Inhaled nitric oxide protects transgenic SAD mice from sickle cell disease-specific lung injury induced by hypoxia/reoxygenation.
Central to the pathophysiology of sickle cell disease are the vaso-occlusive events that lead to tissue damages and life-threatening complications. Lungs are particularly vulnerable to vaso-occlusion because of their specific vasculature. We developed a mouse model of hypoxia/reoxygenation lung injury closely mimicking the lung pathology of patients with sickle cell disease. This model involves the exposure of transgenic sickle cell (SAD) mice to hypoxia (8% oxygen) for 4, 10, and 46 hours followed by 2 hours of reoxygenation. Gene expression profiling of SAD lung tissue pointed to the specific induction of genes involved in the response to ischemic stress and microcirculation remodeling: Hspcb, Hsp86-1, Nfe2l2, Ace, and Fgf7. Hypoxia/reoxygenation also induced a marked increase in bronchoalveolar (BAL) total leukocyte and neutrophil counts, BAL total protein content, and BAL tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), IL-1alpha, and macrophage inflammatory protein 2 (MIP-2) levels, all indicators of enhanced inflammatory response as compared with control mice. Nitric oxide (NO) was administered to SAD mice. NO (40 ppm) inhalation protected SAD mice from the histopathologic lesions of ischemic/reperfusion lung injury with corresponding normalization and/or modulation of tissue gene expression profiles. Inhaled NO (1) significantly reduced the increase in BAL total protein content, BAL total leukocyte, and neutrophil counts; (2) modulated BAL cytokine network; and (3) did not affect hemoglobin and methemoglobin levels. The present study provides evidences for the beneficial effects of inhaled NO in pulmonary injury induced by hypoxia/reoxygenation in a mouse model of sickle cell disease (SCD) and opens new avenues in drug design based on tissue gene expression profiling.
de Franceschi
Lucia
L
Department of Clinical and Experimental Medicine, Section of Internal Medicine, Policlinico GB Rossi, Piazzale L. Scuro, 10, 37134 Verona, Italy. lucia.defranceschi@univr.it
Baron
Antonella
A
Scarpa
Aldo
A
Adrie
Christophe
C
Janin
Anne
A
Barbi
Stefano
S
Kister
Jean
J
Rouyer-Fessard
Philippe
P
Corrocher
Roberto
R
Leboulch
Philippe
P
Beuzard
Yves
Y
D000280:Administration, Inhalation; D000755:Anemia, Sickle Cell / Q000150:complications* / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D000860:Hypoxia / Q000188:drug therapy* / Q000473:pathology; D008168:Lung / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000008:administration & dosage / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D011668:Pulmonary Veno-Occlusive Disease / Q000188:drug therapy* / Q000473:pathology
D009569:Nitric Oxide; D010100:Oxygen