Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis

Abstract

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.

Intermittent Hypoxia Severity in Animal Models of Sleep Apnea

“…It is also remarkable that the Bohr effect (shifting of the dissociation curve as blood CO 2 /pH increases/decreases) applies to mammalian blood with a magnitude range that also closely follows a heterogonic relationship (Riggs, 1960 ), a factor that could further amplify the human-mouse difference, particularly when CO 2 increases during obstructive apneas are taken into account (Farré et al, 2007 ). Interestingly, the earlier reports on detectable differences among hemoglobin dissociation curves in human and mouse blood have been subsequently confirmed as measurement techniques have improved (Gray and Steadman, 1964 ; Severinghaus, 1979 ; Mouneimne et al, 1990 ; Geng et al, 2016 ). Figure 1 (top) clearly shows that for any given SaO 2 value, PaO 2 is always lower for human than for mouse blood.…”

“…SaO 2 and PaO 2 : arterial oxygen saturation and partial pressure, respectively. The dissociation curves for human and mouse blood were redrawn from data in Severinghaus ( 1979 ) and Geng et al ( 2016 ), respectively. (Bottom) Relationship between equivalent (same PaO 2 ) values of SaO 2 in human and mouse blood.…”

Development and validation of an oxygen dissociation assay, a screening platform for discovering, and characterizing hemoglobin–oxygen affinity modifiers

“… 5 , 6 In addition, increasing the Hb–O 2 affinity may benefit hypoxemia related to pulmonary diseases as it will increase O 2 saturation in the lungs. 7 , 8 Alternatively, decreasing Hb–O 2 affinity could be useful in diseases such as tumor hypoxia, wound healing, or ischemia where increased O 2 delivery to tissues is needed. 1 For these reasons, various Hb modifiers have been identified that either increase (5-HMF, tucaresol, BW12C, voxelotor [previously known as GBT440], GBT1118) or decrease (RSR-13, ITPP) Hb–O 2 affinity.…”

“… 1 For these reasons, various Hb modifiers have been identified that either increase (5-HMF, tucaresol, BW12C, voxelotor [previously known as GBT440], GBT1118) or decrease (RSR-13, ITPP) Hb–O 2 affinity. 5 , 7 , 9 …”

The Evolving Pharmacotherapeutic Landscape for the Treatment of Sickle Cell Disease

“…Voxelotor is oral, once-daily drug that binds to the α-chain of HbS, stabilizing the molecule in the R-state conformation, which is known to interrupt HbS polymerization. 101,165,166 The target for HbS modification with voxelotor is 20%-30%. In phase 1/2 trials, Voxelotor inhibited HbS polymerization, RBC sickling, and hemolysis, with a consequent increase in Hb concentration, while also demonstrating an acceptable safety profile and was well tolerated.…”