High pCO2 levels are observed in patients with respiratory failure ventilated with the """"""""permissive hypercapnia"""""""" strategy. We and other investigators have recently reported that elevated pCO2 levels can have deleterious effects on the alveolar epithelium. Specifically, we have reported that hypercapnia leads to short and long term dysfunction of the alveolar epithelium by inhibiting the alveolar epithelial Na,K-ATPase and impairing alveolar fluid clearance. Therefore, the focus of this application is to determine the specific mechanisms/signaling pathways that lead to alveolar Na,K-ATPase downregulation and impairment in alveolar fluid clearance during hypercapnic conditions. We propose to study the effects of hypercapnia on the alveolar epithelium via four interrelated aims: in experiments pertaining to specific Aim # 1, we will determine whether the soluble adenylyl cyclase participates in the hypercapnia-induced Na,K- ATPase downregulation in the alveolar epithelium;in experiments pertaining to specific Aim #2, we will determine whether hypercapnia-induced JNK activation leads to LIM-domain only protein 7 (LMO7) phosphorylation and Na,K-ATPase endocytosis;in studies pertaining to specific Aim # 3, we will determine whether Na,K-ATPase ubiquitination leads to its downregulation and propose to identify the specific E2 and E3 ubiquitin ligase;and in studies pertaining to specific Aim # 4, we will determine whether hypercapnia further impairs injury in a model of mild ventilator-induced lung injury (VILI) and whether the downregulation of of sAC, JNK, LMO7 and ubiquitination pathway will reverse the deleterious effects of hypercapnia on alveolar fluid clearance in rodents. In the first cycle of this grant, we have completed most of the proposed research and conducted preliminary experiments for each of the current specific aims which support the feasibility of this grant proposal. The proposed experiments will generate novel information on the effects of hypercapnia on the alveolar epithelium and shed light on the mechanisms leading to alveolar epithelial dysfuntion which is of significance to the understanding and treatment of patients with acute lung injury.
Patients with pulmonary edema and acute respiratory distress syndrome (ARDS) are often exposed to hypercapnia (high CO2 levels in the blood) which has deleterious effects on alveolar epithelium and high morbidity rate. This grant proposal focuses on determining the specific mechanisms/signaling pathways that lead to downregulation and impairment in alveolar fluid clearance during hypercapnic conditions. We will study the effects of prolonged hypercapnia on rodents, specifically measuring alveolar fluid clearance. The information generated from the experiments proposed in this grant application will provide new insights to the understanding of the pathophysiology of these diseases and possibly in the treatment of patients with ARDS.
|Misharin, Alexander V; Morales-Nebreda, Luisa; Reyfman, Paul A et al. (2017) Monocyte-derived alveolar macrophages drive lung fibrosis and persist in the lung over the life span. J Exp Med 214:2387-2404|
|Shigemura, Masahiko; Lecuona, Emilia; Sznajder, Jacob I (2017) Effects of hypercapnia on the lung. J Physiol 595:2431-2437|
|Nin, Nicolas; Muriel, Alfonso; Peñuelas, Oscar et al. (2017) Severe hypercapnia and outcome of mechanically ventilated patients with moderate or severe acute respiratory distress syndrome. Intensive Care Med 43:200-208|
|Vadász, István; Sznajder, Jacob I (2017) Gas Exchange Disturbances Regulate Alveolar Fluid Clearance during Acute Lung Injury. Front Immunol 8:757|
|Ceco, Ermelinda; Weinberg, Samuel E; Chandel, Navdeep S et al. (2017) Metabolism and Skeletal Muscle Homeostasis in Lung Disease. Am J Respir Cell Mol Biol 57:28-34|
|Helenius, Iiro Taneli; Nair, Aisha; Bittar, Humberto E Trejo et al. (2016) Focused Screening Identifies Evoxine as a Small Molecule That Counteracts CO2-Induced Immune Suppression. J Biomol Screen 21:363-71|
|Helenius, Iiro Taneli; Haake, Ryan J; Kwon, Yong-Jae et al. (2016) Identification of Drosophila Zfh2 as a Mediator of Hypercapnic Immune Regulation by a Genome-Wide RNA Interference Screen. J Immunol 196:655-667|
|Selfridge, Andrew C; Cavadas, Miguel A S; Scholz, Carsten C et al. (2016) Hypercapnia Suppresses the HIF-dependent Adaptive Response to Hypoxia. J Biol Chem 291:11800-8|
|Bharat, Ankit; Graf, Nicole; Mullen, Andrew et al. (2016) Pleural Hypercarbia After Lung Surgery Is Associated With Persistent Alveolopleural Fistulae. Chest 149:220-7|
|Kanter, Jacob A; Sun, Haiying; Chiu, Stephen et al. (2015) Decreased CXCL12 is associated with impaired alveolar epithelial cell migration and poor lung healing after lung resection. Surgery 158:1073-80; discussion 1080-2|
Showing the most recent 10 out of 38 publications