Distress Syndrome (ARDS) is a life-threatening lung disease that can develop as a result of direct pulmonary injury (e.g. pneumonia) or in association with extrapulmonary illnesses (e.g. sepsis, pancreatitis, major trauma). An aberrant inflammatory response that disrupts epithelial and endothelial barrier protection in the lung is thought to be a key mechanism in ARDS pathophysiology.

 

Figure 4. Teaching points: Pulmonary arterial hypertension (PAH) is caused by progressive histological changes which lead to irreversible remodeling of pulmonary blood vessels. These changes are associated with perivascular infiltration of immune cells, chronic development of vascular leakage, and production of inflammatory mediators. These mechanisms cause endothelial dysfunction and contribute to the hyperproliferative and anti-apoptotic phenotype characteristic of endothelial cells in PAH. 


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Article Title: Pulmonary Circulation in Obesity, Diabetes, and Metabolic Syndrome
 

How to Cite

Phue Khaing, Pooja Pandit, Bharat Awsare, Ross Summer. Pulmonary Circulation in Obesity, Diabetes, and Metabolic Syndrome. Compr Physiol 2019, 10: 297-316. doi: 10.1002/cphy.c190018