Role of Ureaplasma species in neonatal chronic lung disease: epidemiologic and experimental evidence

Abstract

The contribution of Ureaplasma respiratory tract colonization to the pathogenesis of bronchopulmonary dysplasia in preterm infants has been debated for over 20 y. We review the current understanding of the role of inflammation in altered developmental signaling in the preterm lung and the evidence from human studies and experimental models that Ureaplasma-mediated inflammation produces the BPD phenotype. We propose that Ureaplasma infection initiated in utero and augmented postnatally by exposure to volutrauma and oxygen elicits a sustained, dysregulated inflammatory response in the immature lung that impairs alveolarization, and stimulates myofibroblast proliferation and excessive collagen and elastin deposition. Potential strategies to prevent or ameliorate the effects of Ureaplasma infection in utero and in the preterm lung are discussed.

Figures

Figure 1. Proposed model for role of Ureaplasma infection in BPD pathogenesis

In this schematic, prolonged intraamniotic exposure of the fetal lung to Ureaplasma infection and maternal and fetal derived cytokines, recruits inflammatory cells, and alters TGFβ1 developmental signaling in the lung. Postnatal exposure to ventilation and oxygen augments this pro-inflammatory response leading to arrested alveolarization, disordered myofibroblast proliferation, and excessive collagen and elastin deposition.

Figure 2. Comparison of α-smooth muscle actin (α-SMA) immunostaining in human preterm lung specimens

(A) Control non-ventilated infant at 23 wk GA; (B) Other pneumonia case at 24 wk GA ventilated for 2 d; and (C) Ureaplasma-infected infant at 26 wk GA ventilated for 20 d. Lung sections were incubated with anti-α̃SMA antibody and counterstained with hematoxylin. Negative controls were processed in the absence of primary antibody (D) (Magnification 200x). α̃SMA immunoreactive cells were noted surrounding vessel walls (arrows) in (A) and distributed in a pattern of thickened clusters of cells often surrounding terminal airways in other pneumonia and Ureaplasma cases (B and C). The extent of myofibroblast accumulation and percent of lung involvement was greater in Ureaplasma cases than in other pneumonia cases. Reprinted from Viscardi et al. Pediatr Dev Pathol 9:143–151, Copyright © 2006 Society for Pediatric Pathology and the Paediatric Pathology Society, with permission.

Figure 3. Comparison of TGFβ1 immunostaining in human lung specimens

(A) Control non-ventilated infant at 23 wk GA; (B) Other pneumonia case at 24 wk GA ventilated for 2 d; and (C) Ureaplasma-infected infant at 26 wk GA ventilated for 20 d. Lung sections were incubated with anti-TGFβ1 antibody, stained with diaminobenzidine and counterstained with hematoxylin. Negative controls were processed in the absence of primary antibody (D) (Magnification 200x). In lung specimens from infants dying with acute bacterial or Ureaplasma pneumonia, immunostaining was concentrated in focal aggregates of alveolar and interstitial macrophages. Reprinted from Viscardi et al. Pediatr Dev Pathol 9:143–151, Copyright © 2006 Society for Pediatric Pathology and the Paediatric Pathology Society, with permission.

Figure 4. Alpha-SMA positive cells are increased in lung tissue form antenatal Ureaplasma-infected baboons

Lung sections were processed for immunohistochemical staining using a monoclonal anti-human antibody directed against α-SMA (arrows). A) 125d GC; B) 140d GC; C) 125d non-infected ventilated control; and D) 125d antenatal Ureaplasma-infected, ventilated baboon. Magnification 200X. Reprinted from Viscardi et al. Pediatr Res 60:141–146, Copyright © 2006 International Pediatric Research Foundation, Inc., with permission.

Figure 5. TGFβ1 immunostaining in lung specimens of antenatal Ureaplasma-exposed baboons is concentrated in focal aggregates of alveolar and interstitial macrophages

Lung sections were incubated with anti-TGFβ1 antibody, stained with diaminobenzidine and counterstained with hematoxylin. A) 125d GC; B) 140d GC; C) 125d non-infected ventilated control; and D) 125d antenatal Ureaplasma-infected, ventilated baboon. Magnification 200X. Reprinted from Viscardi et al. Pediatr Res 60:141–146, Copyright © 2006 International Pediatric Research Foundation, Inc., with permission.