Pneumocystis Exacerbates Inflammation and Mucus Hypersecretion in a Murine, Elastase-Induced-COPD Model

Abstract

Inflammation and mucus hypersecretion are frequent pathology features of chronic respiratory diseases such as asthma and COPD. Selected bacteria, viruses and fungi may synergize as co-factors in aggravating disease by activating pathways that are able to induce airway pathology. Pneumocystis infection induces inflammation and mucus hypersecretion in immune competent and compromised humans and animals. This fungus is a frequent colonizer in patients with COPD. Therefore, it becomes essential to identify whether it has a role in aggravating COPD severity. This work used an elastase-induced COPD model to evaluate the role of Pneumocystis in the exacerbation of pathology, including COPD-like lung lesions, inflammation and mucus hypersecretion. Animals infected with Pneumocystis developed increased histology features of COPD, inflammatory cuffs around airways and lung vasculature plus mucus hypersecretion. Pneumocystis induced a synergic increment in levels of inflammation markers (Cxcl2, IL6, IL8 and IL10) and mucins (Muc5ac/Muc5b). Levels of STAT6-dependent transcription factors Gata3, FoxA3 and Spdef were also synergically increased in Pneumocystis infected animals and elastase-induced COPD, while the levels of the mucous cell-hyperplasia transcription factor FoxA2 were decreased compared to the other groups. Results document that Pneumocystis is a co-factor for disease severity in this elastase-induced-COPD model and highlight the relevance of STAT6 pathway in Pneumocystis pathogenesis.

Role of the Fungus Pneumocystis in IL1β Pathway Activation and Airways Collagen Deposition in Elastase-Induced COPD Animals

“…In this work, we showed that the presence of inflammation cuffs in the lungs showed results comparable to the previously described [35]. Interestingly, the number of cuffs between animal groups infected (Pc) and COPD infected (ELT-Pc) did not show a significant difference, indicating that not only must the number of cuffs be evaluated, but the size and the cell components of each cuff must to be coherent with the analysis of cytokines previously presented [35]. Another result of this work is the increment of IL1β mRNA levels indicating the activation of the pathway.…”

“…Given the induction of the IL1β pathway in this animal model, and recognizing the association between this pathway and mucus secretion, we initially examined the presence of a cAMP response element (CRE) in promoters of Muc5ac and Muc5b. These mucin genes showed a clear increment in their expressions during the development of COPD induced by elastase and synergically incremented by the presence of Pneumocystis in the previous work [ 35 ]. A CRE sequence was only detected in the promoter of Muc5b ( Figure 4 C).…”

“…Recently, our laboratory group demonstrated an increment in the mRNA levels of several pro-inflammatory cytokines, such as Il6 , Il8 , and Tnf , in an elastase-induced COPD animal model infected with Pneumocystis [ 35 ]. However, it is essential to explore additional inflammatory pathways that may be activated under these conditions.…”

“…animal model infected with Pneumocystis [35]. However, it is essential to explore addi-tional inflammatory pathways that may be activated under these conditions.…”

“…Moreover, limited animal models are exploring the interplay between Pneumocystis and COPD. Recently, the association between COPD and Pneumocystis infection in regard to disease severity has been demonstrated using an elastase-induced COPD rat model showing an increase in inflammation and mucus-related markers [ 35 ]. This new evidence supports the hypothesis that a mild Pneumocystis infection may amplify inflammation or other pathophysiological features, such as fibrosis in respiratory diseases like COPD, either directly or as a co-factor [ 36 ].…”