Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis.
Although exertional dyspnea and worsening hypoxia are hallmark clinical features of idiopathic pulmonary fibrosis (IPF), no drug currently available could treat them. GBT1118 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 GBT1118 in a bleomycin-induced mouse model of hypoxemia and fibrosis. After pulmonary fibrosis and hypoxemia were induced, GBT1118 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 GBT1118 had strong antihypoxemic therapeutic effects with improved arterial oxygen saturation to near normal level. Moreover, GBT1118 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.
Global Blood Therapeutics, South San Francisco, California xgeng@globalbloodtx.com.
Xin
X
Geng
Global Blood Therapeutics, South San Francisco, California.
Kobina
K
Dufu
Global Blood Therapeutics, South San Francisco, California.
Athiwat
A
Hutchaleelaha
Global Blood Therapeutics, South San Francisco, California.
Qing
Q
Xu
Global Blood Therapeutics, South San Francisco, California.
Zhe
Z
Li
Global Blood Therapeutics, South San Francisco, California.
Chien-Ming
CM
Li
Global Blood Therapeutics, South San Francisco, California.
Mira P
MP
Patel
Global Blood Therapeutics, South San Francisco, California.
Nicholas
N
Vlahakis
Global Blood Therapeutics, South San Francisco, California.
Josh
J
Lehrer-Graiwer
Global Blood Therapeutics, South San Francisco, California.
Donna
D
Oksenberg
D000284:Administration, Oral; D000818:Animals; D001547:Benzaldehydes / Q000008:administration & dosage* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D001761:Bleomycin / Q000008:administration & dosage* / Q000009:adverse effects / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004417:Dyspnea / Q000175:diagnosis / Q000209:etiology; D000860:Hypoxia / Q000139:chemically induced* / Q000150:complications / Q000188:drug therapy; D054990:Idiopathic Pulmonary Fibrosis / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D010100:Oxygen / Q000097:blood / Q000378:metabolism*; D010108:Oxyhemoglobins / Q000187:drug effects* / Q000378:metabolism; D011897:Random Allocation
D001547:Benzaldehydes; C000622072:GBT1118; D010108:Oxyhemoglobins; D001761:Bleomycin; D009536:Niacinamide; D003094:Collagen; D010100:Oxygen
Dyspnea; hypoxia; idiopathic pulmonary fibrosis; quality of life