Mechanical ventilation with 02-rich gas (MV-O2) offers life-saving treatment for patients with respiratory failure. Such treatment, however, can cause or aggravate lung injury, leading to neonatal chronic lung disease (CLD) in infants whose lungs are incompletely developed, or to ventilator-induced lung injury (VILl) in older children and adults. Despite recent progress in the management of patients with respiratory failure, notably the use of lung protective ventilation strategies featuring low tidal volumes and peak inflation pressures, acute lung injury remains a major complication of positive-pressure MV-O2. CLD, a variant of BPD,(7) results from lengthy exposure of the developing lung to MV and 02-rich gas. CLD is the leading cause of long-term hospitalization and recurrent respiratory disorders of infants who were born prematurely. It is characterized by failed formation of alveoli and lung micro-vessels, coupled with disordered lung elastin, resulting in structural and functional abnormalities that resemble pulmonary emphysema. Elastin plays a critical role in lung development.(8) A network of elastic fibers in the lung helps to provide structural integrity and distensibility to conducting airways, while enabling expansion and contraction of alveoli, pulsation of blood vessels and elastic recoil of the surrounding matrix. Lungs of infants who died with CLD show thickened, tortuous and irregularly distributed elastic fibers in the connective tissue matrix surrounding distal airspaces.(9-12) These changes were associated with reduced secondary septation and fewer alveoli than in lungs of infants who died without CLD. Urinary excretion of desmosine, a biomarker of elastin degradation, increased during the first week of MV in infants with evolving CLD.(10) Elastin breakdown in this disease has been attributed to inflammation and an imbalance between increased elastolytic activity and deficient protease inhibitors in the lungs of afflicted infants.(13-18) In studies of preterm sheep with evolving CLD,(1) we found that MV-O2 increased lung elastase activity, resulting in lung growth arrest (Fig 1) that was linked to degradation and remodeling of matrix elastin (Fig 2). In mechanically ventilated newborn mice, elevated lung elastase activity was associated with increased TGFB signaling, impaired VEGF signaling (reduced VEGF-A and VEGFR2 proteins), increased apoptosis and scattered elastin, leading to defective formation of alveoli and lung micro-vessels.(2-4) Recently we showed that intrapulmonary treatment of neonatal mice with the serine elastase inhibitor Elafin, or with a TGFB neutralizing antibody (TGPB-Nab), prevented or mitigated the adverse pulmonary effects of prolonged (24h) MV-40%O2.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-A)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
Jiang, Xinguo; Sung, Yon K; Tian, Wen et al. (2014) Graft microvascular disease in solid organ transplantation. J Mol Med (Berl) 92:797-810
Khan, Mohammad Afzal; Nicolls, Mark R; Surguladze, Besiki et al. (2014) Complement components as potential therapeutic targets for asthma treatment. Respir Med 108:543-9
Rabinovitch, Marlene; Guignabert, Christophe; Humbert, Marc et al. (2014) Inflammation and immunity in the pathogenesis of pulmonary arterial hypertension. Circ Res 115:165-75
Beraud, Anne-Sophie; Guillamet, Cristina Vazquez; Hammes, Jessie L et al. (2014) Efficacy of transthoracic echocardiography for diagnosing heart failure in septic shock. Am J Med Sci 347:295-8
Jiang, Xinguo; Tian, Wen; Sung, Yon K et al. (2014) Macrophages in solid organ transplantation. Vasc Cell 6:5
Singh, Amar Bahadur; Li, Hai; Kan, Chin Fung Kelvin et al. (2014) The critical role of mRNA destabilizing protein heterogeneous nuclear ribonucleoprotein d in 3' untranslated region-mediated decay of low-density lipoprotein receptor mRNA in liver tissue. Arterioscler Thromb Vasc Biol 34:8-16
Tian, Wen; Jiang, Xinguo; Sung, Yon K et al. (2014) Leukotrienes in pulmonary arterial hypertension. Immunol Res 58:387-93
Sawada, Hirofumi; Saito, Toshie; Nickel, Nils P et al. (2014) Reduced BMPR2 expression induces GM-CSF translation and macrophage recruitment in humans and mice to exacerbate pulmonary hypertension. J Exp Med 211:263-80
Jiang, Xinguo; Nicolls, Mark R (2014) Working toward immune tolerance in lung transplantation. J Clin Invest 124:967-70
Jiang, Xinguo; Malkovskiy, Andrey V; Tian, Wen et al. (2014) Promotion of airway anastomotic microvascular regeneration and alleviation of airway ischemia by deferoxamine nanoparticles. Biomaterials 35:803-13

Showing the most recent 10 out of 14 publications