Alveolar Type II Epithelial Cell Dysfunction in Rat Experimental Hepatopulmonary Syndrome (HPS)

Abstract

The hepatopulmonary syndrome (HPS) develops when pulmonary vasodilatation leads to abnormal gas exchange. However, in human HPS, restrictive ventilatory defects are also observed supporting that the alveolar epithelial compartment may also be affected. Alveolar type II epithelial cells (AT2) play a critical role in maintaining the alveolar compartment by producing four surfactant proteins (SPs, SP-A, SP-B, SP-C and SP-D) which also facilitate alveolar repair following injury. However, no studies have evaluated the alveolar epithelial compartment in experimental HPS. In this study, we evaluated the alveolar epithelial compartment and particularly AT2 cells in experimental HPS induced by common bile duct ligation (CBDL). We found a significant reduction in pulmonary SP production associated with increased apoptosis in AT2 cells after CBDL relative to controls. Lung morphology showed decreased mean alveolar chord length and lung volumes in CBDL animals that were not seen in control models supporting a selective reduction of alveolar airspace. Furthermore, we found that administration of TNF-α, the bile acid, chenodeoxycholic acid, and FXR nuclear receptor activation (GW4064) induced apoptosis and impaired SP-B and SP-C production in alveolar epithelial cells in vitro. These results imply that AT2 cell dysfunction occurs in experimental HPS and is associated with alterations in the alveolar epithelial compartment. Our findings support a novel contributing mechanism in experimental HPS that may be relevant to humans and a potential therapeutic target.

Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models

“…Similar findings are found in experimental HPS, where reductions in tidal volume, minute ventilation, and mean inspiratory flow rate, attributable to uneven distribution of alveolar ventilation and decreased mean alveolar cord length reflecting alveolar collapse, have been found . These functional and structural alveolar alterations are associated with increased apoptosis of AT2 cells and a resultant decrease in surfactant protein (SP) production (SP‐A, B, C, D) . Surfactant, a lipoprotein complex formed by AT2 cells, maintains alveolar integrity, prevents collapse, and regulates lung injury and inflammation.…”

“…For instance, it is well recognized that HPS may coexist with intrinsic lung abnormalities, although the two processes have been considered distinct. More recently, subtle pulmonary function test abnormalities including lower forced expiratory volume in the first second (FEV1) and forced vital capacity, with a preserved ratio between the two, have been observed in patients with cirrhosis and HPS compared to those without, supporting that ventilation defects may contribute to gas exchange abnormalities in HPS …”

“…Surfactant, a lipoprotein complex formed by AT2 cells, maintains alveolar integrity, prevents collapse, and regulates lung injury and inflammation. Elevated circulating bile acid and TNFα levels, found after CBDL, may contribute to effects on AT2 cells; as exposure to chenodeoxycholic acid, the bile acid nuclear receptor agonist GW4064, or TNFα at physiologic concentrations induced apoptosis and SP loss in cultured AT2 cells . Moreover, AT2 cell integrity and SP production are maintained in PPVL animals, in which circulating bile acids and TNFα levels are not elevated.…”

Mechanisms of decompensation and organ failure in cirrhosis: From peripheral arterial vasodilation to systemic inflammation hypothesis

“…CX3CL1 and VEGF-A produced by circulating monocytes also contribute to angiogenesis, an IPVD pathogenetic factor [100,101]. Other factors, such as eNOS activation through endothelin-B receptor overexpression in the pulmonary endothelium [102][103][104] and a reduced production of alveolar surfactant proteins [105], should be considered. Although the role of inflammation in HPS pathogenesis is not as evident as in ARDS, all previous features suggest a role of BT-induced inflammatory response.…”

Effects of Bisphenol A Metabolite 4-Methyl-2,4-bis(4-hydroxyphenyl)pent-1-ene on Lung Function and Type 2 Pulmonary Alveolar Epithelial Cell Growth

“…Moreover, type 2 alveolar epithelial cells can serve as stem cells to restore and turn over alveolar epithelial cells during lung injury and development1112. Many studies have shown that type 2 alveolar epithelial cell impairment leads to the development of lung diseases, including chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome ( ARDS ), and lung fibrosis13141516.…”