Regional Hypoxia Impacts the Heterogeneity of Inflammatory Lung Disease

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 DESCRIPTION (provided by applicant): Despite significant advances in the understanding of chronic inflammatory lung diseases, data describing the mechanisms underlying regional heterogeneity of disease are lacking. Inflammatory lung diseases such as cystic fibrosis (CF) are characterized by transient and regional mucus plugging, resulting in regions of the lung being subject to acute hypoxia. In CF lung disease, bronchiectasis tends to begin and become most extensive in the upper lobes despite the fact that transient mucus plugging occurs throughout the CF lung. Our preliminary data demonstrate that resident lung macrophages (LMs) in the upper lobe exhibit a more robust inflammatory response to hypoxia compared to lower lobe LMs. Hypoxia is known to cause enhanced inflammation in other tissues via various mechanisms, including increased production of angiotensin II (ANGII). Interestingly, recent studies have shown that a polymorphism in the human angiotensin converting enzyme (ACE) gene, which results in elevated ANGII, is associated with increased severity of lung disease in CF. ANGII has receptors on LMs. LMs are major contributors to the innate immune response and are critical for cytokine secretion and neutrophil recruitment. We found a dose-dependent increase in inflammatory cytokine production by healthy human LMs following treatment with ANGII. We also found increased ANGII in bronchoalveolar lavage (BAL) fluid from CF subjects and, interestingly, these levels were highest in the upper lobes, where bronchiectasis is most prominent. Based upon these data, the overarching hypothesis of this proposal is that hypoxia causes a more aggressive inflammatory response by upper lobe LMs compared to lower lobe LMs via enhanced production of ANGII. Furthermore, we hypothesize that hypoxia induced ANGII is a key factor in the development of regional heterogeneity of CF lung disease. In Aim 1, we will test the hypothesis that hypoxia enhances inflammation but decreases bacterial killing by upper lobe LMs isolated from healthy subjects compared to lower lobe LMs. In Aim 2, we will test the hypothesis that the increased inflammatory response to hypoxia of healthy upper lobe LMs is caused by ANGII and can be blocked by treatment with the ANGII type I (AT1) receptor blocker, losartan. In Aim 3, we will test the hypothesis that, in subjects with CF, LMs isolated from hypoxic regions of the upper lobe, as determined using the novel technique of hyperpolarized gas magnetic resonance imaging, generate increased ANGII and inflammatory cytokines compared to LMs isolated from hypoxic regions of the lower lobe. These studies will determine novel anti-inflammatory strategies to halt the progression of CF lung disease, including the potential repurposing of the AT1 receptor blocker losartan, and to use this work as a model for the study of other inflammatory lung diseases including COPD and asthma.