Open AccessIncreased hemoglobin–oxygen affinity ameliorates bleomycin‐induced hypoxemia and pulmonary fibrosis
Author(s) -
Geng Xin,
Dufu Kobina,
Hutchaleelaha Athiwat,
Xu Qing,
Li Zhe,
Li ChienMing,
Patel Mira P.,
Vlahakis Nicholas,
LehrerGraiwer Josh,
Oksenberg Donna
Publication year - 2016
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.12965
Subject(s) - hypoxemia , medicine , hemoglobin , bleomycin , idiopathic pulmonary fibrosis , oxygen–haemoglobin dissociation curve , pulmonary fibrosis , lung , fibrosis , hypoxia (environmental) , bronchoalveolar lavage , pathology , cardiology , pharmacology , gastroenterology , oxygen , chemotherapy , chemistry , organic chemistry
Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis ( IPF ), no drug currently available could treat them. GBT 1118 is a novel orally bioavailable small molecule that binds to hemoglobin and produces a concentration‐dependent left shift of the oxygen–hemoglobin dissociation curve with subsequent increase in hemoglobin–oxygen affinity and arterial oxygen loading. To assess whether pharmacological modification of hemoglobin–oxygen affinity could ameliorate hypoxemia associated with lung fibrosis, we evaluated GBT 1118 in a bleomycin‐induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT 1118 was administered for eight consecutive days. Hypoxemia was determined by monitoring arterial oxygen saturation, while the severity of pulmonary fibrosis was assessed by histopathological evaluation and determination of collagen and leukocyte levels in bronchoalveolar lavage fluid. We found that hemoglobin modification by GBT 1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT 1118 treatment significantly attenuated bleomycin‐induced lung fibrosis, collagen accumulation, body weight loss, and leukocyte infiltration. This study is the first to suggest the beneficial effects of hemoglobin modification in fibrotic lungs and offers a promising and novel therapeutic strategy for the treatment of hypoxemia associated with chronic fibrotic lung disorders in human, including IPF .